Translational insights into gastrointestinal stromal tumor and current clinical advances.

Gastrointestinal stromal tumor (GIST) is the most common soft tissue sarcoma of the gastrointestinal tract and, in the vast majority of cases, is characterized by activating mutations in KIT or, less commonly, PDGFRA. Mutations in these type III receptor tyrosine kinases (RTKs) account for over 85% of GIST cases, and the majority of KIT primary mutations respond to treatment with the tyrosine kinase inhibitor (TKI) imatinib. However, drug resistance develops over time, most commonly due to secondary kinase mutations. Sunitinib and regorafenib are approved for the treatment of imatinib-resistant GIST in the second and third lines, respectively. However, resistance to these agents also develops and new therapeutic options are needed. In addition, a small number of GISTs harbor primary activating mutations that are resistant to currently available TKIs, highlighting an additional unmet medical need. Several novel and selective TKIs that overcome known mechanisms of resistance in GIST have been developed and show promise in early clinical trials. Additional emerging targeted therapies in GIST include modulation of cellular signaling pathways downstream of KIT, antibodies targeting KIT and PDGFRA and immune checkpoint inhibitors. These advancements highlight the rapid evolution in the understanding of this malignancy and provide perspective on the encouraging horizon of current and forthcoming therapeutic strategies for GIST.

High resolution genetic and physical mapping of the I-3 region of tomato chromosome 7 reveals almost continuous microsynteny with grape chromosome 12 but interspersed microsynteny with duplications on Arabidopsis chromosomes 1, 2 and 3.

The tomato I-3 gene introgressed from the Lycopersicon pennellii accession LA716 confers resistance to race 3 of the fusarium wilt pathogen Fusarium oxysporum f. sp. lycopersici. We have improved the high-resolution map of the I-3 region of tomato chromosome 7 with the development and mapping of 31 new PCR-based markers. Recombinants recovered from L. esculentum cv. M82 x IL7-2 F2 and (IL7-2 x IL7-4) x M82 TC1F2 mapping populations, together with recombinants recovered from a previous M82 x IL7-3 F2 mapping population, were used to position these markers. A significantly higher recombination frequency was observed in the (IL7-2 x IL7-4) x M82 TC1F2 mapping population based on a reconstituted L. pennellii chromosome 7 compared to the other two mapping populations based on smaller segments of L. pennellii chromosome 7. A BAC contig consisting of L. esculentum cv. Heinz 1706 BACs covering the I-3 region has also been established. The new high-resolution map places the I-3 gene within a 0.38 cM interval between the molecular markers RGA332 and bP23/gPT with an estimated physical size of 50-60 kb. The I-3 region was found to display almost continuous microsynteny with grape chromosome 12 but interspersed microsynteny with Arabidopsis thaliana chromosomes 1, 2 and 3. An S-receptor-like kinase gene family present in the I-3 region of tomato chromosome 7 was found to be present in the microsyntenous region of grape chromosome 12 but was absent altogether from the A. thaliana genome.

Fine mapping of the tomato I-3 gene for fusarium wilt resistance and elimination of a co-segregating resistance gene analogue as a candidate for I-3.

The I-3 gene from the wild tomato species Lycopersicon pennellii confers resistance to race 3 of the devastating vascular wilt pathogen Fusarium oxysporum f. sp. lycopersici. As an initial step in a positional cloning strategy for the isolation of I-3, we converted restriction fragment length polymorphism and conserved orthologue set markers, known genes and a resistance gene analogue (RGA) mapping to the I-3 region into PCR-based sequence characterised amplified region (SCAR) and cleaved amplified polymorphic sequence (CAPS) markers. Additional PCR-based markers in the I-3 region were generated using the randomly amplified DNA fingerprinting (RAF) technique. SCAR, CAPS and RAF markers were used for high-resolution mapping around the I-3 locus. The I-3 gene was localised to a 0.3-cM region containing a RAF marker, eO6, and an RGA, RGA332. RGA332 was cloned and found to correspond to a putative pseudogene with at least two loss-of-function mutations. The predicted pseudogene belongs to the Toll interleukin-1 receptor-nucleotide-binding site-leucine-rich-repeat sub-class of plant disease resistance genes. Despite the presence of two RGA332 homologues in L. esculentum, DNA gel blot and PCR analysis suggests that no other homologues are present in lines carrying I-3 that could be alternative candidates for the gene.

Examining the adequacy of quantities available for subsidized antidepressant prescriptions in Australia.

In Australia the Pharmaceutical Benefits Scheme (PBS), a national drug insurance plan, aims to provide around a month's therapy for medication used in chronic conditions. However, there are marked differences among the most commonly used antidepressants in the number of days supply represented by the PBS maximum quantity after adjustment for the defined daily dose (DDD). The DDD is the assumed adult daily dose for a drug and is a WHO drug utilization standard. Whereas the selective serotonin re-uptake inhibitors (SSRIs) and moclobemide largely provide around a month's supply at the DDD, most tricyclic antidepressant (TCA) items provide considerably less than this .A patient tracking study was conducted to determine the average length of time between prescription re-supplies for a number of tricyclic antidepressants and newer antidepressants as a means of measuring the efficiency of PBS supply for the different classes of antidepressant. The number of days between dispensings was similar for patients no matter whether they were taking TCAs, SSRIs or moclobemide, although for the older antidepressants presumably at a much lower prescribed daily dose than the DDD. Care needs to be taken when adjusting usage with the DDD/1000/day unit of measurement in cases where the DDD does not reflect the prescribed daily dose (PDD).

Ocular and dermal irritation studies of some quaternary ammonium compounds.

The primary ocular and dermal irritations of four quaternary ammonium compounds, namely cetylpyridinium chloride (CPC), stearylphenylethyldimethylammonium tosylate (SPDAT), dimethyldistearylammonium bisulfate (DDABS) and tri(N-butyl)benzylammonium 4-hydroxynapththalene-1-sulfonate (TBAHNS), were studied. Both CPC and SPDAT were extremely or severely irritating to the eyes of the test animals, whereas DDABS and TBAHNS were mildly or minimally irritating. Both CPC and SPDAT were also severely or extremely irritating to the skin of the test animals, while DDABS and TBAHNS were non-irritating. These quaternary ammonium compounds have little similarity in chemical structure and possess different solubilities. CPC is very soluble in both lipid and water; SPDAT is very soluble in lipid but only slightly soluble in water; and DDABS and TBAHNS are poorly soluble in either lipid or water. The irritancy of these compounds is likely to be related to their solubility, in addition to the cationic characteristics. It appears that not all quaternary ammonium compounds in this study are irritants. Those that are not soluble are not expected to be absorbed in eye/skin tissues and thus irritation reactions will not take place. The use of in vitro alternatives should be considered when assessing the ocular and dermal irritancy potential of water- and lipid-soluble quaternary ammonium compounds.

Effective treatment of Tourette's syndrome with marijuana.

A single case report is described where marijuana appears to have been an effective treatment modality for symptoms of Tourette's syndrome. Other possible treatment modalities are excluded. It is concluded that there is a need for further work examining the interactions between marijuana, nicotine and the symptomatology of Tourette's syndrome.

The nontraditional use of commercial advertising in prescriber education.

The availability of prescribing guidelines for antibiotics stimulated audits of antibiotic use in Melbourne hospitals. Following such audits, an advertising campaign to change prescribing was conducted at The Royal Melbourne Hospital. The success of this pilot study prompted a wider campaign to examine the power of marketing techniques in influencing prescribing. The Therapeutics Committee of the Victorian Medical Postgraduate Foundation (VMPF-TC) was established to administer this project and to undertake promotional activities. The Victorian Drug Usage Advisory Committee, which was established to advise the Minister for Health on matters relating to drug usage in public hospitals, recommended that posters be used in hospitals to promote rational and cost-effective drug therapy. The VMPF-TC was asked to prepare posters for sale to hospitals on the basis that economies of scale could make it financially viable. Oral rather than parenteral administration of antibiotics was chosen as the theme for the first poster.

Changing antibiotic prescribing by educational marketing.

A controlled cross-over study in 12 Victorian public hospitals was performed to examine the power of marketing techniques in influencing prescribing. The targeted prescribing behaviour was the use of antibiotic prophylaxis in surgery, and the criteria for judging the appropriateness of therapy were its duration and timing, as are detailed in the fourth edition of the booklet Antibiotic guidelines. The first intervention was mounted in 1985 in six hospitals (two metropolitan teaching hospitals, one suburban general hospital and three rural hospitals), and six matched hospitals acted as control hospitals. One year later, the intervention was mounted in the six hospitals that previously had been the control hospitals. The interventional campaign consisted of material that was similar to that which is used by the pharmaceutical industry, including an "academic" representative. Its effect was assessed by audits that were performed before and after the first interventional campaign and again, one year later, after the second interventional campaign. The proportion of antibiotic courses that were assessed as satisfactory in terms of duration increased significantly after the first campaign in the hospitals where the intervention was mounted. No significant changes in prescribing occurred in the control hospitals. In the hospitals which were control hospitals in 1985, and in which the intervention occurred in 1986, the proportion of antibiotic courses that were assessed as satisfactory also increased significantly after the interventional campaign. A fall-off in performance occurred during the 12 months after the campaign in the 1985-interventional hospitals. Calculated cost savings more than outweighed the costs of the campaign. We conclude that inappropriate prescribing behaviour in hospitals can be modified successfully by educational marketing techniques.

Educational antibiotic advertising.

Antibiotic audits that were conducted within our hospital between 1978 and 1982 showed persisting patterns of inappropriate antibiotic use. A commercial advertising agency was commissioned to plan a campaign to change entrenched prescribing habits. Amoxycillin was chosen as the test drug because previous audits consistently had shown that its intravenous administration was prescribed more frequently than was that of benzylpenicillin in the treatment of primary pneumonia. In addition, amoxycillin given by mouth was prescribed six-hourly rather than eight-hourly in one-third of the patients who were surveyed. A three-month remedial campaign used direct mail (pads and pens), display stands and posters, all of which focused on the booklet Antibiotic guidelines. Educational material was placed wherever staff members congregated. At the end of the campaign, intravenously administered amoxycillin was used in only 8% of 50 patients with primary pneumonia and amoxycillin given by mouth was prescribed six-hourly in only 10% of 99 patients. These changed habits were sustained six months after the campaign but showed some fall-off 18 months after the campaign. The campaign costs of $10,000 were recouped within 12 months by savings on drug costs. It is concluded that educational advertising is an effective means of changing prescribing behaviour in a hospital.

Use of antibiotic agents in a large teaching hospital. The impact of Antibiotic Guidelines.

Three surveys of antibiotic use have been conducted at The Royal Melbourne Hospital. The first was conducted in 1978, before the introduction of the booklet, Antibiotic Guidelines; the second was conducted eight months after, and the most recent, four years after, its distribution. In 1978, 30% of 563 patients surveyed were receiving antibiotic therapy; this proportion declined to 28% of 967 patients studied in 1982. At the beginning of 1978, 52% of all treatments audited were judged appropriate when compared with those recommended in the Guidelines; this proportion rose to 72% in the second survey and was maintained at 70% in 1982. Certain inappropriate prescribing patterns persisted, such as the use of amoxycillin for the treatment of primary pneumonia, surgical antibiotic prophylaxis which was started too late, and the failure to simplify therapy when the results of microbiological investigations became available. Antibiotic guidelines facilitate the auditing of antibiotic usage and aid rational prescribing. Nevertheless, additional measures appear necessary if specific patterns of misuse of antibiotic agents are to be corrected.

Comprehension of therapy by non-English speaking hospital patients.

A survey was made of 1,832 patients who attended the Outpatients' Pharmacy of The Royal Melbourne Hospital during a five-day period. We identified 280 patients who did not speak English as their native tongue; of these 257 (90%) answered a series of questions asked by a pharmacist. An interpreter was essential for communication with 73 of the 257, yet only 31 had been previously classified as requiring an interpreter. Sixty-five per cent of the sample had a good knowledge of drug doses, frequency and drug function. Of the remaining 90, 39 were uncertain of the correct dose, 38 could not state the function and 13 knew neither function nor dose. The proportion of poorly informed patients varied significantly between clinics. Although it is routine practice to place cautionary labels on medication containers, only 78% of the patients had knowledge of these special warnings. Many patients were accompanied by friends or children who spoke some English; however, their translations were sometimes inaccurate and misleading. To improve communication with non-English speaking patients, more trained interpreters should be available in the hospital.