A phase 1b/2b multicenter study of oral panobinostat plus azacitidine in adults with MDS, CMML or AML with ⩽30% blasts.

Treatment with azacitidine (AZA), a demethylating agent, prolonged overall survival (OS) vs conventional care in patients with higher-risk myelodysplastic syndromes (MDS). As median survival with monotherapy is <2 years, novel agents are needed to improve outcomes. This phase 1b/2b trial (n=113) was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of panobinostat (PAN)+AZA (phase 1b) and evaluate the early efficacy and safety of PAN+AZA vs AZA monotherapy (phase 2b) in patients with higher-risk MDS, chronic myelomonocytic leukemia or oligoblastic acute myeloid leukemia with <30% blasts. The MTD was not reached; the RP2D was PAN 30 mg plus AZA 75 mg/m2. More patients receiving PAN+AZA achieved a composite complete response ([CR)+morphologic CR with incomplete blood count+bone marrow CR (27.5% (95% CI, 14.6-43.9%)) vs AZA (14.3% (5.4-28.5%)). However, no significant difference was observed in the 1-year OS rate (PAN+AZA, 60% (50-80%); AZA, 70% (50-80%)) or time to progression (PAN+AZA, 70% (40-90%); AZA, 70% (40-80%)). More grade 3/4 adverse events (97.4 vs 81.0%) and on-treatment deaths (13.2 vs 4.8%) occurred with PAN+AZA. Further dose or schedule optimization may improve the risk/benefit profile of this regimen.

Increased Lipocalin 2 level may have important role in thrombotic events in patients with polycythemia vera and essential thrombocythemia.

The aim of our study was to evaluate the possible effect of lipocalin 2 on thrombotic events in polycythemia vera and essential thrombocythemia patients. The samples of 89 patients were collected and RNA based method was used to evaluate the relative gene expression level of lipocalin 2. 74 samples were available for evaluation. Drawing a cut off point at level 30 relative expression rate, 13 patients with elevated lipocalin 2 expression had thrombotic events during the course of their disease. Based on these data high lipocalin 2 expression level seems to have strong positive predictive value on thrombotic events in patients with polycythemia vera and essential thrombocythemia. Lipocalin 2 may be useful in thrombotic risk stratification in these patients.

The existence of lymphoid lineage restricted Philadelphia chromosome-positive acute lymphoblastic leukemia with heterogeneous bcr-abl rearrangement.

Analysis of lineage involvement was performed in 17 Philadelphia chromosome-positive acute lymphoblastic leukemia patients with no history of chronic myeloproliferative disorder. The percentage of blastic cells as defined by flow cytometry matched that of the Ph-positive cells in 14 out of 17 patients. The bcr-abl rearrangement was investigated by fluorescent in situ hybridization in morphologically identified blastic cells, myeloid elements, lymphocytes and erythroblasts using a combined light and fluorescent microscopical imaging. Lymphoid lineage restriction could be determined in all but three of the patients. These 14 patients exhibited heterogeneity in terms of m-bcr and M-bcr types of translocation as revealed by reverse transcription polymerase chain reaction. The three patients with multilineage involvement and M-bcr type of translocation reverted to chronic phase and the percentage of Ph-positive cells remained high. Thus, we could identify an uncommitted stem cell origin among Ph-positive ALLs only in those patients whose disease subsequently proved to be a lymphoid blastic crisis with clinically silent chronic phase.

An open multicentre comparative study of the efficacy, safety and tolerance of fluconazole and itraconazole in the treatment of cancer patients with oropharyngeal candidiasis.

Oropharyngeal candidiasis is a frequent infection in cancer patients who receive cytotoxic drugs. In this study, the efficacy, safety and tolerance of fluconazole and itraconazole were compared in non-neutropenic cancer patients with oropharyngeal candidiasis. Of 279 patients who were randomised between the two treatment groups, 252 patients were considered to be eligible (126 in each group). The clinical cure rate was 74% for fluconazole and 62% for itraconazole (P=0.04, 95% Confidence Interval (CI): 0.5-23.3%). The mycological cure rate was 80% for fluconazole and 68% for itraconazole (P=0.03, 95% CI: 1.2-22.6%). The safety and tolerance profile of both drugs were comparable. This study has shown that in patients with cancer and oropharyngeal candidiasis, fluconazole has a significantly better clinical and mycological cure rate compared with itraconazole.

Photosensitization in ducklings induced by seeds of Cymopterus watsonii and C. longipes.

For 14 days ducklings were fed seeds of Cymopterus watsonii or C. longipes at 100 mg, 500 mg, or 2 g/kg of body weight and exposed to sunlight. Those fed C. longipes at 500 mg showed transient photosensitization. C. watsonii at 2 g induced mild photosensitization at 8 days, with consequent beak deformity and little apparent effect on the birds' health. C. longipes at 2 g induced acute photosensitization within 3 days, with consequent severe damage to the skin of the head, beak, footwebs, and legs. These birds showed extreme stunting within 8 days of first ingesting the seeds, and several weeks later were still very retarded, with severely deformed beaks and footwebs. One bird in this group died at 22 days.

Photosensitizing effects of Cymopterus watsonii and Cymopterus longipes in chickens and turkey poults.

Two-week-old straight-run white broiler chicks and 2-week-old straight-run white turkey poults were fed seed or whole plants Cymopterus watsonii or seed of Cymopterus longipes at 0.4, 0.8, and 1.6% of body weight, and then placed in sunlight for 5 hours each day for 7 days. All plant material produced moderate to severe photosensitivity in chicks. Toxic signs included photophobia; red discoloration of beak, comb, and feet; loss of feathers in the periorbital area; dried serous fluid on comb and edge of beak; keratoconjunctivitis; and multiple lesions on feet and legs. Turkey poults showed a syndrome similar to that of chicks. Mortality was particularly high in turkeys fed C. longipes seed. Toxic signs in turkeys 6 weeks after treatment included tremors in the legs; upturning and shortening of the upper beak; and shortening disfigurement, and gangrene of the toes. Two phototoxic furocoumarins, oxypeucedanin and isoimperitorin, were isolated from C. longipes seed. Either compound, administered orally, produced photosensitivity in 2-week-old chicks.

The susceptibility of young chickens, ducks, and turkeys to the photosensitizing effect of Ammi visnaga seeds.

Young chickens, ducks, and turkeys were exposed to sunlight and fed various amounts of Ammi visnaga seeds for 14 days in an attempt to induce photosensitization. In chickens, seeds at 1.25% in the diet had no effect whereas 3% induced mild signs of photosensitization within 6 to 8 days. No visible effects resulted in ducklings from 1.5, 3 and 6% in the diet, or in turkey poults from 3%. These differences appear to be due to differences between these avian species in the metabolism of the photodynamic agent.

Efficacy of pralidoxime iodide and obidoxime dichloride as antidotes in diazinon-poisoned goslings.

The antidotal efficacy of pralidoxime iodide and obidoxime dichloride was investigated in goslings poisoned by a supralethal dose of the organophosphorus insecticide diazinon. Various doses of both drugs were administered by intramuscular injection when the poisoned birds were unable to walk. Pralidoxime at 100 mg/kg brought about a complete and speedy clinical recovery. Fifty mg/kg induced recovery in 4 of 6 poisoned goslings, and 25 mg/kg successfully trated only 1 of 6 birds. Obidoxime at 25 mg/kg showed no therapeutic properties whereas 50 and 100 mg/kg delayed the death of some birds by several hours. At 100 mg/kg, all goslings had transient signs of intoxication, which precluded the use of this compound as an antidote at higher doses. The mode of action of these antidotes in diazinon-poisoned goslings is discussed.

Effect of tiamulin administered by various methods and dosages on turkeys at different ages.

Healthy male turkeys not receiving monensin in their feed were treated with tiamulin by various methods and at different ages. Nine cycles of treatments were performed at the ages of 26, 40, 61, 89, 103, 117, 131, 145, and 160 days. Intramuscular of subcutaneous injections of 12.5 mg/kg tiamulin up to 145 days did not result in any signs of toxicity or impair growth rate. Administration at a dose of up to 25 mg/kg, using the drinking-water-deprivation technique, caused no effect in turkeys up to 160 days (marketing age).

Chronic lesions in geese photosensitized by Ammi majus.

Chronic lesions of the beak, footweb, and eye of geese photosensitized by the comsumption of Ammi majus (L.) are described, 7 weeks after the acute symptoms commenced. Sixty-four (48%) of the 133 birds in the flock showed various degrees of abnormality. All affected birds had stunting of the upper beak and cicatrization and thickening of the footweb. Eighty-nine percent of the affected birds showed ocular involvement, comprising chemosis, blepharoconjunctivitis, keratitis, symblepharon, ankyloblepharon, cicatricial ectropium, and mydriasis.

Stability of prothrombin times in sheep dosed with natural and synthetic anticoagulants.

Sheep were dosed with natural and synthetic anticoagulants to prolong prothrombin time (PT) in the one stage PT test. The stability of subsequent values of PT of up to 40 seconds was measured at various times over a 24 hour period in plasma and whole blood stored at 0, 20 and 30 degrees C, representing ideal to unsuitable conditions of sample preparation and storage. In contrast to cautions in the literature, the various treatments had little influence on PT. These findings should encourage the use of PT in field diagnosis and research in sheep by surmounting the tenet of the difficulty in effectively preserving blood samples for PT determinations.

Fluoroacetamide (1081) oisoning in wild birds.

An outbreak of poisoning in four greylag geese (Anser anser) and 35-45 teal (Anas crecca) is described. Laboratory findings led to the conclusion that a wheat bait containing the rodenticide fluoracetamide (1081) caused the poisoning. Circumstantial evidence incriminated fluoracetamide as the cause of death in white-fronted geese (Anser albifrons), mallards (Anas platyrhynchos), and chukars (Alectoris chukar).

The efficacy of acetamide for the treatment of experimental Dichapetalum cymosum (gifblaar) poisoning in sheep.

High mortality of livestock is caused annually by the plant, Dichapetalum cymosum (gifblaar), in the Northern Transvaal. So far no therapeutic measures have been developed for the prevention or treatment of this poisoning. In this presentation, the efficacy of acetamide as therapy for experimental gifblaar poisoning was tested in 18 sheep. When 2.5-5 g/kg of acetamide was dosed to sheep at various intervals before and sometimes after the administration of 5 g/kg of gifblaar, 1 out of 5 survived, compared with 0 out of 2 controls. Dosing of 2 g/kg of acetamide before and/or simultaneously with or after 1 g/kg gifblaar prevented mortality as 5 out of 5 treated sheep survived compared with none of the 5 controls. The experiments indicate that acetamide has demonstrable therapeutic value as an antidote for the prevention of experimental gifblaar poisoning in sheep. Further investigations should determine the feasibility and applicability of these findings under field conditions in sheep and cattle.

Acute and chronic manifestations of Ammi majus induced photosensitisation in ducks.

The acute and chronic symptoms seen in ducks following Ammi majus induced photosensitisation are described. The acute changes were inflammatory in nature whereas the chronic changes included severe deformities of the beak and footwebs, mydriasis and eccentric location of the pupil.

Hepatic cirrhosis suggesting aflatoxicosis in a flock of geese.

An outbreak of hepatic cirrhosis in a flock of young geese was investigated. The affected geese were cyanotic with purple beaks, shanks and footwebs. On post mortem examination severe atrophy of the liver was seen and, histologically, extensive areas of necrosis, cirrhosis and bile duct proliferation were prominent. Liver function tests and serum enzyme levels confirmed that the liver damage was extensive. The findings are compared with those found in aflatoxicosis of other avian species.

The effect of tiamulin administered by different routes and at different ages to turkeys receiving monensin in their feed.

Healthy turkeys receiving 80 ppm monensin in their feed were injected at 26, 40 and 61 days of age with tiamulin at dosages of 12.5 and 25 mg/kg body weight. The aim of the study was to develop a regime for medicating with tiamulin turkeys receiving monensin in their feed, and which would circumvent the known toxicity created by the simultaneous administration of the two drugs. One injection of 12.5 mg/kg tiamulin up to the age of 61 days or 2 injections of 12.5 mg/kg tiamulin up to 40 days of age caused no mortality or adverse reaction.

A comparative physical evaluation of four X-ray films.

In this study, four general purpose radiographic films (Agfa Gevaert Curix RP-1, duPont Cronex 4, Fuji RX, and Kodak XRP-1) were compared using three independent techniques. By examining the characteristic curves for the four films, film speed and contrast were compared over the diagnostically useful density range. These curves were generated using three methods: (1) irradiation of a standard film cassette lined with high-speed screens, covered by a twelve-step aluminum wedge; (2) direct exposure of film strips to an electro-luminescent sensitometer; and (3) direct irradiation of a standard film cassette lined with high-speed screens. The latter technique provided quantitative values for film speed and relative contrast. All three techniques provided virtually properly identical results and indicate that under properly controlled conditions simplified methods of film testing can give results equivalent to those obtained by more sophisticated techniques.

[Effect of retinoic acid on the cytogenetic remission in the first chronic phase of chronic myeloid leukemia treated with interferon]. / Retinsav hatása a citogenetikai remisszióra krónikus myeloid leukaemia interferonnal kezelt elsó krónikus fázisában.

Cytogenetic responses of 11 chronic myeloid leukemic (CML) patients during the first chronic phase, treated with the combination of all-trans retinoic acid (ATRA) + interferon (IFN) were compared to 9 other CML patients of phase one, treated with interferon monotherapy. Metaphase and interphase cytogenetics and a semiquantitative polymerase chain reaction (PCR) were used to evaluate the cytogenetic responses. Two of the 11 patients in the ATRA + interferon treated group were withdrawn, one of them because of interferon intolerance, and the other because of compliance failure. Among the 9 ATRA + interferon treated patients 6 major cytogenetic responses could be detected and 3 of them were complete. Of the 9 patients treated with IFN monotherapy only 2 major cytogenetic responses could be registered. No severe adverse effects were observed. The first results suggest that the ATRA + interferon combination may be superior in achieving cytogenetic remission in the first chronic phase of CML.

[Successful treatment of hepatocellular carcinoma with All-trans-retinoic acid]. / Hepatocellularis carcinoma eredményes All-transz-retinsav kezelése.

A 44-year-old female patient was admitted to our department with diagnosis of malignant lymphoma. The abdominal USG and CT showed multiple liver lesions with partial portal vein thrombosis, moderately increased alfa-fetoprotein (AFP), ASAT, ALAT (2x normal value), serology was negative for HBV and HCV. Liver transplantation was suggested but refused because of portal vein thrombosis. ATRA (45 mg/m2/day orally) was given on the basis of the assumption that HCC and acute promyelocytic leukaemia share similar oncogenic pathway (alter the RAR alpha and beta receptors). She was gained 15 kg-s and has resumed her work as a teacher for the last 20 months. Abdominal CT showed a complete regression of the intrahepatic tumour.

[Detection of minimal residual diseases in B-cell tumors using PCR specific for the immunoglobulin heavy chain gene]. / A minimális reziduális betegség kimutatása B-sejtes tumorok esetében az immunglobulin nehézlánc génre specifikus polimeráz láncreakció segítségével.

In B-cell non-Hodgkin's lymphomas (NHL), clonal rearrangement of the immunoglobulin heavy chain (IgH) gene provides a useful marker for the detection of minimal residual disease (MRD) after treatment. To explore clinical usefulness of polymerase chain reaction (PCR) analysis of clonal IgH gene rearrangement in the detection of MRD a follow up study of 10 patients with B-cell NHL have been performed. At the time of diagnosis, tumor DNAs were PCR-amplified using sense primer specific for the heavy chain variable region (VH) and antisense primer specific for the heavy chain joining region (JH) of the IgH gene. The clonal rearrangement of IgH gene detected by PCR was used as clonal marker to determine MRD after treatment. In three cases, where clinical remission was not achieved, clonal IgH gene rearrangement was detected after the treatment. In seven cases, clinical remission was achieved after induction therapy but the PCR analysis revealed clonal IgH gene rearrangement in three of the cases. In all of the three cases, where MRD was detected by PCR, clinical relapse developed after 7-28 months of the therapy. In all cases that have relapsed, the IgH gene rearrangement was identical at the time of initial diagnosis and at the relapse. This study demonstrates that PCR analysis of clonal IgH gene rearrangement is a useful method to monitor and detect MRD before clinical relapse.