Therapeutic applications of germline testing for cancer predisposition genes in Asia in the real world.

BACKGROUND: Germline genetic testing is traditionally carried out in patients suspected with hereditary cancer syndrome for enhanced cancer surveillance and/or preventive strategies, but is increasingly carried out for therapeutic indications. MATERIALS AND METHODS: We conducted a retrospective review of patients who underwent germline genetic testing at our centre to determine the prevalence of actionable pathogenic germline variants (PGV) and their clinical utility. RESULTS: From 2000 to 2022, 1154 cancer patients underwent germline testing, with the majority (945/1154) tested with multi-gene panels. Four hundred and eleven (35.6%) patients harboured a PGV and 334 (81%) were clinically actionable. BRCA1/2 accounted for 62.3% of actionable mutations, followed by mismatch repair (18%), and other homologous recombination repair (HRR) genes (19.7%). One hundred and fifty-two germline-positive patients have advanced cancers, and 79 received germline-directed therapies (poly ADP ribose polymerase inhibitors = 75; immunotherapy = 4). Median duration of immunotherapy and poly ADP ribose polymerase were 20.5 months (range 5-40 months) and 8 months (range 1-76 months), respectively. Among BRCA/HRR mutation carriers who received platinum-based chemotherapy, pathological complete response rate in the neoadjuvant setting was 53% (n = 17 breast cancers) and objective response rate was >80% in the advanced setting (n = 71). CONCLUSIONS: One-third of cancer patients tested carried a PGV and ∼80% were clinically actionable. Three-quarters of germline-positive advanced cancer patients received germline-directed therapies in the real world, underscoring the practical utility of germline testing to guide cancer therapeutics.

Endothelium-Independent Vasodilatory Effect of Sailuotong (SLT) on Rat Isolated Tail Artery.

BACKGROUND: Sailuotong (SLT) is a standardized three-herb formulation consisting of extracts of Panax ginseng, Ginkgo biloba, and Crocus sativus for the treatment of vascular dementia (VaD). Although SLT has been shown to increase cerebral blood flow, the direct effects of SLT on vascular reactivity have not been explored. This study aims to examine the vasodilatory effects of SLT and the underlying mechanisms in rat isolated tail artery. METHODS: Male (250-300 g) Wistar Kyoto (WKY) rat tail artery was isolated for isometric tension measurement. The effects of SLT on the influx of calcium through the cell membrane calcium channels were determined in Ca2+-free solution experiments. RESULTS: SLT (0.1-5,000 µg/ml) caused a concentration-dependent relaxation in rat isolated tail artery precontracted by phenylephrine. In the contraction experiments, SLT (500, 1,000, and 5,000 µg/mL) significantly inhibited phenylephrine (0.001 to 10 µM)- and KCl (10-80 mM)-induced contraction, in a concentration-dependent manner. In Ca2+-free solution, SLT (500, 1,000, and 5,000 µg/mL) markedly suppressed Ca2+-induced (0.001-3 mM) vasoconstriction in a concentration-dependent manner in both phenylephrine (10 µM) or KCl (80 mM) stimulated tail arteries. L-type calcium channel blocker nifedipine (10 µM) inhibited PE-induced contraction. Furthermore, SLT significantly reduced phenylephrine-induced transient vasoconstriction in the rat isolated tail artery. CONCLUSION: SLT induces relaxation of rat isolated tail artery through endothelium-independent mechanisms. The SLT-induced vasodilatation appeared to be jointly meditated by blockages of extracellular Ca2+ influx via receptor-gated and voltage-gated Ca2+ channels and inhibition of the release of Ca2+ from the sarcoplasmic reticulum.

Prediction of motivational impairment: 12-month follow-up of the randomized-controlled trial on extended early intervention for first-episode psychosis.

BACKGROUND: Amotivation is prevalent in first-episode psychosis (FEP) patients and is a major determinant of functional outcome. Prediction of amotivation in the early stage of psychosis, however, is under-studied. We aimed to prospectively examine predictors of amotivation in FEP patients in a randomized-controlled trial comparing a 1-year extension of early intervention (Extended EI, 3-year EI) with step-down psychiatric care (SC, 2-year EI). METHODS: One hundred sixty Chinese patents were recruited from a specialized EI program for FEP in Hong Kong after they have completed this 2-year EI service, randomly allocated to Extended EI or SC, and followed up for 12 months. Assessments on premorbid adjustment, onset profiles, baseline symptom severity and treatment characteristics were conducted. Data analysis was based on 156 subjects who completed follow-up assessments. RESULTS: Amotivation at 12-month follow-up was associated with premorbid adjustment, allocated treatment condition, and levels of positive symptoms, disorganization, amotivation, diminished expression (DE) and depression at study intake. Hierarchical multiple regression analysis revealed that Extended EI and lower levels of DE independently predicted better outcome on 12-month amotivation. CONCLUSION: Our findings indicate a potentially critical therapeutic role of an extended specialized EI on alleviating motivational impairment in FEP patients. The longer-term effect of Extended EI on amotivation merits further investigation.

Validation of a microdose probe drug cocktail for clinical drug interaction assessments for drug transporters and CYP3A.

A microdose cocktail containing midazolam, dabigatran etexilate, pitavastatin, rosuvastatin, and atorvastatin has been established to allow simultaneous assessment of a perpetrator impact on the most common drug metabolizing enzyme, cytochrome P450 (CYP)3A, and the major transporters organic anion-transporting polypeptides (OATP)1B, breast cancer resistance protein (BCRP), and MDR1 P-glycoprotein (P-gp). The clinical utility of these microdose cocktail probe substrates was qualified by conducting clinical drug interaction studies with three inhibitors with different in vitro inhibitory profiles (rifampin, itraconazole, and clarithromycin). Generally, the pharmacokinetic profiles of the probe substrates, in the absence and presence of the inhibitors, were comparable to their reported corresponding pharmacological doses, and/or in agreement with theoretical expectations. The exception was dabigatran, which resulted in an approximately twofold higher magnitude for microdose compared to conventional dosing, and, thus, can be used to flag a worst-case scenario for P-gp. Broader application of the microdose cocktail will facilitate a more comprehensive understanding of the roles of drug transporters in drug disposition and drug interactions.

Transporters affecting biochemical test results: Creatinine-drug interactions.

Creatinine is eliminated by the kidneys through a combination of glomerular filtration and active transport. Drug-induced increases in serum creatinine (SCr) and/or reduced creatinine renal clearance are used as a marker for acute kidney injury. However, inhibition of active transport of creatinine can result in reversible and, therefore, benign increases in SCr levels. Herein, the transporters involved in creatinine clearance are discussed, in addition to limitations of using creatinine as a biomarker for kidney damage.

Poster - Thur Eve - 58: The clinical significance of couch top modeling in VMAT and IMRT treatment planning.

In recent years, carbon fibre couch tops have become popular in radiation therapy with marketed attributes such as high tensile strength, light weight, and relative radiotranslucence. We have performed a detailed analysis of the iBEAM evo couch top using two models created in the Pinnacle v9.0 treatment planning system. The first model is a single ROI, and its thickness and shape was determined based on attenuation factor measurements in cylindrical phantoms. The second model is a thin shell made of two ROIs with exact outer dimensions as the real couch top. The couch top attenuation was found to range from 2% to 6.5% for a 6 MV beam energy. The two models were found to match the attenuation factor measurements to within 4.2% and 1.7%, respectively. The clinical impact of the couch top models was examined in 4 VMAT and 4 IMRT prostate plans by comparing mean and maximum point doses, DVHs, and measurements (VMAT plans only) using Gamma analysis. A very small, but clinically insignificant difference was observed between the two couch top models for both VMAT and IMRT plans. The lack of a couch top model in treatment planning was also examined and found to result in ∼ 1% average underdose to the PTV. This study suggests that the iBEAM evo couch top is relatively radiotranslucent for typical VMAT and IMRT delivery as long as the number of control points with extremely oblique beam angles is relatively small.

Evaluation of the first commercial Monte Carlo dose calculation engine for electron beam treatment planning.

The purpose of this study is to perform a clinical evaluation of the first commercial (MDS Nordion, now Nucletron) treatment planning system for electron beams incorporating Monte Carlo dose calculation module. This software implements Kawrakow's VMC++ voxel-based Monte Carlo calculation algorithm. The accuracy of the dose distribution calculations is evaluated by direct comparisons with extensive sets of measured data in homogeneous and heterogeneous phantoms at different source-to-surface distances (SSDs) and gantry angles. We also verify the accuracy of the Monte Carlo module for monitor unit calculations in comparison with independent hand calculations for homogeneous water phantom at two different SSDs. All electron beams in the range 6-20 MeV are from a Siemens KD-2 linear accelerator. We used 10,000 or 50,000 histories/cm2 in our Monte Carlo calculations, which led to about 2.5% and 1% relative standard error of the mean of the calculated dose. The dose calculation time depends on the number of histories, the number of voxels used to map the patient anatomy, the field size, and the beam energy. The typical run time of the Monte Carlo calculations (10,000 histories/cm2) is 1.02 min on a 2.2 GHz Pentium 4 Xeon computer for a 9 MeV beam, 10 x 10 cm2 field size, incident on the phantom 15 x 15 x 10 cm3 consisting of 31 CT slices and voxels size of 3 x 3 x 3 mm3 (total of 486,720 voxels). We find good agreement (discrepancies smaller than 5%) for most of the tested dose distributions. We also find excellent agreement (discrepancies of 2.5% or less) for the monitor unit calculations relative to the independent manual calculations. The accuracy of monitor unit calculations does not depend on the SSD used, which allows the use of one virtual machine for each beam energy for all arbitrary SSDs. In some cases the test results are found to be sensitive to the voxel size applied such that bigger systematic errors (>5%) occur when large voxel sizes interfere with the extensions of heterogeneities or dose gradients because of differences between the experimental and calculated geometries. Therefore, user control over voxelization is important for high accuracy electron dose calculations.

Dose measurement based on spectral chi-square minimization using GAFchromic MD-55 film.

A new method of measuring dose using GAFchromic MD-55-2 type film is proposed. It involves 2D fitting of optical density, as a function of both wavelength and dose, to a set of measured calibration data. An unknown dose to a film can then be determined by minimizing the chi-square between the measured optical densities and the fitted calibration data. The methodology was tested, using 60Co calibration, by measuring the dose deposited in films irradiated by a 32p source in a semi-infinite geometry. The results are compared with the expected dose obtained From beta counting, taking into account the dose loss correction due to various attenuating materials, including the film substrate itself, which was determined to be 20%. It was found that the root mean relative deviation between the measured and expected doses was approximately 3%. The excellent agreement also demonstrated the possibility of calibration between gamma and beta particles.

Early correction of severe unilateral infant ptosis with the Mersilene mesh sling.

Ten consecutive cases of severe unilateral congenital ptosis were surgically corrected before 1 year of age (range 3-11 months) in an attempt to achieve early functional and cosmetic improvement. In all cases, a frontalis suspension using Mersilene mesh was performed. With a mean follow-up of 40.3 months (range 33-54 months), all patients achieved normal or near normal eyelid position and all had their chin-up head posture resolved. One patient developed a mild exposure keratitis that was treated successfully with topical antibiotics and lubricants. Our findings suggest that the Mersilene mesh sling has good potential for ptosis management in infants who are too young for fascial harvesting. However, a larger series with a longer follow-up period is required before the eventual safety and efficacy of the Mersilene mesh sling can be properly ascertained.

Congenital cystic eye with multiple ocular and intracranial anomalies.

We describe a newborn with congenital cystic eye, contralateral persistent hyperplastic primary vitreous, and cerebrocutaneous abnormalities. The cerebrocutaneous abnormalities consisted of agenesis of the corpus callosum, midbrain deformity, malformed sphenoid bone, right upper eyelid coloboma, and a left periocular hamartoma. The results of karyotype analysis of the patient and his parents were normal. The association of congenital cystic eye with contralateral persistent hyperplastic primary vitreous has not been previously reported, to our knowledge. Although no unifying diagnosis exists for the collection of anomalies demonstrated in this patient, the term cranial ectodermopathy broadly classifies most of the defects.

Prismatic scanning method for improving visual acuity in patients with low vision.

Frequently, patients with macular lesions and others who are visually handicapped do not receive adequate low vision care by ophthalmologists if a routine trial of low vision aids has no gratifying results. This paper describes for the first time a technique in which functional vision was achieved with the aid of prismatic scanning in patients for whom the usual low vision aids had proved ineffectual. The procedure in which prisms are used to achieve functional vision in patients with macular lesions in uncomplicated, inexpensive, and rapid; indeed, it can be used by an ophthalmologist in routine office practice with existing equipment.

Juvenile xanthogranuloma.

Juvenile xanthogranuloma (JXG) is a disease of unknown etiology and pathogenesis which was first recognized by dermatologists. The ocular complications provide the primary concern and notably affect the iris, producing spontaneous hemorrhages in the anterior chamber. Secondary glaucoma and blindness are real threats unless the condition is recognized in the early stages and satisfactory treatment instituted. Other ocular manifestations include epibulbar lesions with corneal involvement and proptosis due to orbital lesions of JXG.

Post-traumatic ophthalmic vein arterialization.

An unusual case of post-traumatic exophthalmos without pulsation, bruit or thrill, due to missile injury is presented. Arterialization of the ophthalmic vein represents one of the very few situations where an eye injury can lead to exsanguination and dealth unless the diagnosis is made early. Prompt carotid arteriography is advised to document the pathologic process and guide appropriate therapy.