Database of evidence for precision oncology portal.

Summary: A database of curated genomic variants with clinically supported drug therapies and other oncological annotations is described. The accompanying web portal provides a search engine with two modes: one that allows users to query gene, cancer type, variant type or position for druggable mutations, and another to search for and to visualize, on three-dimensional protein structures, putative druggable sites that cluster with known druggable mutations. Availability and implementation: http://dinglab.wustl.edu/depo.

Integrative omics analyses broaden treatment targets in human cancer.

BACKGROUND: Although large-scale, next-generation sequencing (NGS) studies of cancers hold promise for enabling precision oncology, challenges remain in integrating NGS with clinically validated biomarkers. METHODS: To overcome such challenges, we utilized the Database of Evidence for Precision Oncology (DEPO) to link druggability to genomic, transcriptomic, and proteomic biomarkers. Using a pan-cancer cohort of 6570 tumors, we identified tumors with potentially druggable biomarkers consisting of drug-associated mutations, mRNA expression outliers, and protein/phosphoprotein expression outliers identified by DEPO. RESULTS: Within the pan-cancer cohort of 6570 tumors, we found that 3% are druggable based on FDA-approved drug-mutation interactions in specific cancer types. However, mRNA/phosphoprotein/protein expression outliers and drug repurposing across cancer types suggest potential druggability in up to 16% of tumors. The percentage of potential drug-associated tumors can increase to 48% if we consider preclinical evidence. Further, our analyses showed co-occurring potentially druggable multi-omics alterations in 32% of tumors, indicating a role for individualized combinational therapy, with evidence supporting mTOR/PI3K/ESR1 co-inhibition and BRAF/AKT co-inhibition in 1.6 and 0.8% of tumors, respectively. We experimentally validated a subset of putative druggable mutations in BRAF identified by a protein structure-based computational tool. Finally, analysis of a large-scale drug screening dataset lent further evidence supporting repurposing of drugs across cancer types and the use of expression outliers for inferring druggability. CONCLUSIONS: Our results suggest that an integrated analysis platform can nominate multi-omics alterations as biomarkers of druggability and aid ongoing efforts to bring precision oncology to patients.

Driver Fusions and Their Implications in the Development and Treatment of Human Cancers.

Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy.

Posterior-Only Vertebral Column Resection for Fused Spondyloptosis.

STUDY DESIGN: Retrospective review. OBJECTIVES: To describe 3 cases of a posterior-only vertebral column resection (pVCR) for the treatment of spondyloptosis in the setting of prior spinal fusions. SUMMARY OF BACKGROUND DATA: Lumbosacral spondyloptosis is a rare spinal deformity with a number of surgical options, none of which demonstrate clear superiority. The use of an L5 vertebral column resection, via combined anterior and posterior approaches, to restore lumbosacral alignment has been described though is accompanied by high rates of neurological deficit. METHODS: Review of 3 cases of spondyloptosis with prior spinal fusions in which a staged pVCR was used for deformity reconstruction. RESULTS: Three females, ages 39, 54, and 28, developed spondyloptosis with progressive lumbosacral kyphosis and sagittal malalignment after prior in-situ posterolateral spinal fusions. All were treated with staged pVCRs. At ultimate follow-up, imaging revealed improvement in sagittal balance of 6.1 cm (56%) in the 39-year-old and 12 cm (67%) in the 54-year-old, 21.1 cm (92%) in the 28-year-old. All patients had improvement in outcome scores with perfect satisfaction scores despite the 54-year-old having a persistent right foot drop. CONCLUSION: Posterior-only VCR for spondyloptosis is a technically demanding surgical option offering significant radiographic and clinical improvement, but carries a risk for L5 nerve root deficit as in any spondyloptosis treatment.

Protein-structure-guided discovery of functional mutations across 19 cancer types.

Local concentrations of mutations are well known in human cancers. However, their three-dimensional spatial relationships in the encoded protein have yet to be systematically explored. We developed a computational tool, HotSpot3D, to identify such spatial hotspots (clusters) and to interpret the potential function of variants within them. We applied HotSpot3D to >4,400 TCGA tumors across 19 cancer types, discovering >6,000 intra- and intermolecular clusters, some of which showed tumor and/or tissue specificity. In addition, we identified 369 rare mutations in genes including TP53, PTEN, VHL, EGFR, and FBXW7 and 99 medium-recurrence mutations in genes such as RUNX1, MTOR, CA3, PI3, and PTPN11, all mapping within clusters having potential functional implications. As a proof of concept, we validated our predictions in EGFR using high-throughput phosphorylation data and cell-line-based experimental evaluation. Finally, mutation-drug cluster and network analysis predicted over 800 promising candidates for druggable mutations, raising new possibilities for designing personalized treatments for patients carrying specific mutations.

Radiation Therapy for Residual or Recurrent Atypical Meningioma: The Effects of Modality, Timing, and Tumor Pathology on Long-Term Outcomes.

BACKGROUND: Optimal use of stereotactic radiosurgery (SRS) vs external beam radiation therapy (EBRT) for treatment of residual/recurrent atypical meningioma is unclear. OBJECTIVE: To analyze features associated with progression after radiation therapy. METHODS: Fifty radiation-naive patients who received SRS or EBRT for residual and/or recurrent atypical meningioma were examined for predictors of progression using Cox regression and Kaplan-Meier analyses. RESULTS: Thirty-two patients (64%) received adjuvant radiation after subtotal resection, 12 patients (24%) received salvage radiation after progression following subtotal resection, and 6 patients (12%) received salvage radiation after recurrence following gross total resection. Twenty-one patients (42%) received SRS (median 18 Gy), and 7 (33%) had tumor progression. Twenty-nine patients (58%) received EBRT (median 54 Gy), and 13 (45%) had tumor progression. Whereas tumor volume (P = .53), SRS vs EBRT (P = .45), and adjuvant vs salvage (P = .34) were not associated with progression after radiation therapy, spontaneous necrosis (hazard ratio [HR] = 82.3, P < .001), embolization necrosis (HR = 15.6, P = .03), and brain invasion (HR = 3.8, P = .008) predicted progression in univariate and multivariate analyses. Tumors treated with SRS/EBRT had 2- and 5-year actuarial locoregional control rates of 91%/88% and 71%/69%, respectively. Tumors with spontaneous necrosis, embolization necrosis, and no necrosis had 2- and 5-year locoregional control rates of 76%, 92%, and 100% and 36%, 73%, and 100%, respectively (P < .001). CONCLUSION: This study suggests that necrosis may be a negative predictor of radiation response regardless of radiation timing or modality. ABBREVIATIONS: AM, atypical meningiomaEBRT, external beam radiation therapyGTR, gross total resectionLC, locoregional controlOS, overall survivalPOE, preoperative embolizationRT, radiation therapySRS, stereotactic radiosurgerySTR, subtotal resection.

An evidence-based treatment algorithm for the management of WHO Grade II and III meningiomas.

The management of WHO Grade II "atypical" meningiomas (AMs) and Grade III "malignant" meningiomas (MMs) remains controversial and under-investigated in prospective studies. The roles of surgery, radiation therapy, radiosurgery, and chemotherapy have been incompletely delineated. This has left physicians to decipher how they should treat patients on a case-by-case basis. In this study, the authors review the English-language literature on the management and clinical outcomes associated with AMs and MMs diagnosed using the WHO 2000/2007 grading criteria. Twenty-two studies for AMs and 7 studies for MMs were examined in detail. The authors examined clinical decision points using the literature and concepts from evidence-based medicine. Acknowledging the retrospective nature of the studies concerning AM and MM, the authors did find evidence for the following clinical strategies: 1) maximal safe resection of AM and MM; 2) active surveillance after gross-total resection of AM; 3) adjuvant radiation therapy after subtotal resection of AM, especially in the absence of putative radioresistant features; and 4) adjuvant radiation therapy after resection of MM.

Simpson Grade I-III Resection of Spinal Atypical (World Health Organization Grade II) Meningiomas is Associated With Symptom Resolution and Low Recurrence.

BACKGROUND: Because of their rarity, outcomes regarding spinal atypical meningiomas (AMs) remain unclear. OBJECTIVE: To describe the recurrence rate and postoperative outcomes after resection of spinal AMs, and to discuss an appropriate resection strategy and adjuvant therapy for spinal AMs. METHODS: Data from all patients who presented with spinal AMs to 2 tertiary referral centers between 1998 and 2013 were obtained by chart review. RESULTS: From 102 patients with spinal meningioma, 20 AM tumors (7 cervical, 11 thoracic, 2 thoracolumbar) were identified in 18 patients (median age, 50 years [range, 19-75] at time of resection; 11% male; median follow-up, 32 months [range, 1-179] after resection). Before resection, patients had sensory deficits (70%), pain (70%), weakness (60%), ataxia (50%), spasticity (65%), and incontinence (35%). One tumor presented asymptomatically. Simpson grade I, II, III, and IV resection were achieved in 3 (15%), 13 (65%), 2 (10%), and 2 (10%) tumors, respectively. One patient that underwent Simpson grade III resection received adjuvant radiation therapy. After Simpson grade I-III or gross total resection, no tumors recurred (0%; confidence interval, 0%-17.6%). After Simpson grade IV resection, 1 tumor recurred (50%; confidence interval, 1.3%-98.7%). With the exception of 1 patient who had bilateral paraplegia perioperatively, all other patients experienced improvement of preoperative symptoms after surgery (median time, 3.6 months [range, 1-13] after resection). CONCLUSION: Despite published cases suggesting an aggressive clinical course for spinal AMs, this series of spinal AMs reports that gross total resection without adjuvant radiation therapy resulted in symptom resolution and low recurrence.

Management of atypical cranial meningiomas, part 1: predictors of recurrence and the role of adjuvant radiation after gross total resection.

BACKGROUND: Indications for external beam radiation therapy (EBRT) for atypical meningiomas (AMs) remain unclear. OBJECTIVE: To analyze features associated with recurrence in AM patients after gross total resection (GTR) and to assess the relative benefit of EBRT in a retrospective cohort study. METHODS: One hundred fifty-one primary AMs after GTR (88 female patients; median follow-up, 45.0 months) were examined for possible predictors of recurrence (age, sex, location, volume, bone involvement, brain invasion). The Fisher exact and Wilcoxon rank-sum tests were used to analyze the association between these predictors and use of EBRT. The impact on recurrence for these predictors and EBRT was analyzed with Kaplan-Meier and Cox regression. RESULTS: Of 151 patients, 13 (8.6%) experienced recurrence after GTR (median, 47.0 months). Multivariate analysis identified elevated mitotic index (P = .007) and brain invasion (P = .002) as predictors of recurrence. Larger volume (P = .96) was not associated with recurrence but was more likely to prompt EBRT (P = .001). Recurrences occurred in 11 of 112 with GTR (9.8%; median, 44 months) and 2 of 39 with GTR/EBRT (5.1%; median, 133 months). The 2-, 5-, and 10-year progression-free survival rates after GTR vs GTR/EBRT were 97%, 86%, and 68% vs 100%, 100%, and 78%. Kaplan-Meier analysis demonstrated no difference in progression-free survival or overall survival after GTR vs GTR/EBRT (P = .8, P > .99). CONCLUSION: Brain invasion and high mitotic rates may predict recurrence. After GTR of AMs, EBRT appears not to affect progression-free survival and overall survival, suggesting that observation rather than EBRT may be indicated after GTR.

Management of atypical cranial meningiomas, part 2: predictors of progression and the role of adjuvant radiation after subtotal resection.

BACKGROUND: The efficacies of adjuvant stereotactic radiosurgery (SRS) and external beam radiation therapy (EBRT) for atypical meningiomas (AMs) after subtotal resection (STR) remain unclear. OBJECTIVE: To analyze the clinical, histopathological, and radiographic features associated with progression in AM patients after STR. METHODS: Fifty-nine primary AMs after STR were examined for predictors of progression, including the impact of SRS and EBRT, in a retrospective cohort study. RESULTS: Twenty-seven patients (46%) progressed after STR (median, 30 months). On univariate analysis, spontaneous necrosis positively (hazard ratio = 5.2; P = .006) and adjuvant radiation negatively (hazard ratio = 0.3; P = .009) correlated with progression; on multivariate analysis, only adjuvant radiation remained independently significant (hazard ratio = 0.3; P = .006). SRS and EBRT were associated with greater local control (LC; P = .02) and progression-free survival (P = .007). The 2-, 5-, and 10-year actuarial LC rates after STR vs STR/EBRT were 60%, 34%, and 34% vs 96%, 65%, and 45%. The 2-, 5-, and 10-year actuarial progression-free survival rates after STR vs STR/EBRT were 60%, 30%, and 26% vs 96%, 65%, and 45%. Compared with STR alone, adjuvant radiation therapy significantly improved LC in AMs that lack spontaneous necrosis (P = .003) but did not improve LC in AMs with spontaneous necrosis (P = .6). CONCLUSION: Adjuvant SRS or EBRT improved LC of AMs after STR but only for tumors without spontaneous necrosis. Spontaneous necrosis may aid in decisions to administer adjuvant SRS or EBRT after STR of AMs.

Enhanced non-volatile and updatable holography using a polymer composite system.

Updatable holography is considered as the ultimate technique for true 3D information recording and display. However, there is no practical solution to preserve the required features of both non-volatility and reversibility which conflict with each other when the reading has the same wavelength as the recording. We demonstrate a non-volatile and updatable holographic approach by exploiting new features of molecular transformations in a polymer recording system. In addition, by using a new composite recording film containing photo-reconfigurable liquid-crystal (LC) polymer, the holographic recording is enhanced due to the collective reorientation of LC molecules around the reconfigured polymer chains.