Canadian Consensus for Biomarker Testing and Treatment of TRK Fusion Cancer in Pediatric Patients

Neurotrophic tyrosine receptor kinase gene fusions (NTRK) are oncogenic drivers present at a low frequency in most tumour types (<5%), and at a higher frequency (>80%) in a small number of rare tumours (e.g., infantile fibrosarcoma [IFS]) and considered mutually exclusive with other common oncogenic drivers. Health Canada recently approved two tyrosine receptor kinase (TRK) inhibitors, larotrectinib (for adults and children) and entrectinib (for adults), for the treatment of solid tumours harbouring NTRK gene fusions. In Phase I/II trials, these TRK inhibitors have demonstrated promising overall response rates and tolerability in patients with TRK fusion cancer who have exhausted other treatment options. In these studies, children appear to have similar responses and tolerability to adults. In this report, we provide a Canadian consensus on when and how to test for NTRK gene fusions and when to consider treatment with a TRK inhibitor for pediatric patients with solid tumours. We focus on three pediatric tumour types: non-rhabdomyosarcoma soft tissue sarcoma/unspecified spindle cell tumours including IFS, differentiated thyroid carcinoma, and glioma. We also propose a tumour-agnostic consensus based on the probability of the tumour harbouring an NTRK gene fusion. For children with locally advanced or metastatic TRK fusion cancer who have either failed upfront therapy or lack satisfactory treatment options, TRK inhibitor therapy should be considered.     

In vitro screen of a small molecule inhibitor drug library identifies multiple compounds that synergize with oncolytic myxoma virus against human brain tumor-initiating cells

Background

Brain tumor-initiating cells (BTICs) are stem-like cells hypothesized to form a disease reservoir that mediates tumor recurrence in high-grade gliomas. Oncolytic virotherapy uses replication-competent viruses to target and kill malignant cells and has been evaluated in clinic for glioma therapy with limited results. Myxoma virus (MyxV) is a safe and highly effective oncolytic virus (OV) in conventional glioma models but, as seen with other OVs, is only modestly effective for patient-derived BTICs. The objective of this study was to determine whether MyxV treatment against human BTICs could be improved by combining chemotherapeutics and virotherapy.

Methods

A 73-compound library of drug candidates in clinical use or preclinical development was screened to identify compounds that sensitize human BTICs to MyxV treatment in vitro, and synergy was evaluated mathematically in lead compounds using Chou-Talalay analyses. The effects of combination therapy on viral gene expression and viral replication were also assessed.

Results

Eleven compounds that enhance MyxV efficacy were identified, and 6 were shown to synergize with the virus using Chou-Talalay analyses. Four of the synergistic compounds were shown to significantly increase viral gene expression, indicating a potential mechanism for synergy. Three highly synergistic compounds (axitinib, a VEGFR inhibitor; rofecoxib, a cyclooxygenase-2 inhibitor; and pemetrexed, a folate anti-metabolite) belong to classes of compounds that have not been previously shown to synergize with oncolytic viruses in vitro.

Conclusions

This study has identified multiple novel drug candidates that synergistically improve MyxV efficacy in a preclinical BTIC glioma model.     

Episcleral plaque brachytherapy using 'BARC I-125 Ocu-Prosta seeds' in the treatment of intraocular tumors: a single-institution experience in India

Context:

To analyze the results of episcleral plaque brachytherapy using indigenous Bhabha Atomic Research Centre (BARC) Iodine-125 Ocu-Prosta seeds for the management of intraocular tumors from a single institute.

AIM:

To report our initial experience and learning curve on the use of ‘BARC I-125 Ocu-Prosta seeds’ for the management of intraocular tumors such as choroidal melanomas, retinoblastomas and vasoproliferative tumors (VPT).

Materials and Methods:

We retrospectively reviewed 13 eyes of 13 patients who underwent ophthalmic brachytherapy between May 2008 to March 2012. Nine cases had choroidal melanomas; three had retinoblastomas while one case had VPT.

Results:

For choroidal melanomas the average apical diameter before brachytherapy was 7.6 mm and average largest basal diameter was 12.1 mm, respectively, which reduced to 4.2 mm and 7.7 mm after the procedure at an average follow-up of 24 months (range 10-43 months). Retinoblastoma and VPT also showed good regression after brachytherapy.

Conclusion:

Plaque radiotherapy using ¹²⁵I seeds can be performed under peribulbar anesthesia and provides a viable option for the management of intraocular cancer with minimal invasiveness and surgical complications. Patients in our studies experienced excellent local tumor control. With the availability of indigenous ‘BARC I-125 Ocu-Prosta seeds’ locally, cost effective ophthalmic brachytherapy can be performed in India.     

Knowledge,awareness and attitude of eye donation among non-clinical staff of a tertiary eye hospital in South India

Purpose:This study aimed to evaluate the knowledge, awareness and attitude of eye donation among non-clinical staff of tertiary eye hospitals and to convey a positive attitude toward eye donation by enhancing their awareness and knowledge.Methods:An online cross-sectional study was conducted among the non-clinical staff from all centers of a tertiary eye care hospital across Tamil Nadu. Quiz link was emailed to non-clinical staff of all the centers. On completion of the quiz, the participants viewed their respective scores and the correct answers to all questions. This activity was presumed to subsequently improve their knowledge and clear up the myths on eye donation.Results:Two hundred twenty-eight non-clinical staff from 11 hospitals participated in the quiz. Mean age was 35.3 ± 9.8 years and 130 were female staff (57.05%). One hundred eighty-one participants (79.39%) scored over 50% of the total 17 queries. One hundred eighty-six (81.58%) and 142 (62.28%) participants scored over 50% in the awareness section and knowledge section, respectively. Eye bank volunteers (73, 32.02%) were the main source of information. Twenty-four (10.53%) had already taken pledge for eye donation and 175 (76.75%) were willing to pledge, 29 (12.72%) were not willing to pledge. Twenty-two out of these 29 (75.86%) had no specific reason for not pledging. Family, religious reasons, lack of clarity and fear were least cited reasons (13.79%).Conclusion:Non-clinical staff of an eye hospital are easily approachable and are expected to be more knowledgeable by the general public around them. They might act as primary motivators in raising awareness within their family, friends, relatives and neighbors.     

Characterization of brain-reactive autoantibodies in murine models of systemic lupus erythematosus

Using the Western blot technique we analyzed the sera of five strains of mice that develop a disease like systemic lupus erythematosus (SLE), along with two normal strains, for their binding specificities against isolated mouse integral brain membrane proteins. This report describes the distribution and frequency of the more than 200 brain-reactive autoantibodies in the 126 animals tested and verifies the hypothesis of diversity in anti-brain antibodies produced during autoimmune conditions such as SLE. These results emphasize the importance of characterizing the brain-reactive autoantibodies in the sera or cerebrospinal fluid of SLE patients with central nervous system involvement.     

Is it necessary to use three mandatory loading doses when commencing therapy for neovascular age-related macular degeneration using bevacizumab? (BeMOc Trial)

Purpose

To determine whether a Pro Re Nata (PRN) regimen with three initial mandatory loading doses results in better functional and anatomical outcome compared with a PRN regimen without initial loading when using intravitreal bevacizumab in patients with minimal classic or occult choroidal neovascularisation secondary to age-related macular degeneration.

Methods

Patients were randomised (1 : 1) to Loading (LD group) or No Loading (NLD group) and treated with open label intravitreal bevacizumab. In the LD group, patients received two mandatory doses after the baseline dose before entering the PRN phase and in the NLD group, patients did not receive mandatory doses after the baseline dose. Six-weekly evaluations were performed up to week 54 and retreatment was done based on OCT criteria. Visual stability and reduction in central retinal thickness were compared between groups.

Results

49 patients were in the NLD group and 50 patients were in the LD group. At the 12-month end point, 84% of the patients in the LD group achieved visual stability (<15 letter loss) compared with 67% of the patients in the NLD group (P<0.05). The mean reduction in central macular thickness was 105.35 μm in the LD group and 81.45 μm in the NLD group (P>0.05). There was no significant difference in scores of VFQ-25 questionnaire testing between the two groups and no serious ocular or systemic side effects were observed.

Conclusion

The results supported our hypothesis that a loading dose leads to slightly better visual stability in terms of proportions of patients experiencing moderate visual loss, but did not support the hypothesised difference in anatomical outcome.     

Polo-like kinase 1 inhibition kills glioblastoma multiforme brain tumor cells in part through loss of SOX2 and delays tumor progression in mice

Glioblastoma multiforme (GBM) ranks among the deadliest types of cancer and given these new therapies are urgently needed. To identify molecular targets, we queried a microarray profiling 467 human GBMs and discovered that polo-like kinase 1 (PLK1) was highly expressed in these tumors and that it clustered with the proliferative subtype. Patients with PLK1-high tumors were more likely to die from their disease suggesting that current therapies are inactive against such tumors. This prompted us to examine its expression in brain tumor initiating cells (BTICs) given their association with treatment failure. BTICs isolated from patients expressed 110-470 times more PLK1 than normal human astrocytes. Moreover, BTICs rely on PLK1 for survival because the PLK1 inhibitor BI2536 inhibited their growth in tumorsphere cultures. PLK1 inhibition suppressed growth, caused G(2) /M arrest, induced apoptosis, and reduced the expression of SOX2, a marker of neural stem cells, in SF188 cells. Consistent with SOX2 inhibition, the loss of PLK1 activity caused the cells to differentiate based on elevated levels of glial fibrillary acidic protein and changes in cellular morphology. We then knocked glial fibrillary acidic protein (GFAP) down SOX2 with siRNA and showed that it too inhibited cell growth and induced cell death. Likewise, in U251 cells, PLK1 inhibition suppressed cell growth, downregulated SOX2, and induced cell death. Furthermore, BI2536 delayed tumor growth of U251 cells in an orthotopic brain tumor model, demonstrating that the drug is active against GBM. In conclusion, PLK1 level is elevated in GBM and its inhibition restricts the growth of brain cancer cells.