Benign Brenner tumour of the ovary: CT and MRI features.

AIM: To evaluate the computed tomography (CT) and magnetic resonance imaging (MRI) features of benign Brenner tumours (BBT) of the ovary. MATERIAL AND METHODS: This was a retrospective two-centre study comprising 35 female patients with a definitive diagnosis of BBT at histology in whom CT and/or MRI examinations had been performed. Two experienced radiologists reviewed the CT and MRI features of 39 ovarian BBT retrospectively with consensus reading. The morphological appearance and size of each tumour were recorded. The presence or absence of calcifications within the solid portion was noted at CT. The reviewed characteristics at MRI included qualitative assessment of the signal intensity of the solid portion on diffusion sequence and contrast enhancement, compared to that of the myometrium. RESULTS: CT and MRI images were available for 27 and 28 lesions, respectively. Sixteen patients had both CT and MRI examinations. BBT were unilateral in 89% of patients, and 49% of lesions were solid and 51% were mixed. Calcifications were depicted at CT in 70.4% of lesions. When present, the cystic portion was multilocular in 85% of cases and corresponded to a mucinous lesion in 74% of cases. Enhancement of the solid portion at MRI was inferior or equal to that of the myometrium in 89% of cases and signal on high b-values diffusion images was deemed low or moderate in 93% of cases. CONCLUSION: The combined CT and MRI findings of a unilateral fibrous ovarian mass containing punctate calcifications often associated with a multilocular cyst suggest the diagnosis of ovarian BBT.

EFFICACY DATA OF CYANTRANILIPROLE CONTAINING INSECTICIDE PREPARATION ON CABBAGE ROOT FLY (DELIA RADICUM LINNAEUS) IN WINTER OILSEED RAPE.

The increasing pressure of oilseed rape pests emphasized the need to improve the insecticide portfolio, i.e. register new active ingredients with new insecticide mode of action. The tested seed treatment formulation applied at 32; 40 and 50 UAT rate of containing cyantraniliprole as active substance. 40 UAT rate gives acceptable control of the Cabbage root fly in each trial. Despite the long lasting flight and egg laying period of cabbage root fly, the standard control products and also this product give 50-65% efficacy. It is enough to reduce damage of the Cabbage root fly and prevent economical damage in oilseed rape.

[MORPHOLOGICAL CHANGES OF GASTRIC MUCOSA AFTER INSERTION OF INTRAGASTRIC BALLOON].

Morphological changes in gastric mucosa were studied, optimal terms of bariatric operations performance after intragastric balloon (IGB) insertion were determined. Before the IGB insertion in 10 (35.7%) patients, in accordance to histological investigations, the changes in gastric mucosa were not revealed, and in 18 (64.3%) - chronic gastritis was established. In accordance to endoscopic investigation results, immediately after the IGB removal in 23 (82.1%) patients a pronounced erythematous gastropathy was noted, and in 5 (17.9%) - erosive gastropathy. While investigating the gastric mucosa biopsies in all the patients a prominent inflammatory changes were revealed, including significant edema, pronounced lymphocytic infiltration. In accordance to esophagogastroduodenoscopy data on the 14-th day of endoscopic monitoring in 6 (21.4%) patients pathological changes of gastric mucosa were not revealed, in 22 (78.6 %) - erythematous gastropathy was noted, and in accordance to histological investigation - chronic gastritis. Persistence of IGB in gastric cavity during 6 mo caused a morphological changes in gastric mucosa - a significant inflammation, what was confirmed by endoscopic and histological investigations data. The gastric mucosa structure normalization was observed in 14 days after the IGB removal, that's why a radical bariatric intervention is recommended to perform not earlier the term established.

IL-17A-mediated sRANK ligand elevation involved in postmenopausal osteoporosis.

UNLABELLED: The role of proinflammatory IL-17 cytokine was studied in postmenopausal bone loss between 31 osteopenic and 41 osteoporotic women. The effect of serum IL-17A, soluble receptor activator of NF-κB (sRANK) ligand, and osteoprotegerin (OPG) levels on lumbar bone mineral densities was measured. The results demonstrated an increased IL-17A-mediated sRANK ligand elevation in postmenopausal osteoporotic bone loss. INTRODUCTION: IL-17 proinflammatory cytokine is a new inducer of bone loss. Postmenopausal osteoporosis represents a cross talk between estrogen deprivation and increased immune reactivity. The role of IL-17 was studied in the bone loss of postmenopausal osteoporosis. METHODS: Serum IL-17A, sRANK ligand, and OPG levels were investigated on bone mineral densities (BMDs) in the total lumbar (L1-L4) region in 18 pre- and 72 postmenopausal women. IL-17A, sRANK ligand, OPG levels, and BMDs were measured with enzyme-linked immunosorbent assay (ELISA) and dual-energy X-ray absorptiometry (DXA). RESULTS: Increased serum IL-17A, sRANK ligand, and OPG levels were demonstrated in postmenopausal osteoporotic women compared to osteopenic women (3.65 ± 0.61 vs 3.31 ± 0.43 ng/ml for IL-17A, P < 0.007; 2.88 ± 0.84 vs 2.49 ± 0.61 ng/ml for sRANK ligand, P < 0.027; and 1.43 ± 0.07 vs 1.39 ± 0.07 ng/ml for OPG, P < 0.038). In postmenopausal women, IL-17A levels correlated inversely with total lumbar BMDs (P < 0.008, r = -0.279) and positively with sRANK ligand levels (P < 0.0001, r = 0.387) or the ratio of sRANK ligand and OPG (P < 0.013, r = 0.261), but did not with OPG levels alone. CONCLUSION: Increased IL-17A levels are involved in postmenopausal osteoporosis, playing a role in the bone-resorpting processes.

Sorafenib tolerability in elderly patients with advanced renal cell carcinoma: results from a large pooled analysis.

BACKGROUND: Elderly patients tend to be underrepresented in renal cell carcinoma (RCC) clinical trials. The Sorafenib RCC Integrated Database includes data from six clinical trials and two expanded-access studies evaluating sorafenib monotherapy in >4600 patients with RCC. Using this database, sorafenib tolerability and treatment patterns were analysed according to age group (<55, 55-<65, 65-<75, or ≥ 75 years). METHODS: Dosing patterns, and incidence, prevalence and cumulative incidence of drug-related adverse events (DRAEs) and fatal DRAEs were assessed. RESULTS: Overall, 4684 patients were evaluable (<55 years, n=1126; 55-<65, n=1579; 65-<75, n=1382; ≥ 75, n=559). Treatment patterns were generally similar across subgroups, although sorafenib treatment duration was ∼30% shorter in the ≥ 75-years subgroup. There were no substantial differences in any-grade DRAEs with sorafenib between subgroups. Drug-related adverse events and dose modifications due to DRAEs tended to occur in months 0-3 and declined thereafter; there was no evidence of cumulative toxicity. Fatal DRAEs were rare (0.7% overall; 95% confidence interval, 0.5-1.0%). CONCLUSION: Sorafenib was well tolerated regardless of age in a heterogeneous population of RCC patients.

Cytomolecular identification of individual wheat-wheat chromosome arm associations in wheat-rye hybrids.

Chromosome pairing in the meiotic metaphase I of wheat-rye hybrids has been characterized by sequential genomic and fluorescent in situ hybridization allowing not only the discrimination of wheat and rye chromosomes, but also the identification of the individual wheat and rye chromosome arms involved in the chromosome associations. The majority of associations (93.8%) were observed between the wheat chromosomes. The largest number of wheat-wheat chromosome associations (53%) was detected between the A and D genomes, while the frequency of B-D and A-B associations was significantly lower (32 and 8%, respectively). Among the A-D chromosome associations, pairing between the 3AL and 3DL arms was observed with the highest frequency, while the most frequent of all the chromosome associations (0.113/cell) was found to be the 3DS-3BS. Differences in the pairing frequency of the individual chromosome arms of wheat-rye hybrids have been discussed in relation to the homoeologous relationships between the constituent genomes of hexaploid wheat.

Characterization of a new 4BS.7HL wheat-barley translocation line using GISH, FISH, and SSR markers and its effect on the ß-glucan content of wheat.

A spontaneous interspecific Robertsonian translocation was revealed by genomic in situ hybridization (GISH) in the progenies of a monosomic 7H addition line originating from a new wheat 'Asakaze komugi' × barley 'Manas' hybrid. Fluorescence in situ hybridization (FISH) with repetitive DNA sequences (Afa family, pSc119.2, and pTa71) allowed identification of all wheat chromosomes, including wheat chromosome arm 4BS involved in the translocation. FISH using barley telomere- and centromere-specific repetitive DNA probes (HvT01 and (AGGGAG)(n)) confirmed that one of the arms of barley chromosome 7H was involved in the translocation. Simple sequence repeat (SSR) markers specific to the long (L) and short (S) arms of barley chromosome 7H identified the translocated chromosome segment as 7HL. Further analysis of the translocation chromosome clarified the physical position of genetically mapped SSRs within 7H, with a special focus on its centromeric region. The presence of the HvCslF6 gene, responsible for (1,3;1,4)-ß-D-glucan production, was revealed in the centromeric region of 7HL. An increased (1,3;1,4)-ß-D-glucan level was also detected in the translocation line, demonstrating that the HvCslF6 gene is of potential relevance for the manipulation of wheat (1,3;1,4)-ß-D-glucan levels.

Toxicity and time lapse between immunotherapy and stereotactic radiotherapy of brain metastases.

PURPOSE: Stereotactic radiotherapy (SRT) is the standard treatment for brain metastases of non-small-cell lung cancer (NSCLC) and melanoma, mostly in combination with immunotherapy. The objective was to retrospectively evaluate the influence of the time-lapse between immunotherapy and stereotactic radiotherapy on toxicity. PATIENTS AND METHODS: From 2016 to 2019, 59 patients treated with SRT for 103 brain metastases of NSCLC (60%) and melanoma (40%) in combination with concomitant immunotherapy (≤30 days) were included. The prescribed dose was 20Gy/1f or 33Gy/3f at the isocentre and 14Gy or 23.1Gy (70%) respectively at the PTV envelope (PTV=GTV+2mm). The mean tumour diameter was 14mm (4-52mm). The immunotherapies used were anti-PD1 and anti-PDL1. The 103 metastases were classified into 3 groups according to the time-lapse between instatement of immunotherapy and instatement of SRT for the patient concerned: 7 (7%) in group A (≤7 days), 38 (37%) in group B (7 to 14 days) and 58 (56%) in group C (14 to 30 days). RESULTS: The mean follow-up was 10.1 months. The median overall survival was 11.5 months for NSCLC and 12.5 months for melanoma. The percentage of local control (LC) at one year was 65.1% (93.6% for NSCLC and 26.5% for melanoma). The time-lapse between immunotherapy and SRT was not a significant predictor of LC (P=0.86), while the histology was (P<0.001). The proportion of grade≥3 toxicities was 5.1%, and that of radionecrosis was 9.7% (among these patients, 80% were non-symptomatic): 0%, 13.1% and 8.6% for groups A, B and C respectively. The time-lapse between immunotherapy and SRT was not a significant predictor of toxicity. Only tumour volume was a significant predictive factor (P=0.03). CONCLUSION: The time lapse between immunotherapy and SRT does not influence brain toxicity. The tumour volume remains the main factor.

Phase 1 trial of ralimetinib (LY2228820) with radiotherapy plus concomitant temozolomide in the treatment of newly diagnosed glioblastoma.

BACKGROUND AND PURPOSE: This phase 1 trial aimed to determine the maximum tolerated dose (MTD; primary objective) of a p38-MAPK inhibitor, ralimetinib, with radiotherapy (RT) and chemotherapy (TMZ), in the treatment of newly diagnosed glioblastoma (GBM) patients. MATERIALS AND METHODS: The study was designed as an open-label dose-escalation study driven by a Tite-CRM design and followed by an expansion cohort. Ralimetinib was administered orally every 12 h, 7 days a week, for 2 cycles of 2 weeks at a dose of 100, 200 or 300 mg/12 h. Patients received ralimetinib added to standard concurrent RT (60 Gy in 30 fractions) with TMZ (75 mg/m2/day) and 6 cycles of adjuvant TMZ (150-200 mg/m2 on days 1-5 every 28 days). RESULTS: The MTD of ralimetinib was 100 mg/12 h with chemoradiotherapy. The three patients treated at 200 mg/12 h presented a dose-limiting toxicity: one patient had a grade 3 face edema, and two patients had a grade 3 rash and grade 3 hepatic cytolysis (66%). Of the 18 enrolled patients, 15 received the MTD of ralimetinib. At the MTD, the grade ≥ 3 adverse events during concomitant chemoradiotherapy were hepatic cytolysis (2/15 patients), dermatitis/rash (1/15), lymphopenia (1/15) and nausea/vomiting (1/15). No interaction of TMZ and ralimetinib when administrated concomitantly has been observed. Inhibition of pMAPKAP-K2 (-54%) was observed in peripheral blood mononuclear cells. CONCLUSION: This phase 1 trial is the first trial to study the combination of a p38-MAPK inhibitor, ralimetinib, with radiotherapy (RT) and chemotherapy (TMZ), in the treatment of newly diagnosed glioblastoma (GBM) patients. The MTD of ralimetinib was 100 mg/12 h. The most frequent dose-limiting toxicities were hepatic cytolysis and rash.

Control of experimental diabetes mellitus in rats by transplantation of fetal pancreases.

Experimental diabetes mellitus in young adult Lewis rats was successfully treated by transplantation of fetal pancreases from syngeneic fetuses. Complete or partial control lasting up to 165 days was achieved in 64 percent of recipients by using two to three pancreases of fetal age (15 to 18(1/2) days) placed under each kidney capsule. Islets of Langerhans without exocrine elements were present in the transplants.

Complete reversal of experimental diabetes mellitus in rats by a single fetal pancreas.

Complete reversal of streptozotocin-induced diabetes mellitus in adult rats will follow transplantation of a single fetal pancreas if the organ is first grown in a normal syngeneic carrier before transfer to the diabetic recipient. Careful control of the blood sugar of diabetic recipients may enhance the function of a single donor organ and thus improve histocompatibility matching.

Physical mapping of a 7A.7D translocation in the wheat-Thinopyrum ponticum partial amphiploid BE-1 using multicolour genomic in situ hybridization and microsatellite marker analysis.

The absence of chromosome 7D in the wheat-Thinopyrum ponticum partial amphiploid BE-1 was detected previously by multicolour genomic in situ hybridization, sequential FISH (fluorescence in situ hybridization) using repetitive DNA probes, and SSR marker analysis. In the present study the previous cytogenetic and SSR marker analyses were expanded to include 25 other SSR markers assigned to wheat chromosomes 7A and 7D to confirm the presence of a 7A.7D translocation and to specify its composition. An almost complete chromosome 7A and a short chromosome segment derived from the terminal region of 7DL were detected, confirming the presence of a terminal translocation involving the distal regions of 7AL and 7DL. In both cases the position of the translocation breakpoint was different from that of known deletion lines. The identification of the 7AL.7DL translocation and its breakpoint position provides a new physical landmark for future physical mapping studies, opening up the possibility of more precise localization of genes or molecular markers within the terminal regions of 7DL and 7AL.

Automated UHPLC separation of 10 pharmaceutical compounds using software-modeling.

Human mistakes are still one of the main reasons of underlying regulatory affairs that in a compliance with FDA's Data Integrity and Analytical Quality by Design (AQbD) must be eliminated. To develop smooth, fast and robust methods that are free of human failures, a state-of-the-art automation was presented. For the scope of this study, a commercial software (DryLab) and a model mixture of 10 drugs were subjected to testing. Following AQbD-principles, the best available working point was selected and conformational experimental runs, i.e. the six worst cases of the conducted robustness calculation, were performed. Simulated results were found to be in excellent agreement with the experimental ones, proving the usefulness and effectiveness of an automated, software-assisted analytical method development.

Importance of hepatic portal circulation for insulin action in streptozotocin-diabetic rats transplanted with fetal pancreases.

The importance of the hepatic portal circulation in the response to insulin was assessed in streptozotocin-diabetic rats transplanted with syngeneic fetal pancreases. Partial reversal of diabetes was accomplished by transplantation of two or three fetal pancreases beneath the capsule of the kidney; complete reversal followed shunting of the venous drainage from the transplants to the liver. Plasma glucose after streptozotocin of 509+/-31 mg/dl (mean+/-SEM) fell after transplantation to 395+/-23 and after the shunt to 143+/-5 mg/dl. Urine volume fell from 84+/-4 to 50+/-5 ml/d and then to normal (17+/-1 ml/d) after the shunt. Glucose excretion which was 8.1+/-0.3 g/d after streptozotocin fell after transplantation to 4.8+/-0.3 g/d and after the shunt completely disappeared from the urine. The disappearance rate of glucose injected into the circulation, which was 0.50+/-0.07%/min in untreated diabetes, increased to 1.39+/-0.38%/min after transplantation and to 2.52+/-0.31%/min after the shunt, not different from normal controls (2.79+/-0.25). Plasma immunoreactive insulin (IRI) was below normal (25-35 muU/ml) and unresponsive to glucose in untreated diabetic rats. After transplantation IRI levels ranged from 73-223 muU/ml and there was no rise after glucose injection. After the shunt both the basal IRI (36+/-5 muU/ml) and the peak response to glucose at 10 min (58+/-7 muU/ml) were the same as in normal controls (42+/-4 and 62+/-7 muU/ml, respectively). The fall in IRI after the shunt is explained by increased extraction of insulin passing into the liver and also diminished secretion. After removal of the transplants plasma glucose and urine values returned almost to pretransplant levels. Secretion of insulin by transplanted pancreases into the liver enhances the effectiveness probably by increased extraction and action and reveals the importance of the normal route for insulin delivery.

Population Pharmacokinetics of Liposomal Irinotecan in Patients With Cancer.

Nanoliposomal irinotecan (nal-IRI) is a liposomal formulation of irinotecan with a longer half-life (t1/2 ), higher plasma total irinotecan (tIRI), and lower SN-38 maximum concentration (Cmax ) compared with nonliposomal irinotecan. Population pharmacokinetic (PK) analysis of nal-IRI was performed for tIRI and total SN-38 (tSN38) using patient samples from six studies. PK-safety association was evaluated for neutropenia and diarrhea in 353 patients. PK-efficacy association was evaluated from a phase III study in pancreatic cancer NAPOLI1. Efficacy was associated with longer duration of unencapsulated SN-38 (uSN38) above a threshold and higher Cavg of tIRI, tSN38, and uSN38. Neutropenia was associated with uSN38 Cmax and diarrhea with tIRI Cmax . Baseline predictive factors were race, body surface area, and bilirubin. Analysis identified PK factors associated with efficacy, safety, and predictive baseline factors. The results support the benefit of nal-IRI dose of 70 mg/m2 (free-base; equivalent to 80 mg/m2 salt base) Q2W over 100 mg/m2 Q3W.

Glyburide-stimulated glucose transport in cultured muscle cells via protein kinase C-mediated pathway requiring new protein synthesis.

To study the mechanism of action of sulfonylurea agents on peripheral tissues without the potentially confounding influences of insulin, the direct effect of glyburide (i.e., in the absence of insulin) was evaluated in the L6 cultured myogenic cell line. Glyburide approximately doubled the incorporation of [14C]-glucose into glycogen. The rate-determining enzymes of glycogen metabolism, glycogen synthase and glycogen phosphorylase, were unaffected by the drug. Glucose transport (2-deoxyglucose uptake) was also approximately doubled. The phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) also doubled glucose transport and showed the same lag period (4-6 h) as glyburide before an effect occurred. Blockade of protein kinase C activity by either 1-(5-isoquinolinesulfonyl)-2 methyl piperazine (H7) or chronic exposure to TPA completely abolished the stimulation by glyburide. Cycloheximide, a protein synthesis inhibitor, also completely eliminated the effect of glyburide. The presence of ATP-sensitive K+ channels was assessed by measuring 86Rb efflux in ATP-depleted L6 muscle cells and RINm5F cells (which served as a positive control). Such channels were present and responded appropriately to glyburide and diazoxide in pancreatic beta-cells but were not present in muscle cells. Glyburide stimulation of glucose transport was completely eliminated by both Quin 2, an intracellular chelator of Ca2+, and verapamil, a Ca2+ channel blocker. However, glyburide did not raise intracellular Ca2+ levels. We conclude that glyburide stimulates glucose transport in cultured L6 muscle cells by a protein kinase C-mediated pathway that requires new protein synthesis. Although intracellular Ca2+ metabolism may also be involved, the initial step in the mechanism of action is probably different between pancreatic beta-cells and muscle cells.

Fetal pancreas transplantation for reversal of streptozotocin-induced diabetes in rats.

Streptozotocin-induced diabetes in rats was completely reversed by transplantation of syngeneic fetal pancreases placed beneath the kidney capsule. To accomplish complete reversal of diabetes, four or more pancreases were necessary; three resulted in partial reversal, and two produced a slight but significant effect in some recipients. Removal of the transplants resulted in the prompt return of diabetes. The islets of Langerhans in the transplants functioned homeostatically; this was indicated by regular normal blood glucose values, in addition to normal findings in blood IRI response and glucose disappearance rate after glucose injection. Disappearance of exocrine elements, with only ducts and fibrous tissue remaining, resulted in a pure endocrine organ. The advantages of this technie, such as ease of accessibility for placement, observation, and removal, are of great importance for possible application to humans.

The biosynthetic gene cluster for the microtubule-stabilizing agents epothilones A and B from Sorangium cellulosum So ce90.

BACKGROUND: Epothilones are produced by the myxobacterium Sorangium cellulosum So ce90, and, like paclitaxel (Taxol((R))), they inhibit microtubule depolymerisation and arrest the cell cycle at the G2-M phase. They are effective against P-glycoprotein-expressing multiple-drug-resistant tumor cell lines and are more water soluble than paclitaxel. The total synthesis of epothilones has been achieved, but has not provided an economically viable alternative to fermentation. We set out to clone, sequence and analyze the gene cluster responsible for the biosynthesis of the epothilones in S. cellulosum So ce90. RESULTS: A cluster of 22 open reading frames spanning 68,750 base pairs of the S. cellulosum So ce90 genome has been sequenced and found to encode nine modules of a polyketide synthase (PKS), one module of a nonribosomal peptide synthetase (NRPS), a cytochrome P450, and two putative antibiotic transport proteins. Disruptions in the genes encoding the PKS abolished epothilone production. The first PKS module and the NRPS module are proposed to co-operate in forming the thiazole heterocycle of epothilone from an acetate and a cysteine by condensation, cyclodehydration and subsequent dehydrogenation. The remaining eight PKS modules are responsible for the elaboration of the rest of the epothilone carbon skeleton. CONCLUSIONS: The overall architecture of the gene cluster responsible for epothilone biosynthesis has been determined. The availability of the cluster should facilitate the generation of designer epothilones by combinatorial biosynthesis approaches, and the heterologous expression of epothilones in surrogate microbial hosts.

Beneficial effect of pentoxifylline on thyroid associated ophthalmopathy (TAO)*: a pilot study.

We have previously found that pentoxifylline (Ptx) inhibited cytokine induced HLA-DR expression and glycosaminoglycan (GAG) synthesis by retroorbital fibroblasts. We have now tested the clinical efficacy of Ptx in treating TAO. Ten patients with moderately severe ophthalmopathy were selected for study. All patients were euthyroid before and during the 12 weeks of the Ptx therapy. Serum GAG, TNF-alpha, anti-TSH-receptor, anti-eye muscle, anti-thyroglobulin and anti-thyroid peroxidase antibodies were determined sequentially. At the end of 12 weeks eight of the ten patients showed improvement in soft tissue but not in proptosis or extraocular muscle involvement. At baseline the levels of GAG (5.2+/-0.92 mg/dl v.s. 0.7+/-0.14 mg/dl, p<0.001) and TNF-alpha (33.6+/-6.6 pg/ml v.s. 5.4+/-1.3 pg/ml, p<0.001) were increased in patients compared to controls. They gradually decreased in the eight patients who responded to Ptx: after 4, 8 and 12 weeks of therapy serum GAG was 3.4+/-0.42 mg/dl, 2.5+/-0.77 mg/dl (p<0.01) and 1.1+/-0.2 mg/dl (p<0.001), respectively and serum TNF-alpha was 20.9+/-4.8 pg/ml, 14.9+/-2.2 pg/ml (p<0.05) and 9.7+/-1.8 pg/ml (p<0.01), respectively. Serum GAG and TNF alpha did not fall in the two patients who did not respond. The titre of anti-eye muscle antibodies but not anti-thyroid antibodies were lower at 12 weeks. Ptx has a beneficial effect on inflammatory symptoms of TAO and associated laboratory parameters in the majority of patients.