Evaluation of radiological and clinical efficacy of ^{90}Y-DOTATATE} therapy in patients with progressive metastatic midgut neuroendocrine carcinomas

Background: To evaluate the radiological and clinical therapeutic effectiveness of ^{90}Y-octreotate [DOTATATE] inpatients with progressive somatostatin receptor-positive midgut neuroendocrine carcinomas (GEPNETs). Material/Methods: The study group: 34 patients, with histological proven extensive non-resectable and progressive midgut GEP-NETs. Radionuclide therapy (^{90}Y-DOTATATE) was given i.v. with a mean activity per administration 3,82 GBq. Initial clinical tumor responses were assessed 6-7 weeks after therapy completion and then once 3-monthly. The objective tumor response was classified according to the RECIST, initially between 4-6 months and then after each of the 6 months interval. Results: At 6 months after treatment completion, radiological tumor response was observed in 6 subjects with PR (19%), 25 presented SD (78%) and single had PD (3%). Overall clinical response to therapy at 6 months follow-up was observed in 23 patients (68%), SD in 5 patients (15%) and PD in 6 (18%). A year after therapy radiological tumour response was seen in 11 patients (44%), SD had 12 subjects (44%) and DP was noted in 2 patients. Two years after completed therapy PR was seen in 6 patients (33%), SD in additional 11 subjects (61%), single patient had PD. Clinical response to treatment in terms of PR and SD were noted in 22 patients (88%) after 1 year and in 14 patients (87%) after 2 years. Median PFS was 20 months, while the median OS was 23 months. In the 6 patients with clinical PD within initial 6 months the median PFS was 6 months and OS 11 months, while in those with SD or PR PFS was 22 months and OS 26 months (P<0.05). Conclusions: Therapy with ^{90}Y-DOTATATE} is effective in terms of clinical response, however the radiological response measured by the RECIST criteria underestimates benefits of this type of therapy in patients with progressive somatostatin receptor-positive midgut neuroendocrine carcinomas

Strong and Long-Lasting Antinociceptive and Anti-inflammatory Conjugate of Naturally Occurring Oleanolic Acid and Aspirin

The conjugate 8 was obtained as a result of condensation of 3-hydroxyiminooleanolic acid morfolide (7) and aspirin in dioxane. Analgesic effect of OAO-ASA (8) for the range of doses 0.3 – 300.0 mg/kg (p.o.) was performed in mice using a hot plate test. Anti-inflammatory activity was assessed on carrageenan-induced paw edema in rats for the same range of doses. The conjugate OAO-ASA (8) did not significantly change locomotor activity of mice, therefore sedative properties of the compound should be excluded. The compound 8 proved a simple, proportional, dose-dependent analgesic action and expressed strong anti-inflammatory activity showing a reversed U-shaped, dose-dependent relation with its maximum at 30.0 mg/kg. After its combined administration with morphine (MF, 5.0 mg/kg, s.c.) the lowering of antinociceptive activity was found; however, the interaction with naloxone (NL, 3.0 mg/kg, s.c.) did not affect the antinociceptive effect of OAO-ASA (8), therefore its opioid mechanism of action should be rather excluded. After combined administration with acetylsalicylic acid (ASA, 300.0 mg/kg, p.o.) in hot-plate test, the examined compound 8 enhanced the antinociceptive activity in significant way. It also shows that rather the whole molecule is responsible for the antinociceptive and anti-inflammatory effect of the tested compound 8, however it cannot be excluded that the summarizing effect is produced by ASA released from the compound 8 and the rest of triterpene derivative. The occurrence of tolerance for triterpenic derivative 8 was not observed, since the analgesic and anti-inflammatory effects after chronic administration of the conjugate OAO-ASA (8) was on the same level as after its single treatment. It seemed that the anti-inflammatory mechanism of action of OAO-ASA (8) is not simple, even its chronic administration lowered both blood concentration of IL-6 and mRNA IL-6 expression. However, the effects of the conjugate OAO-ASA (8) on TNF-α level and mRNA expression were opposite. Moreover, compound 8 did not change unequivocally mRNA TLR1, and TLR3 expression. Concluding, the obtained results regarding the antinociceptive and anti-inflammatory activity of new conjugate of oleanolic acid oxime and acetylsalicylic acid (OAO-ASA 8) are very interesting, but for explanation of its mechanism of action, more detailed studies are necessary

An observational study of the risk of neonatal macrosomia, and early gestational diabetes associated with selected candidate genes for type 2 diabetes mellitus polymorphisms in women with gestational diabetes mellitus

Objectives: 1) to analyse the prevalence of selected candidate genes for type 2 diabetes mellitus polymorphisms (IRS1 G972R; ENPP1 K121Q; ADRB3 W64R) among women with gestational diabetes; and 2) to investigate any association between variants of these genes and risk of neonatal macrosomia.Material and methods: We conducted a prospective observational study of a group of women (N = 140) in singleton pregnancies who delivered at term. Characteristics of the study group at enrolment: age: 32.0 ± 4.9 years; GA: 26.6 ± 7.5 weeks; HbA1c: 5.6 ± 0.6%; fasting blood glucose: 102.3 ± 16.3 mg/dL; insulin treatment (G2DM): 65.7%; chronic hypertension: 11.4%; gestational hypertension: 17.9%; preeclampsia: 1.4%; birth weight: 3590 ± 540 g; birth weight ≥ 4000 g (macrosomia): 18.6%; caesarean section: 44.3%; and female newborns: 57.1%.Results: The maternal metabolic characteristics at the time of booking did not differ between polymorphisms. Macrosomia was insignificantly more frequent in females (22.5%) than in males (13.3%) (p = 0.193). Only maternal height and body weight at the time of booking significantly predicted birth weight (R = 0.27, p = 0.007; R = 0.25, p = 0.005, respectively). IRS1 G972R GR and ENPP1 K121Q KQ polymorphisms were associated with an insignificantly increased risk for macrosomia. Carriers of the heterozygotic variant of the IRS 1 gene were significantly more likely to be diagnosed with GDM/DiP in the first trimester: OR 5.2, 95% CI: 1.4; 19.2; p = 0.014.Conclusions: 1) having similar metabolic characteristics, carriers of specific variants of T2DM candidate genes might be at increased risk of delivery of macrosomic newborns; 2) any association between genetic variants and macrosomia in this population might be gender-specific; and 3) allelic variation in the IRS1 gene is associated with early GDM/DiP

Afferent visual system damage after optic neuritis in MOG-IgG-seropositive versus AQP4-IgG-seropositive patients

Background Antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) have been reported in patients with aquaporin-4 antibody (AQP4-IgG)-negative neuromyelitis optica spectrum disorders (NMOSD). The objective of this study was to describe optic neuritis (ON)-induced neuro-axonal damage in the retina of MOG-IgG-positive patients in comparison with AQP4-IgG-positive NMOSD patients. Methods Afferent visual system damage following ON was bilaterally assessed in 16 MOG-IgG-positive patients with a history of ON and compared with that in 16 AQP4-IgG-positive NMOSD patients. In addition, 16 healthy controls matched for age, sex, and disease duration were analyzed. Study data included ON history, retinal optical coherence tomography, visual acuity, and visual evoked potentials. Results Eight MOG-IgG-positive patients had a previous diagnosis of AQP4-IgG-negative NMOSD with ON and myelitis, and eight of (mainly recurrent) ON. Twenty-nine of the 32 eyes of the MOG-IgG-positive patients had been affected by at least one episode of ON. Peripapillary retinal nerve fiber layer thickness (pRNFL) and ganglion cell and inner plexiform layer volume (GCIP) were significantly reduced in ON eyes of MOG- IgG-positive patients (pRNFL = 59 ± 23 μm; GCIP = 1.50 ± 0.34 mm3) compared with healthy controls (pRNFL = 99 ± 6 μm, p < 0.001; GCIP = 1.97 ± 0.11 mm3, p < 0.001). Visual acuity was impaired in eyes after ON in MOG-IgG-positive patients (0.35 ± 0.88 logMAR). There were no significant differences in any structural or functional visual parameters between MOG-IgG-positive and AQP4 -IgG-positive patients (pRNFL: 59 ± 21 μm; GCIP: 1.41 ± 0.27 mm3; Visual acuity = 0.72 ± 1.09 logMAR). Importantly, MOG-IgG-positive patients had a significantly higher annual ON relapse rate than AQP4-IgG-positive patients (median 0.69 vs. 0.29 attacks/year, p = 0.004), meaning that on average a single ON episode caused less damage in MOG-IgG-positive than in AQP4-IgG- positive patients. pRNFL and GCIP loss correlated with the number of ON episodes in MOG-IgG-positive patients (p < 0.001), but not in AQP4-IgG- positive patients. Conclusions Retinal neuro-axonal damage and visual impairment after ON in MOG-IgG-positive patients are as severe as in AQP4-IgG- positive NMOSD patients. In MOG-IgG-positive patients, damage accrual may be driven by higher relapse rates, whereas AQP4-IgG-positive patients showed fewer but more severe episodes of ON. Given the marked damage in some of our MOG-IgG-positive patients, early diagnosis and timely initiation and close monitoring of immunosuppressive therapy are important

99mTc-EDDA/HYNIC-octreotate - a new radiotracer for detection and staging of NET. A case of metastatic duodenal carcinoid

Somatostatin receptor scintigraphy (SRS) has become a routine imaging method for the diagnostics of neuroendocrine tumours (NET). 99mTc-EDDA/HYNIC-octreotate (Polatom, Poland) is a new radiotracer with high affinity for SSTR2 and similar physiological biodistribution to 111In-Octreoscan. We present a case of a 47-year-old man with disseminated duodenal carcinoid. The patient had been operated due to the tumour mass detected in pancreatic head area. Histopathology revealed carcinoid of the duodenal wall with local lymph node and liver metastases. The patient was qualified for chemotherapy stopped due to severe leucopenia. 99mTc EDDA/HYNIC-octreotate scintigraphy was performed for staging and to determine SSTR status of the tumour before planned 90Y-DOTATATE therapy. The multiple metastatic lesions were detected all over the body. The high quality images with high target/non target ratio were obtained. 99mTc-MDP scintigraphy confirmed multiple bone metastases. On the basis of SRS result the patient was qualified for 90Y-DOTA-TATE therapy. In conclusion, 99mTc EDDA/HYNIC-octreotate can be regarded as a promising tracer for staging and to determine SSTR status of NET

Screening for impact of popular herbs improving mental abilities on the transcriptional level of brain transporters

There are a number of compounds that can modify the activity of ATP-binding cassette (ABC) and solute carrier (SLC) transporters in the blood-brain barrier (BBB). The aim of this study was to investigate the effect of natural and synthetic substances on the expression level of genes encoding transporters present in the BBB (mdr1a, mdr1b, mrp1, mrp2, oatp1a4, oatp1a5 and oatp1c1). Our results showed that verapamil caused the greatest reduction in the mRNA level while other synthetic (piracetam, phenobarbital) and natural (codeine, cyclosporine A, quercetin) substances showed a selective inhibitory effect. Moreover, extract from roots of Panax ginseng C. A. Meyer exhibited a decrease of transcription against selected transporters whereas extract from Ginkgo biloba L. leaves resulted in an increase of the expression level of tested genes except for mrp2. Extract from aerial parts of Hypericum perforatum L. was the only one to cause an increased mRNA level for mdr1 and oatp1c1. These findings suggest that herbs can play an important role in overcoming the BBB and multidrug resistance against pharmacotherapy of brain cancer and mental disorders, based on the activity of selected drug-metabolizing enzymes and transporters located in the BBB

Efficacy and safety of 90Y-DOTATATE therapy in neuroendocrine tumours

Wstęp: Celem pracy była ocena skuteczności oraz toksyczności celowanej terapii receptorowej (PRRT) guzów neuroendokrynnych z wykorzystaniem analogu somatostatyny Tyr3-octreotate znakowanego 90Y (90Y-DOTATATE). Materiał i metody: Do badania włączono 46 pacjentów z rozsianym lub nieoperacyjnym guzem NET. 90Y-DOTATATE podawano w 3&#8211;5 kursach w odstępach 4&#8211;9-tygodniowych. Każdorazowo wyznaczano aktywność terapeutyczną, uwzględniając taką całkowitą powierzchnię ciała, by nie przekroczyć sumarycznej wartości 7,4 GBq/m2. Przed terapią i po niej wykonano oznaczenia parametrów morfotycznych, nerkowych oraz wątrobowych, a także stężenia chromograniny A. Wyniki: Spośród 46 leczonych pacjentów jeden chory zmarł przed zakończeniem pełnego cyklu terapeutycznego, a 16 po zakończeniu terapii, w tym jeden z powodu zawału serca. W 12. miesiącu obserwacji stwierdzono 47% stabilizacji, 31% częściowych odpowiedzi oraz 9% progresji wśród 45 pacjentów, którzy ukończyli leczenie. Pięciu chorych zmarło przed 12. miesiącem obserwacji. W jednym przypadku utracono możliwość uzyskania informacji o chorym po 12 miesiącach. Okres czasu bez progresji choroby wyniósł 37,4 miesiąca. W ciągu pierwszego roku od zakończenia terapii zaobserwowano jedynie przejściowe obniżenie wartości morfotycznych krwi oraz przejściowy wzrost stężenia kreatyniny i spadek wartości przesączania kłębuszkowego (GFR). Wnioski: Celowana terapia receptorowa z użyciem 90Y-DOTATATE może być skuteczną oraz stosunkowo bezpieczną metodą leczenia prowadzącą do częściowej odpowiedzi lub stabilizacji choroby u większości pacjentów. (Endokrynol Pol 2011; 62 (5): 392&#8211;400)Background: The aim of this study was to assess the efficacy and toxicity of peptide receptor radionuclide therapy (PRRT) with the use of the high affinity somatostatin receptor subtype 2 analogue, 90Y labelled Tyr3-octreotate, (90Y-DOTATATE) in neuroendocrine tumours (NETs). Material and methods: 46 patients with disseminated or non-operable NET were enrolled in this study. The 90Y-DOTATATE therapeutic activity was calculated per total body surface area up to a total of 7.4 GBq/m2 administered in three to five cycles, repeated every four to nine weeks. Before and after the therapy, blood tests for haematology, kidney and liver function, and chromogranin A were performed. Results: Out of 46 90Y-DOTATATE treated patients, one died before completing the therapy and 16 died after completing the therapy, among them one due to myocardial infarction. After 12 month follow-up, stabilisation of disease was observed in 47%, partial remission in 31%, and progression in 9% of the 45 patients who completed the therapy. Five patients died before completion of 12 months of follow-up. One of the patients died due to myocardial infarction. In one case, the information after 12 months is incomplete. The progression free survival was 37.4 months. During 12 months follow-up, transient decrease of PLT, WBC and haemoglobin values was observed. A transient increase of creatinine level (within normal ranges) and decrease of GFR values were found. Conclusions: NETs 90Y-DOTATATE therapy results in symptomatic relief and tumour mass reduction. The mild critical organ toxicity does not limit the PRRT of NETs. (Pol J Endocrinol 2011; 62 (5): 392&#8211;400

Deep learning enables spatial mapping of the mosaic microenvironment of myeloma bone marrow trephine biopsies

Bone marrow trephine biopsy is crucial for the diagnosis of multiple myeloma. However, the complexity of bone marrow cellular, morphological, and spatial architecture preserved in trephine samples hinders comprehensive evaluation. To dissect the diverse cellular communities and mosaic tissue habitats, we developed a superpixel-inspired deep learning method (MoSaicNet) that adapts to complex tissue architectures and a cell imbalance aware deep learning pipeline (AwareNet) to enable accurate detection and classification of rare cell types in multiplex immunohistochemistry images. MoSaicNet and AwareNet achieved an area under the curve of &amp;gt;0.98 for tissue and cellular classification on separate test datasets. Application of MoSaicNet and AwareNet enabled investigation of bone heterogeneity and thickness as well as spatial histology analysis of bone marrow trephine samples from monoclonal gammopathies of undetermined significance (MGUS) and from paired newly diagnosed and post-treatment multiple myeloma. The most significant difference between MGUS and newly diagnosed multiple myeloma (NDMM) samples was not related to cell density but to spatial heterogeneity, with reduced spatial proximity of BLIMP1+ tumor cells to CD8+ cells in MGUS compared with NDMM samples. Following treatment of multiple myeloma patients, there was a reduction in the density of BLIMP1+ tumor cells, effector CD8+ T cells, and T regulatory cells, indicative of an altered immune microenvironment. Finally, bone heterogeneity decreased following treatment of MM patients. In summary, deep-learning based spatial mapping of bone marrow trephine biopsies can provide insights into the cellular topography of the myeloma marrow microenvironment and complement aspirate-based techniques

Influence of the Melissa officinalis

Melissa officinalis (MO, English: lemon balm, Lamiaceae), one of the oldest and still most popular aromatic medicinal plants, is used in phytomedicine for the prevention and treatment of nervous disturbances. The aim of our study was to assess the effect of subchronic (28-fold) administration of a 50% ethanol extract of MO leaves (200 mg/kg, p.o.) compared with rosmarinic acid (RA, 10 mg/kg, p.o.) and huperzine A (HU, 0.5 mg/kg, p.o.) on behavioral and cognitive responses in scopolamine-induced rats. The results were linked with acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and beta-secretase (BACE-1) mRNA levels and AChE and BuChE activities in the hippocampus and frontal cortex of rats. In our study, MO and HU, but not RA, showed an improvement in long-term memory. The results were in line with mRNA levels, since MO produced a decrease of AChE mRNA level by 52% in the cortex and caused a strong significant inhibition of BACE1 mRNA transcription (64% in the frontal cortex; 50% in the hippocampus). However, the extract produced only an insignificant inhibition of AChE activity in the frontal cortex. The mechanisms of MO action are probably more complicated, since its role as a modulator of beta-secretase activity should be taken into consideration