587 - Thermally triggered theranostics for pancreatic cancer

Conference abstract

Idiopathic intracranial hypertension (IIH) - observations on 6 clinical cases

Идиапатичната интракраниална хипертензия (ИИХ) е неврологично заболяване, което клинически протича основно с офталмологична симптоматика.Цел: Да се направи литературен обзор и се представят дългосрочните наблюдения върху клинични случаи с ИИХ.Материал и методи: Литературният обзор е изграден на базата на търсене в 4057 заглавия в PubMed, от които 206 пълнотекстови статии от последните 5 г. Представят се и се обсъждат резултатите от дългосрочното наблюдение върху 6 клинични случая с различна динамика на заболяването в хода на лечението и проследяването.Резултати: Диагнозата се постави на базата на клиничната картина, наличието на едем на папилите и изключване на други заболявания, протичащи с интракраниална хипертензия (липса на промени в лабораторното изследване на лумбален пунктат и липсата на находка при КАТ и ЯМР на гл. мозък, отхвърляне на тромбоза на церебралните венозни синуси чрез ЯМР венография). При първите двама пациенти се проведе неврохирургично лечение (вентрикуло-перитонеален шънт), поради тежко протичане на заболяването. Дългосрочният резултат бе неблагоприятен. При останалите 4 пациента, поради по-леката тежест на заболяването, се проведе консервативно лечение с високи дoзи Acetazolamide и последващо титриране на дозата за минимум 9-12 месеца. При всички се постигна успех с възстановяване на зрителната функция, обратно развитие на едема на папилите и задържане на ефекта в рамките на 2-4 години.Заключение: Своевременната диагностика и лечение, както и добрата интердисциплинарна колаборация са основни фактори, които могат да предотвратят развитието на тежка двустранна необратима загуба на зрителна функция при пациенти с ИИХ.Idiopathic intracranial hypertension (IIH) is a neurological disease that has predominantly ophthalmological clinical signs.Aim: To perform review of literature and present the long-term observation results on clinical cases with IIH.Material and methods: The literature review is based on PubMed search of 4057 publications, among which 206 full text articles from the last 5 years. We present and discuss our observations on 6 clinical cases with different clinical characteristics and response to treatment in the long-term follow-up course.Results: The diagnosis was based on the clinical picture, presence of papilledema, and exclusion of other diseases that can cause intracranial hypertension (check-up of cerebrospinal fluid, cranial CTscan and MRI, exclusion of thrombosis of the cerebral venous sinuses - MRI venography). The first two presented patients underwent neurosurgical treatment (ventriculo-peritoneal shunting), because of the severe course of the disease. The long-term result was unfavorable. The rest 4 patients, due to the moderate severity of the disease, were treated conservatively with high dose Acetazolamide and titration of the dose for a minimum of 9-12 months. In all 4 patients there was successful recovery of visual function, absorbtion of the papilledema and retention of the result for a period of 2 to 4 years.Conclusion: The correct timely diagnosis and treatment, along with good interdisciplinary collaboration, are the main prerequisite factors that can prevent severe bilateral irreversible loss of visual function in patients with IIH

Attachment style moderates partner presence effects on pain : A laser-evoked potentials study

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly citedSocial support is crucial for psychological and physical well-being. Yet, in experimental and clinical pain research, the presence of others has been found to both attenuate and intensify pain. To investigate the factors underlying these mixed effects, we administered noxious laser stimuli to 39 healthy women while their romantic partner was present or absent, and measured pain ratings and laser-evoked potentials to assess the effects of partner presence on subjective pain experience and underlying neural processes. Further, we examined whether individual differences in adult attachment style, alone or in interaction with the partner's level of attentional focus (manipulated to be either on or away from the participant) might modulate these effects. We found that the effects of partner presence versus absence on pain-related measures depended on adult attachment style but not partner attentional focus. The higher participants' attachment avoidance, the higher pain ratings and N2 and P2 local peak amplitudes were in the presence compared to the absence of the romantic partner. As laser-evoked potentials are thought to reflect activity relating to the salience of events, our data suggest that partner presence may influence the perceived salience of events threatening the body, particularly in individuals who tend to mistrust others.Peer reviewedFinal Published versio

Cardiac Safety of TGF-β Receptor I Kinase Inhibitor LY2157299 Monohydrate in Cancer Patients in a First-in-Human Dose Study

Transforming growth factor-beta (TGF-β) signaling plays an important role in the fetal development of cardiovascular organs and in the repair mechanisms of the heart. Hence, inhibitors of the TGF-β signaling pathway require a careful identification of a safe therapeutic window and a comprehensive monitoring of the cardiovascular system. Seventy-nine cancer patients (67 glioma and 12 solid tumor) enrolled in a first-in-human dose study and received the TGF-β inhibitor LY2157299 monohydrate (LY2157299) as monotherapy (n = 53) or in combination with lomustine (n = 26). All patients were monitored using 2D echocardiography/color and Spectral Doppler (2D Echo with Doppler) every 2 months, monthly electrocardiograms, thorax computer tomography scans every 6 months, and monthly serum brain natriuretic peptide (BNP), troponin I, cystatin C, high-sensitivity C-reactive protein (hs-CRP). Administration of LY2157299 was not associated with medically relevant cardiovascular toxicities, including patients treated ≥6 months (n = 13). There were no increases of troponin I, BNP, or hs-CRP or reduction in cystatin C levels, which may have been considered as signs of cardiovascular injury. Blood pressure was generally stable during treatment. Imaging with echocardiography/Doppler showed an increase in mitral and tricuspid valve regurgitation by two grades of severity in only one patient with no concurrent clinical symptoms of cardiovascular injury. Overall, this comprehensive cardiovascular monitoring for the TGF-β inhibitor LY2157299 did not detect medically relevant cardiac toxicity and hence supports the evaluation of LY2157299 in future clinical trials

Phase 1b/2a study of galunisertib, a small molecule inhibitor of transforming growth factor-beta receptor I, in combination with standard temozolomide-based radiochemotherapy in patients with newly diagnosed malignant glioma

Altres ajuts: This trial was funded by Eli Lilly and Company.The online version of this article contains supplementary material, which is available to authorized users

Pharmacokinetic, pharmacodynamic and biomarker evaluation of transforming growth factor-β receptor I kinase inhibitor, galunisertib, in phase 1 study in patients with advanced cancer

Purpose Transforming growth factor-beta (TGF-β) signaling plays a key role in epithelial-mesenchymal transition (EMT) of tumors, including malignant glioma. Small molecule inhibitors (SMI) blocking TGF-β signaling reverse EMT and arrest tumor progression. Several SMIs were developed, but currently only LY2157299 monohydrate (galunisertib) was advanced to clinical investigation. Design The first-in-human dose study had three parts (Part A, dose escalation, n = 39; Part B, safety combination with lomustine, n = 26; Part C, relative bioavailability study, n = 14). Results A preclinical pharmacokinetic/pharmacodynamic (PK/PD) model predicted a therapeutic window up to 300 mg/day and was confirmed in Part A after continuous PK/PD. PK was not affected by co-medications such as enzyme-inducing anti-epileptic drugs or proton pump inhibitors. Changes in pSMAD2 levels in peripheral blood mononuclear cells were associated with exposure indicating target-related pharmacological activity of galunisertib. Twelve (12/79; 15 %) patients with refractory/relapsed malignant glioma had durable stable disease (SD) for 6 or more cycles, partial responses (PR), or complete responses (CR). These patients with clinical benefit had high plasma baseline levels of MDC/CCL22 and low protein expression of pSMAD2 in their tumors. Of the 5 patients with IDH1/2 mutation, 4 patients had a clinical benefit as defined by CR/PR and SD ≥6 cycles. Galunisertib had a favorable toxicity profile and no cardiac adverse events. Conclusion Based on the PK, PD, and biomarker evaluations, the intermittent administration of galunisertib at 300 mg/day is safe for future clinical investigation

Comparison of (semi-)automatic and manually adjusted measurements of left ventricular function in dual source computed tomography using three different software tools

To assess the accuracy of (semi-)automatic measurements of left ventricular (LV) functional parameters in cardiac dual-source computed tomography (DSCT) compared to manually adjusted measurements in three different workstations. Forty patients, who underwent cardiac DSCT, were included (31 men, mean age 58 ± 14 years). Multiphase reconstructions were made with ten series at every 10% of the RR-interval. LV function analysis was performed on three different, commercially available workstations. On all three workstations, end-systolic volume (ESV), end-diastolic volume (EDV), LV ejection fraction (LVEF) and myocardial mass (MM) were calculated as automatically as possible. With the same DSCT datasets, LV functional parameters were also calculated with as many manual adjustments as needed for accurate assessment for all three software tools. For both semi-automatic as well as manual methods, time needed for evaluation was recorded. Paired t-tests were employed to calculate differences in LV functional parameters. Repeated measurements were performed to determine intra-observer and inter-observer variability. (Semi-)automatic measurements revealed a good correlation with manually adjusted measurements for Vitrea (LVEF r = 0.93, EDV r = 0.94, ESV r = 0.98 and MM r = 0.94) and Aquarius (LVEF r = 0.96, EDV r = 0.94, ESV r = 0.98 and MM r = 0.96). Also, good correlation was obtained for Circulation, except for LVEF (LVEF r = 0.45, EDV r = 0.93, ESV r = 0.92 and MM r = 0.86). However, statistically significant differences were found between (semi-)automatically and manually adjusted measurements for LVEF (P < 0.05) and ESV (P < 0.001) in Vitrea, all LV functional parameters in Circulation (P < 0.001) and EDV, ESV and MM (<0.001) in Aquarius Workstation. (Semi-)automatic measurement of LV functional parameters is feasible, but significant differences were found for at least two different functional parameters in all three workstations. Therefore, expert manual correction is recommended at all times