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The article analyzes the problem of developing and implementing an information system for quality assurance of higher education. The purpose of the article is to research modern methodological, technical and software tools used in the process of developing and implementing an information system for quality assurance of higher education. The peculiarities of the development of the announced information system were analyzed, on the basis of which the requirements for the design of the information system were determined, the possibilities of modification and development of the information system for ensuring the quality of education were investigated, and ways of its improvement were proposed.

BackgroundThe etiology of Inflammatory Bowel Disease (IBD) is unclear but involves both genetics and environmental factors, including the gut microbiota. Indeed, exacerbated activation of the gastrointestinal immune system toward the gut microbiota occurs in genetically susceptible hosts and under the influence of the environment. For instance, a majority of IBD susceptibility loci lie within genes involved in immune responses, such as caspase recruitment domain member 9 (Card9). However, the relative impacts of genotype versus microbiota on colitis susceptibility in the context of CARD9 deficiency remain unknown.ResultsCard9gene directly contributes to recovery from dextran sodium sulfate (DSS)-induced colitis by inducing the colonic expression of the cytokine IL-22 and the antimicrobial peptidesReg3βandReg3γindependently of the microbiota. On the other hand,Card9is required for regulating the microbiota capacity to produce AhR ligands, which leads to the production of IL-22 in the colon, promoting recovery after colitis. In addition, cross-fostering experiments showed that five weeks after weaning, the microbiota transmitted from the nursing mother before weaning had a stronger impact on the tryptophan metabolism of the pups than the pups’ own genotype.ConclusionsThese results show the role of CARD9 and its effector IL-22 in mediating recovery from DSS-induced colitis in both microbiota-independent and microbiota-dependent manners.Card9genotype modulates the microbiota metabolic capacity to produce AhR ligands, but this effect can be overridden by the implantation of a WT or “healthy” microbiota before weaning. It highlights the importance of the weaning reaction occurring between the immune system and microbiota for host metabolism and immune functions throughout life. A better understanding of the impact of genetics on microbiota metabolism is key to developing efficient therapeutic strategies for patients suffering from complex inflammatory disorders.

Background: Patients with inflammatory bowel disease (IBD) are at an increased risk of developing Clostridioides difficile infection (CDI). Treatment of CDI in patients with IBD is challenging due to higher failure rates and concomitant IBD activity. Objectives: We performed a multicentre cohort study in patients with IBD who received fecal microbiota transplantation (FMT) for recurrent CDI (rCDI), to further investigate factors that influence the clinical outcome and course of both rCDI and IBD. Design: This is a multicentre cohort study conducted in five European FMT centres. Methods: Adult IBD patients treated with FMT for rCDI were studied. Cure was defined as clinical resolution of diarrhoea or diarrhoea with a negative C. difficile test. The definition of an IBD flare was record based. Long-term follow-up data were collected including new episodes of CDI, IBD flares, infections, hospital admissions, and death. Results: In total, 113 IBD patients underwent FMT because of rCDI. Mean age of the patients was 48 years; 64% had ulcerative colitis. Concomitant rCDI was associated with an IBD flare in 54%, of whom 63% had received IBD remission-induction therapy prior to FMT. All FMT procedures were preceded by vancomycin treatment, 40% of patients received FMT via colonoscopy. CDI cure rate was 71%. Long-term follow-up data were available in 90 patients with a median follow-up of 784 days (402–1251). IBD activity decreased in 39% of patients who had active IBD at baseline, whereas an IBD flare occurred in only 5%. During follow-up of up to 2 years, 27% of the patients had infections, 39% were hospitalized, 5% underwent colectomy, and 10% died (median age of these latter patients: 72 years). Conclusion: FMT for rCDI in IBD patients is safe and effective, and IBD exacerbation after FMT is infrequent. Further studies should investigate the effects on IBD course following FMT.

Background Inflammatory bowel diseases (IBD) associated with primary immunodeficiency (PID) remain poorly known. We aimed to isolate characteristics of IBD associated with PID. Methods Using a GETAID register, we reviewed medical files of recorded patients with PID and IBD (Crohn’s disease, ulcerative colitis (UC) or microscopic colitis) followed in 9 adult university hospitals. Results of genetic investigations were available for 46 patients (62%). Results 74 patients (30 F, 44M) were included with a mean age of 26 years (median: 24 years) at diagnosis of IBD. Forty-four (59%) patients had Crohn’s disease with anoperineal lesions in 12, 26(35%) patients had microscopic (mainly lymphocytic) colitis and 4 patients had UC. PID was predominantly antibody deficiency in 40(54%) patients [34 common variable immunodeficiency, 4 X-linked agammaglobulinemia, 2 selective IgA deficiencies], disease of immune dysregulation in 18(24%) patients [CTLA4, LRBA, NFKB1, TNFAi3, XIAP deficiencies, STAT3 and STAT1 hyperactivation], phagocytosis deficiency in 15(20%) patients (12 chronic granulomatous diseases (CGD), 3 congenital neutropenia] and C1s deficiency (n=1). In order of frequency, Crohn’s disease was associated with antibody deficiencies (52%), phagocytosis deficiencies (29%) and immune dysregulation (18%), microscopic colitis with antibody deficiencies (65%), immune dysregulation (27%) and more rarely with phagocytosis deficiencies (8%) and UC with antibody deficiencies (75%) and immune dysregulation (25%). 46% of patients received immunoglobulin supplementation, 70% steroids, equally corticosteroids and budesonide, 49% biotherapy mainly anti-TNF-alpha antibody (38%) and ustekinumab (16%), 23% immunosuppressive drugs, mainly azathioprine and sirolimus and 18% aminosalicylates. Three patients (2 CGD, 1 XIAP) had been treated with allogeneic stem cell transplantation (SCT) and one patient (TNFRS13B deficiency) with autologous SCT. Eleven (15%) patients had intestinal surgery, mainly ileocecal resection. During follow-up [mean: 16 years], 51% of patients had transient or sustained clinical remission mainly with an anti-TNF-alpha antibody, ustekinumab, steroids (budesonide) and specific therapy (targeted therapy such as abatacept and ASCT), 41% of patients had severe infections, 22% developed neoplasia mainly gastrointestinal dysplasia and/or cancers (n=8), B cell lymphoma (n=3) and 4 patients died. Conclusion At adulthood in our series, IBD associated with PID are mainly Crohn’s disease and lymphocytic colitis. The first most frequent associated PID is antibody deficiency. Biotherapies (anti-TNF-alpha antibody, ustekinumab), steroids and specific therapies are commonly used to induce clinical remission.

Background We used the postoperative recurrence model to better understand the role of AIEC bacteria in Crohn’s disease (CD), taking advantage of a well-characterized postoperative cohort. Methods From the REMIND prospective, multicenter cohort of operated CD patients (ileocolonic resection), AIEC identification was performed within the surgical specimen (M0) (N=181 patients) and the neo-terminal ileum (n=119 patients/181) during colonoscopy performed 6 months after surgery (M6). Endoscopic postoperative recurrence was graded using Rutgeerts’ index, which was interpreted, either from a clinical point of view (postoperative endoscopic recurrence ≥ i2b or severe ≥ i3), or from a pathophysiological point of view (reappearance of the first ileal lesions = i1 and more advanced postoperative ileal recurrence = i2b + i3). The mucosa-associated microbiota was analyzed by 16S sequencing at M0 and M6. Relative risks (RR) or odds ratios (OR) were adjusted on potential confounders ((gender, smoking, CD duration, CD phenotype, prior bowel resection, indication for surgery, granuloma, preventive treatment, antibiotics). Results Among the 228 patients included at the time of the analyzes, the search for AIEC was carried out in 181 patients at M0, and 119 patients at M6. Among these 181 patients included in our study, 46.3% did not receive any preventive treatment for endoscopic postoperative endoscopic recurrence while 24.3% have been treated with anti-TNF to prevent postoperative recurrence. AIEC prevalence was two-fold higher within the neo-terminal ileum at M6 (30.3%) than within the surgical specimen (14.9%) (p Conclusion Based on the postoperative recurrence model, our data support the role of AIEC in the early steps of ileal CD.

Introduction et but de l’etude Le role de la nutrition sur les symptomes des maladies auto-immunes est largement discute. L’objectif de cette etude etait de decrire et comparer la prise en charge de la nutrition dans trois aires therapeutiques ainsi que de determiner les attentes des patients en termes d’information et de services en lien avec ce sujet. Materiel et methodes Un questionnaire en ligne, elabore et valide par un comite scientifique multidisciplinaire, a ete propose entre avril et mai 2019 aux patients francais inscrits dans les communautes polyarthrite rhumatoide (PR), rhumatisme psoriasique, spondyloarthrite, maladie de Crohn (MC), rectocolite hemorragique et psoriasis de la plateforme Carenity.com, une communaute de patients en ligne generant des donnees en vie reelle. Resultats et analyse statistique Trois cents patients ont ete inclus (50 patients par pathologie, 78 % de femmes, 48 ans en moyenne, diagnostiques depuis 12 ans en moyenne). Quarante huit pour cent des patients etaient en surpoids ou souffraient d’obesite et 4 % ont deja realise une chirurgie bariatrique. Quarante quatre pour cent ont change leurs habitudes alimentaires depuis leur diagnostic, le plus souvent de leur propre initiative (69 %), moins souvent sur les conseils d’un professionnel de la sante (PFS) (31 %). Soixante six pour cent des patients qui ont modifie leur alimentation ont ressenti un changement suite a cette modification. La perte de poids et une meilleure forme physique (27 %) sont les deux principaux changements observes. En revanche, 21 % ont vu leur niveau de fatigue augmenter et 15 % observent des troubles du sommeil. Plus de la moitie des patients (56 %, 167/300) ont recu un conseil nutritionnel au cours de leur prise en charge. Les conseils les plus frequents etaient la reduction de la consommation de gluten (25 %), de sel (23 %) ou de fibres (21 %). Le specialiste a principalement propose des regimes sans fibre (61 %) ou sans sel (60 %) tandis que le dieteticien ou autre PFS a davantage dirige les patients vers des regimes hyperproteines (54 %), faibles en calorie (50 %) ou sans gluten (49 %). Les patients atteints de MICI ont davantage beneficie de regimes sans fibre, tandis que le regime sans sel est particulierement prescrit aux patients atteints de PR. Toutefois, seulement 23 % des patients (69/300) se sont vu offrir un support d’information ou un service lie a la nutrition. Les principaux outils fournis etaient des brochures (9 %), un suivi par un nutritionniste (9 %) et des sites web dedies a la nutrition (5 %). Le niveau de satisfaction des patients ayant beneficie de ces outils etant assez faible (moyenne : 4,7/10), la qualite des outils et services proposes pourrait etre amelioree. Interroges sur leurs besoins en termes de services et d’information sur la nutrition, les patients evoquent spontanement, les conseils pratiques sur la prise en charge nutritionnelle (44/300, 15 %), suivis par de l’information sur l’alimentation (43/300, 14 %) et des conseils nutritionnels personnalises (30/300, 10 %). Conclusion Bien qu’il soit demontre que l’approche nutritionnelle peut avoir un impact positif sur les maladies auto-immunes, elle reste encore minoritaire aupres des patients interroges. Les outils et services dedies pourraient etre developpes.

SummaryBackground Anti-tumour necrosis factor (TNF) agents have improved the care of Crohn's disease (CD). After the first anti-TNF discontinuation, it is possible to switch to another anti-TNF. Three anti-TNF agents are available for ulcerative colitis (infliximab, adalimumab and golimumab), but only the first 2 have been approved for CD because golimumab has not been studied for this indication. Aim To report the efficacy and safety of golimumab in CD. Methods Crohn's disease patients who received golimumab were identified in 12 French tertiary centres and were retrospectively analysed. The primary endpoint was the duration of golimumab treatment before escalation or discontinuation. The clinical response was defined as a decrease of more than 3 points in the Harvey-Bradshaw index or by global physician assessment. Results One hundred and fifteen patients were included. The golimumab treatment duration was 9.8 months (0.55-44), and 48.7% of the patients were still under treatment at the end of follow-up. Clinical response was observed in 55.8% of the patients after a mean duration of 3.8 months. The probability of remaining under treatment without escalation at 6, 12 and 24 months was 54.6%, 34.9% and 19.3% respectively. In multivariate analysis, discontinuation of the first anti-TNF agent due to intolerance (odds ratio, OR = 2.16; 95% CI, confidence interval [1.25-3.86]; P = .005) and co-immunosuppression for more than 6 months (OR = 3.98; 95% CI [2.3-7.1]; P < .0001) were predictive factors of efficacy. Six per cent of the patients discontinued treatment due to intolerance. Conclusion After failure of infliximab or adalimumab for Crohn's disease, golimumab was safe and seemed beneficial in half of the patients.

La flore ou microbiote intestinal est l’ensemble des microorganismes (principalement des bacteries) qui colonisent notre tube digestif. Un etre humain heberge 1014 bacteries dans son tractus digestif soit dix fois plus que de cellules eucaryotes. Le microbiote est adapte a son environnement et il existe une relation etroite de mutualisme entre microbiote et hote. Plus de 70% des bacteries qui composent le microbiote intestinal ne sont pas cultivables par les methodes classiques. Ces dernieres annees, l’avenement de la biologie moleculaire a permis l’analyse plus complete du microbiote intestinal et la description de sa grande diversite, en s’affranchissant des limites de la culture. Le microbiote intestinal represente une biomasse importante possedant de grandes capacites fonctionnelles dont l’hote beneficie largement, le faisant considerer par certains comme un « organe cache ».

Background Androgen deprivation therapy (ADT) is standard treatment for rising PSA with/without circulating tumor cells (CTCs) but adverse events (AEs) limit patient acceptance. We report results of SM-88 (D,L-alpha-metyrosine; racemetyrosine [USAN]) in combination with a CYP3A4 inducer, mTOR inhibitor and catalyst that does not lower testosterone (T). Methods Phase 2 with a rising PSA (per PCWG3), no disease on imaging and detectable CTCs. Results From Sept 2016-April 2019, 35 subjects consented; 23 evaluable (completed >1 cycle); 60.9% were post RT. Mean age 70.6; BMI 28.9; 21.7% black. Mean T rose (319.1 to 346.0 ng/dL p = 0.08) over 12 weeks. Subjects did not report side effects commonly associated with hormone suppression. Assessments of EORTC measured domains sexual health, overall health, and quality of life remained stable, with depression, hot flushes, and enlarged breast reported as “Not at all” (remained at 1). There was no detectable worsening in any domain of EORTC QLQ-C30 or QLQ-PR25. No clinically significant changes were seen in weight, hct, glu, urinary N telopeptide, MAP (in normotensives and hypertensives), heart rate, Ca ++, LDH, bsAlkPhos, triglycerides, albumin, or QTc. NLR decreased at the end of cycle 1 in 75% of those with radiographic and/or PSA progression vs 53% of those who did not. 15/23 (65.2%) subjects reported experiencing an AE. 1 unrelated Grade 3; 18/35 (51.4%) at least possibly related to drug. No AEs were related to T levels. There were no skeletal or cardiovascular events. From initial diagnosis of PSA rise 100% (23/23) remained metastases free. PSA declined (4% 1/23) stabilized (83% 19/23) or rose (13% 3/23). 56.5% (13/23) subjects experienced an improvement in median PSA DT. Median DT time improved from 6.2 to 8.0 months for all subjects completing 3 cycles of therapy. CTCs were > 5 in 100% at baseline. After 12 weeks, there was a 65.3% (-100% to -8.8%) median CTC decrease from baseline (n = 18), with all subjects having CTC counts below baseline and 2 undetectable. Conclusions SM-88 may delay the start of HT and be useful when normal T is preferred. QOL was maintained without ADT AEs. Favorable effects on PSA and CTCs kinetics were observed consistent with a favorable treatment effect. Trials to confirm these benefits are planned. Clinical trial identification NCT02796898. Legal entity responsible for the study Tyme Inc. Funding Tyme Inc. Disclosure G. Del Priore: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Tyme Inc. G.H. Sokol: Advisory / Consultancy: Tyme Inc. A. Vandell: Full / Part-time employment: Tyme Inc. All other authors have declared no conflicts of interest.

79 Background: Treatment for rising PSA non-metastatic prostate cancer (nmPC) includes multifaceted hormone therapies (HT) associated with increasing related toxicity; in aggregate the risk benefit ratio is not ideal. We report on the use before HT, of SM-88, a novel combination therapy (amino acid analogue, CYP3A4 inducer, mTOR inhibitor and catalyst) based on the Warburg effect without known hormone related toxicity. Methods: Prospective ongoing Phase II of SM-88 (230 mg po bid) in recurrent nmPC with rising PSA (PCWG3 definition), no radiographically identified metastases at baseline and detectable CTCs. Results: From Sept 2016 to Dec 2017, there have been 31 consented (34 planned) with 23 evaluable (completed > 1 cycle). Mean age 68.9; BMI 28.7; 38% black and 62% post RT. Mean testosterone (T) rose from 319 to 382 ng/dl (p=.19). Typical HT related side-effects were not observed: 96% of subjects reported no hot flashes, 91% no gynecomastia, 83% interest and 61% activity in sex, 78% excellent or nearly so overall health and 74% excellent QOL on at least 50% of their EORTC questionnaires; weight (-0.2 kg), hct (0%), glu (+2 mg/dl), urinary N telopeptide (-4.2 nmol), MAP (normotensives -2 mmHg, hypertensives -3 mmHg), heart rate (-2.4 beats/min), QTc (-3 ms) with no newly emergent >480 ms, serum Ca++ (-0.006 mg/dL), LDH (+6.4 u/L), bsAlkPhos (+6.2 u/L), triglycerides (-5.2 mg/dL), total protein (0.05 g/dL) and albumin (0.02 g/dL). Neutrophil lymphocyte ratio decreased at the end of cycle 1 in 100% (n=5, median 2.4) of those who progressed to subsequent therapy vs 47% of those who did not (p=.05). AEs occurred in 16 subjects: 1 unrelated Grade (G) 3; 0 G 4; 14/26 G 1-2 possibly related to drug. No AEs were related to T levels. From initial diagnosis of PSA rise (median 9, 3-18 months), 96% (22/23) have remained metastases free and 78% (18/23) remained free of additional HT (pG2. SM88 may be useful in prostate cancer patients who are more sensitive or vulnerable to HT related toxicity while maintaining stable PSA values. Prospective trials are planned to confirm its utility. Clinical trial information: NCT02796898.

83 Background: Absolute PSA change is an imperfect surrogate of clinical benefit; CTCs and PSA doubling time (DT) may also be used as a surrogate of progression (PD). Hormone therapy (HT) often leads to a rapid decline in PSA, however non-HT may be effective without causing a decline in absolute PSA or testosterone (T). SM-88, a non-HT novel combination Warburg effect therapy (amino acid analogue, CYP3a4 inducer, mTOR inhibitor and catalyst) does not affect T. We report outcomes leading to subsequent therapies of an ongoing PSA recurrent, non-metastatic PC trial. Methods: Prospective Phase II of rising PSA (per PCWG3), detectable CTCs, and no baseline lesions. Results: Since September 2016, 31 subjects enrolled with 17 on study for > 12 weeks. Mean age 68.9; BMI 28.7; 38% black and 62% post RT. Mean T increased 61 mg/dl from baseline 319 mg/dl (p=0.19). 82% (14/17) subjects experienced an improvement in PSA DT and 67% (10/15) experienced a decline in CTCs of >30%. Overall median PSA DT time on enrollment was 5.3 (1.4 – 37.6) and improved to 6.5 (Wilcoxon p=0.02) (see table). 3/4 subjects with PD failed to maintain a CTC drop >60% vs 2/17 without PD (p=.03); median time to nadir CTC was 3 cycles (1-7). Subjects avoiding subsequent therapy averaged a 50% CTC decline (15-100%). CTC and PSA DT effects were not correlated to T level. AEs possibly related to drug/unrelated were: No grade (G) 4 or 5; 0/1 G3; 1/7 G2; 13/19 G1. As reported elsewhere, typical HT-related side effects were not observed. Including all patients with >1 month of data, from initial diagnosis of PSA rise (median 9 months; 3-18), 96% (22/23) have remained metastases-free and 78% (18/23) remained free of additional HT (p

277 Background: SM88 is an oral tyrosine isomer ( TI) and repurposed drugs (CYP3a4 inducer, mTOR inhibitor, oxidative stress catalyst). This regimen has reported no drug related grade 3, 4 or 5 adverse events (JCO 2013 31: e22095) and potential clinical activity in PC (JCO 2018 36: TPS 4156). PC patients have risk factors for malabsorption and a cachexia syndrome rendering some oral therapies potential unreliable. We present PK data from the completely enrolled first stage of an ongoing dose finding phase II in PC. Methods: Open label randomized TI (control – 230 mg bid vs. experimental - 430 mg bid) along with the lowest approved doses of the other agents. Samples were drawn from four patients at pre-dose and up to six h post dosing on cycle day one for two cycles after a single dose of all four components. Results: Mean age: 71.3 (59 – 80), BMI = 25.3 (21.9 – 28.8) and median three prior chemo lines, two post-pancreas surgery and one s/p RT. There was no evidence that the combination altered the expected PKs at C2. There were no serious drug related adverse events. Favorable RECIST, PERCIST or biomarker activity was documented at both TI dose levels. The PK results of the repurposed drugs were consistent with the published data for these agents, despite the combination use and lower than typical label doses; data will be provided. These results were consistent with previous animal and healthier patient PK of SM88. Conclusions: Single dose C1 and C2 TI PKs are consistent with preclinical predictions (ESMO 2016. Ann Oncol (2016) 27 (supp_6): 1605P) and those previously reported in a healthier population of cancer patients (JCO 2018 36: TPS 4156). Based on these results and PK ones from the repurposed drugs, additional data is being collected in order to define the ongoing phase II expansion cohort dose. SM-88 appears to have predictable PK even in heavily pretreated PC patient with prior radiotherapy and surgery. Clinical trial information: NCT03512756. [Table: see text]

We describe experiments that isolate and characterize multiple adaptable mechanisms that influence responses of orientation-selective neurons in primary visual cortex (V1) of anesthetized macaque (Macaca fascicularis). The results suggest that three adaptable stages of machinery shape neural responses in V1: a broadly tuned early stage and a spatio-temporally tuned later stage, both of which provide excitatory input, and a normalization pool that is also broadly tuned.The early stage and the normalization pool are revealed by adapting gratings that themselves fail to evoke a response from the neuron: either low temporal frequency gratings at the null orientation or gratings of any orientation drifting at high temporal frequencies. When effective, adapting stimuli that altered the sensitivity of these two mechanisms caused reductions of contrast gain and often brought about a paradoxical increase in response gain due to a relatively greater desensitization of the normalization pool.The tuned mechanism is desensitized only by stimuli well matched to a neuron's receptive field. We could thus infer desensitization of the tuned mechanism by comparing effects obtained with adapting gratings of preferred and null orientation modulated at low temporal frequencies.

TPS4156Background: Treatment options for recurrent/refractory advanced pancreatic cancer (PC) include largely ineffective toxic therapies or palliation. SM-88 is a combination of dysfunctional tyro...

e13100Background: SM-88 is a relatively non-toxic novel combination therapy (dysfunctional tyrosine, CYP3a4 inducer, mTOR inhibitor and oxidative stress catalyst) that has demonstrated efficacy in ...

175 Background: Despite toxicity and no clear survival benefit, non-metastatic recurrent prostate cancer (nmPC) is typically treated with androgen deprivation therapy (ADT). SM88 is a relatively non-toxic novel combination therapy (amino acid analogue, CYP3a4 inducer, mTOR inhibitor and catalyst) based on the Warburg effect, with activity in a variety of cancers including prostate (JCO 2017 35, e16567). Phase I and II results demonstrated stable or rising testosterone levels while achieving a reduction of CTCs (circulating tumor cells) and no radiographic progression events (Annal Oncol 2017, 28(5):274-5). We now report results for toxicities typically seen with ADT. Methods: Prospective ongoing Phase Ib/II of SM88 (230mg po bid) in recurrent nmPC with rising PSA (PCWG3 definition), detectable CTCs, and no radiographically identified metastases at baseline. Results: Since Sept 2016, there have been 17 consented (of 34 planned) with 10 evaluable (completed > 1 cycle) (median 7, range 1-13). Mean age was 71.2 (53-84); all had prior ADT after curative intent RT (50%) or surgery (50%); with no patient currently on ADT. Mean testosterone level was 307.6 ng/dL before SM88 and 349.2 after (p = 0.07, one-tail T test), rising in (5/10) or remained stable except for one patient who entered the trial castrate ( < 2.5). Overall 70% had some grade 1-2 adverse event (AE) but no drug related serious AE. EORTC-QLQ-C30 relating to mental function domain (Q20-28) and QLQ-PR25 intimacy domains (Q44-50) remained stable, including 9 (90%) reporting no or resolved hot flashes; 7 (70%) reporting an improved or stable “interest in sex”; and 6 (60%) having “excellent” “overall health” and “QOL”. Weight and osteoporosis (measured by Urinary NTX) did not worsen; mean EKG QTc (422 ms); mean arterial pressure (95.1 mmHg); glucose (115.2 mg/dl) and hematocrit (41.5%) were not affected. Conclusions: Toxicities typically associated with ADT were not seen with SM88, a novel non-hormonal anti-neoplastic. Despite the limited follow-up, these data suggest that ADT may be avoided or delayed without progression in selected patients with nmPC. A phase III RCT of SM88 vs patient choice of hormonal or active surveillance is planned for confirmation of these results. Clinical trial information: NCT02796898.

In 1996 the American Society for Therapeutic Radiology and Oncology (ASTRO) sponsored a Consensus Conference to establish a definition of biochemical failure after external beam radiotherapy (EBRT). The ASTRO definition defined prostate specific antigen (PSA) failure as occurring after three consecutive PSA rises after a nadir with the date of failure as the point halfway between the nadir date and the first rise or any rise great enough to provoke initiation of therapy. This definition was not linked to clinical progression or survival; it performed poorly in patients undergoing hormonal therapy (HT), and backdating biased the Kaplan-Meier estimates of event-free survival. A second Consensus Conference was sponsored by ASTRO and the Radiation Therapy Oncology Group in Phoenix, Arizona, on January 21, 2005, to revise the ASTRO definition. The panel recommended: (1) a rise by 2 ng/mL or more above the nadir PSA be considered the standard definition for biochemical failure after EBRT with or without HT; (2) the date of failure be determined "at call" (not backdated). They recommended that investigators be allowed to use the ASTRO Consensus Definition after EBRT alone (no hormonal therapy) with strict adherence to guidelines as to "adequate follow-up." To avoid the artifacts resulting from short follow-up, the reported date of control should be listed as 2 years short of the median follow-up. For example, if the median follow-up is 5 years, control rates at 3 years should be cited. Retaining a strict version of the ASTRO definition would allow comparisons with a large existing body of literature.

The purpose of this report is to summarize information on drugs recently approved by the U.S. Food and Drug Administration. Three drugs have recently been approved: Gleevec™ (imatinib mesylate) at a starting dose of 400 or 600 mg daily for the treatment of malignant unresectable and/or metastatic gastrointestinal stromal tumors; Mesnex® (mesna) tablets as a prophylactic agent to reduce the incidence of ifosfamide-induced hemorrhagic cystitis, and Zometa® (zoledronic acid) for the treatment of patients with multiple myeloma and for patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. The recommended dose and schedule is 4 mg infused over 15 minutes every 3-4 weeks. These three drugs represent three different types of drug approval: Gleevec is an accelerated approval and supplemental new drug application (NDA); Mesnex tablets represent an oral formulation of a drug approved 14 years ago as an intravenous formulation, and Zometa represents a standard NDA for a noncytotoxic, supportive-care drug. Information provided includes rationale for drug development, study design, efficacy and safety results, and pertinent literature references.

e16567 Background: SM88 is a novel combination of substituted amino acid ( AA) and repurposed agents with non-toxic activity in a variety of cancers including prostate (PC). Non-metastatic biochemically recurrent PC (nmPC) is ideal for such a well-tolerated, non-androgen based treatment. We present biomarker activity including CTCs (circulating tumor cells) after completion of the Ib dose escalating pharmacokinetic portion of the SM88 development plan. Methods: Planned analysis of an ongoing prospective Phase Ib/II open label study of nmPC (PCWG3 definition). Subject 1 received the 1stdose level of AA, and others received 2x dose. All subjects also received a combination of low dose re-purposed CYP3a4 inducer, oxidative stress catalyst, and mTOR inhibitor. Results: Four subjects completed at least 1 cycle (28d) with all PK sampling as prespecified. Median age was 73(70-80); all had prior ADT that was discontinued 3-6 yrs earlier, and either had curative intent prostatectomy (n = 2) or RT (n = 2); Testosterone level was castrate in one after prior RT. CTCs fell (p < 0.01) to undetectable (n = 1) or by > 25% (n = 3) (see table) while PSA remained stable (PCWG3 criteria). Preliminary LDH, neutrophil/lymphocyte ratio (N:L), urinary NTx, bone specific AlkPhos (bAP) trends are in the table below. There were no drug related serious adverse events (2 grade: 1- pigmentation, 1- vasomotor). EORTC-QLQ30 and PR25 scores were either improved or stable. Conclusions: Treatment with SM88 in patients with nmPC in the completed phase Ib cohort was associated with CTC reduction, and stable biomarker trends including PSA and LDH. There was no significant toxicity or adverse patient reported outcomes. Based on these results, the dose escalation was stopped at the second level and a cohort expansion phase II initiated. A phase III RCT is planned for confirmation of these results. Clinical trial information: NCT02796898. [Table: see text]

e14061 Background: SM88 is a combination of tyrosine isomers ( TI) and repurposed drugs (modulators of CYP3A4, mTOR, and oxidative stress). This regimen has previously reported non-toxic activity in cancers including prostate (PC) ( J Clin Oncol 2013 31: e22095). We present summary data from a completed Ib trial of non-metastatic recurrent PC (nmPC), an ideal candidate for a well-tolerated, non-androgen based treatment. Methods: This was an open-label safety and PK trial of SM88 in patients with nmPC. Cohort 1 received 230 and cohort 2 - 460 mg/day of TI, along with the lowest available doses of the other 3 agents. Multiple samples were drawn at pre-dose and up to 48 h post dosing from 4 patients after a single TI dose; after a single dose of all 4 components; and after 2 weeks of steady state daily combined dosing (SS). Only cohort 2 results are presented. Results: See table below. Each of the 3 approved drugs had expected PK results that will be provided. There was no evidence that the combination altered the expected PKs at SS. There were no serious drug related adverse events. Favorable biomarker activity was documented at both TI dose levels. Conclusions: Single dose and SS TI results from this completed phase Ib trial are consistent with preclinical predictions (ESMO 2016. Ann Oncol (2016) 27 (suppl_6): 1605P). TI PK results changed transiently with the additional components but returned to desirable levels at SS including a higher Cmax, AUC, and more rapid Tmax, indicating rapid absorption. The PK results (not shown) are consistent with the published data for the approved agents, despite the use of lower than typical label doses. Based on these results, the higher TI dose was chosen for the ongoing phase II expansion cohort in nmPC patients. SM-88 appears to have predictable PK as an effective metabolomic regimen for the treatment of advanced prostate cancer devoid of significant toxicities. [Table: see text]

Resume La necrose corticale renale bilaterale est une cause tres rare d'insuffisance renale aigue qui a ete surtout rapporte a des causes obstetricales dans les annees 1970. Nous rapportons ici le premier cas de necrose corticale bilaterale lie a un syndrome des antiphospholipides (SAPL) paraneoplasique.

Magnocellular (M-), but not parvocellular (P-), neurons of the macaque lateral geniculate nucleus (LGN) differ distinctively in their responses to counterphase-modulated and drifting gratings. Relative to stimulation with drifting gratings, counterphase modulation reduces the responses of M- cells in a band around 25 Hz, producing a “notch” in the temporal modulation transfer function (tMTF). The notch is prominent in nearly every M- cell with little variation in the temporal frequency at which it is deepest. The machinery responsible for the notch lies mostly outside the classical linear center. Directly driving the notching mechanism with annular gratings evokes no linear response but elicits a second harmonic (F2) modulation of the discharge accompanied by a drop in the mean discharge (F0). Analysis of the S- potential, which reveals inputs from ganglion cells, shows that 1) tMTFs of the afferent retinal ganglion cells are not notched and 2) during stimulation with annular gratings, the second harmonic component is present, but the drop in the F0 is largely absent from the responses of parasol ganglion cells. These results suggest that the notch is caused by the combined action of the linear response and the second harmonic response, both inherited from retina, and a suppression that originates after the retina. Our results reveal a distinctive signal transformation in the LGN and they show that nearly every M- cell exhibits a spatial nonlinearity like that observed in Y cells of the cat.

Topiramate was approved for the treatment of epilepsy in 1999 and has since been approved for the prevention of migraine headache. It is structurally different from the majority of antiepileptic medications and is pharmacodynamically unique in its ability to inhibit the enzyme carbonic anhydrase. Postmarketing reports of topiramate-associated hypothermia have occurred but this adverse event has not been well characterized. Data mining of an adverse event database was used to assist in the identification of hypothermia.We sought to explore a possible association between the concomitant use of topiramate and valproic acid and the induction of hypothermia.This was a pharmacovigilance case series survey of spontaneous hypothermia, a reported adverse event in patients treated with topiramate and valproic acid, alone and in combination. The U.S. Food and Drug Administration's Adverse Events Reporting System (AERS) database was searched for reports of hypothermia in association with the use of topiramate. A data mining algorithm was used on the AERS to identify scores for hypothermia associated with antiepileptic drugs.We identified 22 unduplicated reports of hypothermia in patients exposed to topiramate. Three of the 22 were confounded by patient overdoses with multiple drugs and not considered. Use of more than one antiepileptic drug was reported in most of the remaining 19 reports. Of these 19 reports, valproic acid was mentioned in 7. Two of the 19 reports mentioned topiramate only. Eleven of the 19 patients were men. The median age of the 19 patients was 40 years (range, 3(1/2)-82 years). Body temperatures ranged from 29.5 degrees C (moderate hypothermia) to 35 degrees C (mild hypothermia) with a median of 34 degrees C. Eleven of 18 reports of hypothermia occurred during the cooler months (one report did not indicate the time of year in which hypothermia occurred). Comorbid conditions included hypothyroidism in six reports, five in patients who received valproic acid concomitantly with topiramate and five reports of hyperammonemia in similarly treated patients. Data mining scores (empirical Bayes geometric mean) for antiepileptic drugs ranged from a high of 5.845 for phenobarbital to 2.956 for gabapentin. Hypothermia was reported 4.7 times more frequently when topiramate was used than was statistically expected.We have found hypothermia, defined as an unintentional drop in body core temperature to35 degrees C, to be associated with concomitant administration of topiramate (a carbonic anhydrase inhibitor) and valproic acid in patients who have tolerated either drug alone. Data mining analysis for topiramate showed a signal of hypothermia. Topiramate was reported 4.72 times more frequently in the database than would be statistically expected when considering all other drugs. Topiramate may act pharmacodynamically to potentiate the effects of valproic acid as a result of its ability to decrease blood HCO(3) (-) and increase blood ammonia levels.

We describe a 71-year-old man who had received warfarin 7.5 mg/day for 5 years for atrial fibrillation, which had maintained his international normalized ratio (INR) within a narrow range of 2.5-3.2. During this 5-year period, he had also been treating himself with the supplement glucosamine hydrochloride 500 mg-chondroitin sulfate 400 mg twice/day for arthritis. The patient then increased his dosage of glucosamine to 1500 mg and chondroitin to 1200 mg twice/day; his INR previous to this change was 2.3. Approximately 3 weeks later, his INR increased to 3.9. His supplement dosage was reduced to glucosamine 750 mg-chondroitin 600 mg/day; a repeat INR done 16 days later was 4.7. The supplement was then stopped, and his warfarin schedule was changed to 7.5 mg every other day alternating with 3.75 mg every other day. Sixteen days later, his INR was 2.6. This case report suggests that a potential interaction exists between warfarin and glucosamine that is associated with an increase in the INR. We therefore performed a pharmacovigilance survey of spontaneously reported adverse events in warfarin-treated patients concomitantly exposed to glucosamine, glucosamine-chondroitin sulfate, or chondroitin sulfate and present a literature review of this apparent drug-drug interaction. Using the United States Food and Drug Administration (FDA) MedWatch database, 20 reports of glucosamine or glucosamine-chondroitin sulfate use with warfarin associated with altered coagulation (manifested by increased INR, or increased bleeding or bruising) were identified. In some cases, a decrease in the supplement dosage was followed by a return of the INR to the previous therapeutic range. Similarly, a decrease in warfarin dosage was followed by a decrease in INR in one patient who received long-term warfarin therapy. One report described an intraventricular bleed and subdural hematoma, which resulted in a persistent vegetative state. The World Health Organization (WHO) adverse drug reactions database documented 21 spontaneous reports of increased INR associated with glucosamine use, 17 of which resolved when glucosamine was stopped. We located one published case report of concomitant use of glucosamine-chondroitin sulfate potentiating the effect of warfarin. In aggregate, the reports from the FDA and WHO, the published case report, and our case report suggest that the use of warfarin and glucosamine may lead to an increased INR. Patients should be advised that the use of the two products may cause an increase in INR, and they should inform their health care provider if they consume glucosamine. More information is necessary to define this interaction.

International audience; Chronic intestinal pseudo-obstruction (CIPO) is a heterogeneous group of rare disorders characterised by symptoms of intestinal obstruction with no mechanical evidence of obstruction. It is caused by ineffective intestinal contractions due to visceral neuropathy and/or neuropathy. In adults, CIPO is mostly secondary. The most common causes are metabolic disorders, connective tissue disorders, neuropathic drug related injuries, paraneoplasic and post-infectious syndromes and amyloidosis. Secondary forms of CIPO have been reported with anti-Hu antibodies. This corresponds to an antineuronal antibody that recognizes a protein expressed in the nuclei of neuron (ANNA-1) and neoplasic cells. The anti-Hu antibody must be searched for in patients over 40 years old with CIPO (associated with small cell lung cancer in 75% of cases). Recently, the association of CIPO and the anti-Hu antibody has been described without associated neoplasia. We report a case of an association of CIPO and anti-Hu antibody without cancer after 13 years of follow-up.

We characterize a hitherto undocumented type of neuron present in the regions bordering the principal layers of the macaque lateral geniculate nucleus. Neurons of this type were distinguished by a high and unusually regular maintained discharge that was suppressed by spatiotemporal modulation of luminance or chromaticity within the receptive field. The response to any effective stimulus was a reduction in discharge, reminiscent of the “suppressed-by-contrast” cells of the cat retina. To a counterphase-modulated grating, the response was a phase-insensitive suppression modulated at twice the stimulus frequency, implying a receptive field comprised of multiple mechanisms that generate rectifying responses. This distinctive nonlinearity makes the neurons well suited to computing a measure of contrast energy; such a signal might be important in regulating sensitivity early in visual cortex.

Biotransformation of chlordiazepoxide was studied in mice following a single 1000-rad dose of hepatic irradiation. Meabolic N-demethylation of chlordiazepoxide in irradiated mice was impaired when tested 3 days after irradiation. No such effect was observed in mice tested 3 weeks or 6 weeks after irradiation. Thus, hepatic irradiation appeared to produce short-lived, reversible impairment of drug-metabolizing function. The effect was small and of uncertain biological significance.

The absorption of oral digoxin and of desmethyldiazepam, from its precursor clorazepate, was studied in seven patients who had received abdominal and/or pelvic radiation therapy for neoplastic disease. All patients were in remission and had normal renal function and no evidence of malabsorption. Single 0.5-mg doses of digoxin tablets and 15-mg doses of clorazepate were administered in the fasting state. Concentrations of digoxin (by radioimmunoassay) and desmethyldiazepam (by gas chromatography) were determined in multiple plasma samples and all urine collected during 24 hours after dosage. The mean (+/- S.E.) weight-normalized area under the 24-hour plasma digoxin concentration curve (WtN-AUC-24) in the patients (722 +/- 40 ng/ml-hr-kg) was similar to that in five normal controls (713 +/- 57 ng/ml-hr-kg), but 24-hour urinary excretion of digoxin in patients (54.5 +/- 4.4 microgram) was significantly less (P less than 0.025) than in controls (83.4 +/- 11.4 microgram). Neither age, sex, nor renal function explained the difference. In the clorazepate study, WtN-AUC-24 for desmethyldiazepam in the patients (187 +/- 19 microgram/ml-hr-kg) was significantly less (P less than 0.01) than in 15 normal control subjects (230 +/- 5 microgram/ml-hr-kg). Age and sex did not explain the difference. Thus, radiation therapy, or the underlying disease, is associated with malabsorption of these two drugs, possibly because of damage to gastric acid-secreting cells.

The case records of 81 patients over the age of 60 were reviewed with respect to complications following lymphangiography. Adverse prognostic factors and complications were studied. Of the 81 patients, 48 were 60-69 years old and 33 were 70 or older; 19 patients had mild risk factors and 16 had severe risk factors. There were only six complications secondary to lymphangiography--two moderate and four mild. No severe complications were noted. This study suggests that age in itself is not a contraindication to lymphangiography.

A case of traumatic intracerebellar hematoma is presented. The salient feature of the patient's early clinical course was delayed, rapid deterioration in the absence of antecedent focal neurological findings. The rarity of this lesion and its high mortality due to delay in correct diagnosis have been previously emphasized. Reported cases have followed a subacute clinical course and deterioration has been preceded by focal neurological findings. Prompt ventricular drainage followed by evacuation of the hematoma can be expected to yield a satisfactory clinical result.

International audience

International audience

International audience