Research Spotlight

Daoud, E.V., Patel, A., Gagan, J., Raisanen, J.M., Snipes, G.J., Mantilla, E., Krothapally, R., Hatanpaa, K.J. and Pan, E. (2021). “Spinal Cord Pilocytic Astrocytoma With FGFR1-TACC1 Fusion and Anaplastic Transformation.” J Neuropathol Exp Neurol 80(3): 283-285.

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Pilocytic astrocytoma (PA) is a WHO grade 1 primary neoplasm that accounts for ∼5.4% of all gliomas, occurs predominantly in childhood and adolescence, and usually arises in the cerebellum or cerebral midline structures. The treatment of choice is surgical resection and the prognosis is excellent, with survival over 95% at 10 years. If a gross total resection (GTR) is achieved, postoperative radiation therapy or chemotherapy is not warranted, with low reported recurrence rates. Development of anaplastic features is extremely uncommon, and many such tumors are associated with prior radiation therapy. However, little is known about the mechanisms and driver mutations associated with PA anaplasia. [No abstract; excerpt from article].

Fam, N.P., von Bardeleben, R.S., Hensey, M., Kodali, S.K., Smith, R.L., Hausleiter, J., Ong, G., Boone, R., Ruf, T., George, I., Szerlip, M., Näbauer, M., Ali, F.M., Moss, R., Bapat, V., Schnitzler, K., Kreidel, F., Ye, J., Deva, D.P., Mack, M.J., Grayburn, P.A., Peterson, M.D., Leon, M.B., Hahn, R.T. and Webb, J.G. (2021). “Transfemoral Transcatheter Tricuspid Valve Replacement With the EVOQUE System: A Multicenter, Observational, First-in-Human Experience.” JACC Cardiovasc Interv 14(5): 501-511.

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OBJECTIVES: The purpose of this observational first-in-human experience was to investigate the feasibility and safety of the EVOQUE tricuspid valve replacement system and its impact on short-term clinical outcomes. BACKGROUND: Transcatheter tricuspid intervention is a promising option for selected patients with severe tricuspid regurgitation (TR). Although transcatheter leaflet repair is an option for some, transcatheter tricuspid valve replacement (TTVR) may be applicable to a broader population. METHODS: Twenty-five patients with severe TR underwent EVOQUE TTVR in a compassionate-use experience. The primary outcome was technical success, with NYHA (NYHA) functional class, TR grade, and major adverse cardiac and cerebrovascular events assessed at 30-day follow-up. RESULTS: All patients (mean age 76 ± 3 years, 88% women) were at high surgical risk (mean Society of Thoracic Surgeons risk score 9.1 ± 2.3%), with 96% in NYHA functional class III or IV. TR etiology was predominantly functional, with mean tricuspid annular diameter of 44.8 ± 7.8 mm and mean tricuspid annular plane systolic excursion of 16 ± 2 mm. Technical success was 92%, with no intraprocedural mortality or conversion to surgery. At 30-day follow-up, mortality was 0%, 76% of patients were in NYHA functional class I or II, and TR grade was ≤2+ in 96%. Major bleeding occurred in 3 patients (12%), 2 patients (8%) required pacemaker implantation, and 1 patient (4%) required dialysis. CONCLUSIONS: This first-in-human experience evaluating EVOQUE TTVR demonstrated high technical success, acceptable safety, and significant clinical improvement. Larger prospective studies are needed to confirm durability and safety and the impact on long-term clinical outcomes.

Gonzalez, D., Mateo, J., Stenzinger, A., Rojo, F., Shiller, M., Wyatt, A.W., Penault-Llorca, F., Gomella, L.G., Eeles, R. and Bjartell, A. (2021). “Practical considerations for optimising homologous recombination repair mutation testing in patients with metastatic prostate cancer.” J Pathol Clin Res Feb 25. [Epub ahead of print].

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Analysis of the genomic landscape of prostate cancer has identified different molecular subgroups with relevance for novel or existing targeted therapies. The recent approvals of the poly(ADP-ribose) polymerase (PARP) inhibitors olaparib and rucaparib in the metastatic castration-resistant prostate cancer (mCRPC) setting signal the need to embed molecular diagnostics in the clinical pathway of patients with mCRPC to identify those who can benefit from targeted therapies. Best practice guidelines in overall biospecimen collection and processing for molecular analysis are widely available for several tumour types. However, there is no standard protocol for molecular diagnostic testing in prostate cancer. Here, we provide a series of recommendations on specimen handling, sample pre-analytics, laboratory workflow, and testing pathways to maximise the success rates for clinical genomic analysis in prostate cancer. Early involvement of a multidisciplinary team of pathologists, urologists, oncologists, radiologists, nurses, molecular scientists, and laboratory staff is key to enable optimal workflow for specimen selection and preservation at the time of diagnosis so that samples are available for molecular analysis when required. Given the improved outcome of patients with mCRPC and homologous recombination repair gene alterations who have been treated with PARP inhibitors, there is an urgent need to incorporate high-quality genomic testing in the routine clinical pathway of these patients.

Moreno-Martinez, D., Aguiar, P., Auray-Blais, C., Beck, M., Bichet, D.G., Burlina, A., Cole, D., Elliott, P., Feldt-Rasmussen, U., Feriozzi, S., Fletcher, J., Giugliani, R., Jovanovic, A., Kampmann, C., Langeveld, M., Lidove, O., Linhart, A., Mauer, M., Moon, J.C., Muir, A., Nowak, A., Oliveira, J.P., Ortiz, A., Pintos-Morell, G., Politei, J., Rozenfeld, P., Schiffmann, R., Svarstad, E., Talbot, A.S., Thomas, M., Tøndel, C., Warnock, D., West, M.L. and Hughes, D.A. (2021). “Standardising clinical outcomes measures for adult clinical trials in Fabry disease: A global Delphi consensus.” Mol Genet Metab Feb 20;S1096-7192(21)00035-4. [Epub ahead of print].

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BACKGROUND: Recent years have witnessed a considerable increase in clinical trials of new investigational agents for Fabry disease (FD). Several trials investigating different agents are currently in progress; however, lack of standardisation results in challenges to interpretation and comparison. To facilitate the standardisation of investigational programs, we have developed a common framework for future clinical trials in FD. METHODS AND FINDINGS: A broad consensus regarding clinical outcomes and ways to measure them was obtained via the Delphi methodology. 35 FD clinical experts from 4 continents, representing 3389 FD patients, participated in 3 rounds of Delphi procedure. The aim was to reach a consensus regarding clinical trial design, best treatment comparator, clinical outcomes, measurement of those clinical outcomes and inclusion and exclusion criteria. Consensus results of this initiative included: the selection of the adaptative clinical trial as the ideal study design and agalsidase beta as ideal comparator treatment due to its longstanding use in FD. Renal and cardiac outcomes, such as glomerular filtration rate, proteinuria and left ventricular mass index, were prioritised, whereas neurological outcomes including cerebrovascular and white matter lesions were dismissed as a primary or secondary outcome measure. Besides, there was a consensus regarding the importance of patient-related outcomes such as general quality of life, pain, and gastrointestinal symptoms. Also, unity about lysoGb3 and Gb3 tissue deposits as useful surrogate markers of the disease was obtained. The group recognised that cardiac T1 mapping still has potential but requires further development before its widespread introduction in clinical trials. Finally, patients with end-stage renal disease or renal transplant should be excluded unless a particular group for them is created inside the clinical trial. CONCLUSION: This consensus will help to shape the future of clinical trials in FD. We note that the FDA has, coincidentally, recently published draft guidelines on clinical trials in FD and welcome this contribution.

Namazi, B., Sankaranarayanan, G. and Devarajan, V. (2021). “A contextual detector of surgical tools in laparoscopic videos using deep learning.” Surg Endosc Feb 8. [Epub ahead of print].

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BACKGROUND: The complexity of laparoscopy requires special training and assessment. Analyzing the streaming videos during the surgery can potentially improve surgical education. The tedium and cost of such an analysis can be dramatically reduced using an automated tool detection system, among other things. We propose a new multilabel classifier, called LapTool-Net to detect the presence of surgical tools in each frame of a laparoscopic video. METHODS: The novelty of LapTool-Net is the exploitation of the correlations among the usage of different tools and, the tools and tasks-i.e., the context of the tools’ usage. Towards this goal, the pattern in the co-occurrence of the tools is utilized for designing a decision policy for the multilabel classifier based on a Recurrent Convolutional Neural Network (RCNN), which is trained in an end-to-end manner. In the post-processing step, the predictions are corrected by modeling the long-term tasks’ order with an RNN. RESULTS: LapTool-Net was trained using publicly available datasets of laparoscopic cholecystectomy, viz., M2CAI16 and Cholec80. For M2CAI16, our exact match accuracies (when all the tools in one frame are predicted correctly) in online and offline modes were 80.95% and 81.84% with per-class F1-score of 88.29% and 90.53%. For Cholec80, the accuracies were 85.77% and 91.92% with F1-scores if 93.10% and 96.11% for online and offline, respectively. CONCLUSIONS: The results show LapTool-Net outperformed state-of-the-art methods significantly, even while using fewer training samples and a shallower architecture. Our context-aware model does not require expert’s domain-specific knowledge, and the simple architecture can potentially improve all existing methods.