Genomic analysis of human brain metastases treated with stereotactic radiosurgery reveals unique signature based on treatment failure.

Stereotactic radiosurgery (SRS) has been shown to be efficacious for the treatment of limited brain metastasis (BM); however, the effects of SRS on human brain metastases have yet to be studied. We performed genomic analysis on resected brain metastases from patients whose resected lesion was previously treated with SRS. Our analyses demonstrated for the first time that patients possess a distinct genomic signature based on type of treatment failure including local failure, leptomeningeal spread, and radio-necrosis. Examination of the center and peripheral edge of the tumors treated with SRS indicated differential DNA damage distribution and an enrichment for tumor suppressor mutations and DNA damage repair pathways along the peripheral edge. Furthermore, the two clinical modalities used to deliver SRS, LINAC and GK, demonstrated differential effects on the tumor landscape even between controlled primary sites. Our study provides, in human, biological evidence of differential effects of SRS across BM's.

Genomic Analysis of Human Brain Metastases Treated with Stereotactic Radiosurgery Under the Phase-II Clinical Trial (NCT03398694) Reveals DNA Damage Repair at the Peripheral Tumor Edge.

Stereotactic Radiosurgery (SRS) is one of the leading treatment modalities for oligo brain metastasis (BM), however no comprehensive genomic data assessing the effect of radiation on BM in humans exist. Leveraging a unique opportunity, as part of the clinical trial (NCT03398694), we collected post-SRS, delivered via Gamma-knife or LINAC, tumor samples from core and peripheral-edges of the resected tumor to characterize the genomic effects of overall SRS as well as the SRS delivery modality. Using these rare patient samples, we show that SRS results in significant genomic changes at DNA and RNA levels throughout the tumor. Mutations and expression profiles of peripheral tumor samples indicated interaction with surrounding brain tissue as well as elevated DNA damage repair. Central samples show GSEA enrichment for cellular apoptosis while peripheral samples carried an increase in tumor suppressor mutations. There are significant differences in the transcriptomic profile at the periphery between Gamma-knife vs LINAC.

Metastatic Cardiac Angiosarcoma to the Lung, Spine, and Brain: A Case Report and Review of the Literature.

BACKGROUND: Metastatic angiosarcoma to the brain is a rare entity without an established management protocol. CASE DESCRIPTION: A man with primary cardiac angiosarcoma presented with a rare brain metastasis. The patient underwent successful resection of the brain metastasis and was initiated on chemotherapy only for his systemic disease. The patient did not develop local recurrence. A review of primary and metastatic central nervous system angiosarcoma, its pathologic features, clinical disease course, treatment strategies, and genomics is also provided. CONCLUSIONS: Angiosarcomas are rare tumors that are difficult to treat. Gross total resection of a central nervous system metastasis is recommended before initiation of adjuvant chemotherapy or radiation therapy. Close follow-up is still required given the propensity for continued metastasis of these tumors. Future treatments may be developed based on the genomics of angiosarcomas.

Ruptured Mycotic Aneurysm and Cerebral Vasospasm in the Setting of Endocarditis and Heart Failure Requiring Cardiothoracic Surgery: Case Report and Literature Review.

BACKGROUND: Ruptured mycotic aneurysm in the setting of cardiac failure and cerebral vasospasm presents unique management challenges. CASE DESCRIPTION: A patient with a ruptured mycotic aneurysm with subarachnoid hemorrhage, cerebral vasospasm, and endocarditis with heart failure successfully underwent craniotomy, neuroendovascular treatment, and cardiopulmonary bypass for mitral valve replacement while in cerebral vasospasm. This case highlights clinical management strategies for a patient with a ruptured mycotic aneurysm, subarachnoid hemorrhage, cerebral vasospasm, endocarditis, and heart failure. CONCLUSIONS: Open craniotomy, neuroendovascular treatment, and cardiac surgery strategies can be used when treating patients with ruptured mycotic aneurysms and cardiac failure. When the patient also has cerebral vasospasm, maintenance of mean arterial pressure is paramount.

Management of posterior fossa tumors and hydrocephalus in children: a review.

OBJECT: Most pediatric patients that present with a posterior fossa tumor have concurrent hydrocephalus. There is significant debate over the best management strategy of hydrocephalus in this situation. The objectives of this paper were to review the pathophysiology model of posterior fossa tumor hydrocephalus, describe the individual risks factors of persistent hydrocephalus, and discuss the current management options. Specifically, the debate over preresection cerebrospinal fluid diversion is discussed. RESULTS: Only 10-40 % demonstrate persistent hydrocephalus after posterior fossa tumor resection. It appears that young age, moderate to severe hydrocephalus, transependymal edema, the presence of cerebral metastases, and tumor pathology (medulloblastoma and ependymoma) on presentation predict postresection or persistent hydrocephalus. The Canadian Preoperative Prediction Rule for Hydrocephalus (CPPRH), a validated prediction model, can be used to stratify patients at point of first contact into high and low risk for persistent hydrocephalus. CONCLUSIONS: A protocol is proposed for managing hydrocephalus that utilizes the CPPRH. Low-risk patients can be monitored conservatively with or without an intraoperative extraventricular drain, while high-risk patients require the use of an intraoperative extraventricular drain, higher postoperative hydrocephalus surveillance, and even consideration for a preoperative endoscopic third ventriculostomy.

Anchor-based classification and type-C inhibitors for tyrosine kinases.

Tyrosine kinases regulate various biological processes and are drug targets for cancers. At present, the design of selective and anti-resistant inhibitors of kinases is an emergent task. Here, we inferred specific site-moiety maps containing two specific anchors to uncover a new binding pocket in the C-terminal hinge region by docking 4,680 kinase inhibitors into 51 protein kinases, and this finding provides an opportunity for the development of kinase inhibitors with high selectivity and anti-drug resistance. We present an anchor-based classification for tyrosine kinases and discover two type-C inhibitors, namely rosmarinic acid (RA) and EGCG, which occupy two and one specific anchors, respectively, by screening 118,759 natural compounds. Our profiling reveals that RA and EGCG selectively inhibit 3% (EGFR and SYK) and 14% of 64 kinases, respectively. According to the guide of our anchor model, we synthesized three RA derivatives with better potency. These type-C inhibitors are able to maintain activities for drug-resistant EGFR and decrease the invasion ability of breast cancer cells. Our results show that the type-C inhibitors occupying a new pocket are promising for cancer treatments due to their kinase selectivity and anti-drug resistance.

Survival following Ommaya reservoir placement for neoplastic meningitis.

The objective of this study was to evaluate the outcomes of patients with neoplastic meningitis (NM) following Ommaya reservoir placement in order to determine whether any patient factors are associated with longer survival. NM is a devastating late manifestation of cancer, and given its dismal prognosis, identifying appropriate patients for Ommaya reservoir placement is difficult. The authors performed a retrospective review of 80 patients who underwent Ommaya reservoir placement at three medical centers from September 2001 through September 2012. The primary outcome was death. Differences in survival were assessed with Kaplan-Meier survival analyses. The Cox proportional hazards and logistic regression modeling were performed to identify factors associated with survival. The primary diagnoses were solid organ, hematologic, and primary central nervous system tumors in 53.8%, 41.3%, and 5%, respectively. The median overall survival was 72.5 days (95% confidence interval 36-122) with 30% expiring within 30 days and only 13.8% surviving more than 1 year. There were no differences in median overall survival between sites (p=0.37) despite differences in time from diagnosis of NM to Ommaya reservoir placement (p<0.001). Diagnosis of hematologic malignancy was inversely associated with death within 90 days (p=0.04; odds ratio 0.34), older age was associated with death within 90 days (p=0.05; odds ratio 1.5, per 10 year increase in age). The prognosis of NM remains poor despite the available treatment with intraventricular chemotherapy. There exists significant variability in treatment algorithms among medical centers and consideration of this variability is crucial when interpreting existing series of Ommaya reservoir use in the treatment of patients with NM.

Homopharma: a new concept for exploring the molecular binding mechanisms and drug repurposing.

BACKGROUND: Drugs that simultaneously target multiple proteins often improve efficacy, particularly in the treatment of complex diseases such as cancers and central nervous system disorders. Many approaches have been proposed to identify the potential targets of a drug. Recently, we have introduced Space-Related Pharmamotif (SRPmotif) method to recognize the proteins that share similar binding environments. In addition, compounds with similar topology may bind to similar proteins and have similar protein-compound interactions. However, few studies have focused on exploring the relationships between binding environments and protein-compound interactions, which is important for understanding molecular binding mechanisms and helpful to be used in discovering drug repurposing. RESULTS: In this study, we propose a new concept of "Homopharma", combining similar binding environments and protein-compound interaction profiles, to explore the molecular binding mechanisms and drug repurposing. A Homopharma consists of a set of proteins which have the conserved binding environment and a set of compounds that share similar structures and functional groups. These proteins and compounds present conserved interactions and similar physicochemical properties. Therefore, these compounds are often able to inhibit the proteins in a Homopharma. Our experimental results show that the proteins and compounds in a Homopharma often have similar protein-compound interactions, comprising conserved specific residues and functional sites. Based on the Homopharma concept, we selected four flavonoid derivatives and 32 human protein kinases for enzymatic profiling. Among these 128 bioassays, the IC50 of 56 and 25 flavonoid-kinase inhibitions are less than 10 µM and 1 µM, respectively. Furthermore, these experimental results suggest that these flavonoids can be used as anticancer compounds, such as oral and colorectal cancer drugs. CONCLUSIONS: The experimental results show that the Homopharma is useful for identifying key binding environments of proteins and compounds and discovering new inhibitory effects. We believe that the Homopharma concept can have the potential for understanding molecular binding mechanisms and providing new clues for drug development.

Pseudarthrosis failures of anterior subaxial cervical spine fusion using a plate with a single screw per vertebral body: a case series.

INTRODUCTION: The UNIPLATE was developed to improve operative times and limit dissection at the lateral margins of the vertebral bodies. The distinguishing character of this plate is its thin design, which requires only one screw per vertebral level (monovertebral screw plate). Most cervical spine plates, in contrast, are designed for two screws per vertebral level (bivertebral screw plate). Limited reports of the biomechanical efficacy of the UNIPLATE are available, and to the authors' knowledge, this report represents the largest clinical study of its use. METHODS: This is a retrospective chart-review study of consecutively treated patients without previous cervical spine surgery undergoing anterior cervical diskectomy and fusion at one or two levels. The primary end point was symptomatic pseudarthrosis requiring revision surgery. Pseudarthrosis is defined as a failure of bony fusion on the operated level seen on thin-cut computed tomography scans performed on symptomatic patients. The rate of revision surgery caused by symptomatic pseudarthrosis was compared between patients undergoing one- and two-level fusion surgeries treated with UNIPLATE compared with other plates with two screws per vertebral level. The minimum follow-up was 18 months. RESULTS: A total of 162 patients were identified, including 125 patients with one-level fusion and 37 patients with two-level fusion surgery. The median follow-up period was 3.3 years. A significantly greater incidence (odds ratio 10.2, P = 0.042) of reoperation for symptomatic pseudarthrosis was noted for patients treated with the UNIPLATE (4 of 13, 31%) compared with patients treated with bivertebral screw plates (1 of 24, 2.5%). No significant difference in reoperation attributable to symptomatic pseudarthrosis was noted for different plating systems for one-level fusion surgeries. CONCLUSIONS: There is an increased rate of reoperation for symptomatic pseudarthrosis after anterior cervical diskectomy and fusion surgery with the use of a monovertebral screw semiconstrained plate, particularly in two-level fusion surgeries. Use of the UNIPLATE system has since been abandoned at our institution in favor of bivertebral screw plating systems.

Total synthetic protoapigenone WYC02 inhibits cervical cancer cell proliferation and tumour growth through PIK3 signalling pathway.

Flavonoids have been intensively explored for their anticancer activity. In this study, a total synthetic flavonoid protoapigenone, known as WYC02, was analysed for its potential anticancer activity on human cervical cancer cells as well as the underlying mechanisms for these effects. The site-moiety maps are used to explore the binding site similarity, pharmacophore and docking pose similarity. The effect of WYC02 on cell viability, migration, invasion and apoptosis as well as the underlying mechanisms was analysed in vitro using human cervical cancer cells. The effect of WYC02 on in vivo tumour growth was assessed in a tumour xenograft study. WYC02 inhibited cell proliferation, MMPs activity, migration and invasion in cervical cancer cells. We speculated that WYC02 might inhibit the activities of PIK3 family proteins, including PIK3CA, PIK3CB, PIK3CD and PIK3CG. Indeed, WYC02 decreased the expression of PIK3 family proteins, especially PIK3CG, through ubiquitination and inhibited the activities of PIK3CG and PIK3 downstream molecules AKT1 and MTOR in cervical cancer cells. Furthermore, PIK3 signalling pathway was involved in the inhibitory effect of WYC02 on cervical cancer cell proliferation and tumour growth in vitro and in vivo. WYC02 inhibits cervical cancer cell proliferation and tumourigenesis via PIK3 signalling pathway and has the potential to be developed as a chemotherapeutic agent in cervical cancer.

KIDFamMap: a database of kinase-inhibitor-disease family maps for kinase inhibitor selectivity and binding mechanisms.

Kinases play central roles in signaling pathways and are promising therapeutic targets for many diseases. Designing selective kinase inhibitors is an emergent and challenging task, because kinases share an evolutionary conserved ATP-binding site. KIDFamMap (http://gemdock.life.nctu.edu.tw/KIDFamMap/) is the first database to explore kinase-inhibitor families (KIFs) and kinase-inhibitor-disease (KID) relationships for kinase inhibitor selectivity and mechanisms. This database includes 1208 KIFs, 962 KIDs, 55 603 kinase-inhibitor interactions (KIIs), 35 788 kinase inhibitors, 399 human protein kinases, 339 diseases and 638 disease allelic variants. Here, a KIF can be defined as follows: (i) the kinases in the KIF with significant sequence similarity, (ii) the inhibitors in the KIF with significant topology similarity and (iii) the KIIs in the KIF with significant interaction similarity. The KIIs within a KIF are often conserved on some consensus KIDFamMap anchors, which represent conserved interactions between the kinase subsites and consensus moieties of their inhibitors. Our experimental results reveal that the members of a KIF often possess similar inhibition profiles. The KIDFamMap anchors can reflect kinase conformations types, kinase functions and kinase inhibitor selectivity. We believe that KIDFamMap provides biological insights into kinase inhibitor selectivity and binding mechanisms.

Space-related pharma-motifs for fast search of protein binding motifs and polypharmacological targets.

BACKGROUND: To discover a compound inhibiting multiple proteins (i.e. polypharmacological targets) is a new paradigm for the complex diseases (e.g. cancers and diabetes). In general, the polypharmacological proteins often share similar local binding environments and motifs. As the exponential growth of the number of protein structures, to find the similar structural binding motifs (pharma-motifs) is an emergency task for drug discovery (e.g. side effects and new uses for old drugs) and protein functions. RESULTS: We have developed a Space-Related Pharmamotifs (called SRPmotif) method to recognize the binding motifs by searching against protein structure database. SRPmotif is able to recognize conserved binding environments containing spatially discontinuous pharma-motifs which are often short conserved peptides with specific physico-chemical properties for protein functions. Among 356 pharma-motifs, 56.5% interacting residues are highly conserved. Experimental results indicate that 81.1% and 92.7% polypharmacological targets of each protein-ligand complex are annotated with same biological process (BP) and molecular function (MF) terms, respectively, based on Gene Ontology (GO). Our experimental results show that the identified pharma-motifs often consist of key residues in functional (active) sites and play the key roles for protein functions. The SRPmotif is available at http://gemdock.life.nctu.edu.tw/SRP/. CONCLUSIONS: SRPmotif is able to identify similar pharma-interfaces and pharma-motifs sharing similar binding environments for polypharmacological targets by rapidly searching against the protein structure database. Pharma-motifs describe the conservations of binding environments for drug discovery and protein functions. Additionally, these pharma-motifs provide the clues for discovering new sequence-based motifs to predict protein functions from protein sequence databases. We believe that SRPmotif is useful for elucidating protein functions and drug discovery.

Safety of microvascular decompression for trigeminal neuralgia in the elderly. Clinical article.

OBJECT: Microvascular decompression (MVD) offers an effective and durable treatment for patients suffering from trigeminal neuralgia (TN). Because the disorder has a tendency to occur in older persons, the risks of surgical treatment in the elderly have been a topic of recent interest. To date, evidence derived from several small retrospective and a single prospective case series has suggested that age does not increase the complication rate associated with surgery. Using a large national database, the authors aimed to study the impact of age on in-hospital complications following MVD for TN. METHODS: Using the Nationwide Inpatient Sample (NIS) for the 10-year period from 1999 to 2008, the authors selected all patients who underwent MVD for TN. The primary outcome of interest was the in-hospital mortality rate. Secondary outcomes of interest were cardiac, pulmonary, thromboembolic, cerebrovascular, and wound complications as well as the duration of hospital stay, total hospital charges, and discharge location. An elderly cohort of patients was first defined as those 65 years of age and older and then redefined as those 75 years and older. RESULTS: A total of 3273 patients who underwent MVD for TN were identified, having a median age of 57 years. Within this sample, 31.5% were 65 years and older and 10.7% were 75 years and older. The in-hospital mortality rate was 0.68% for patients 65 years or older (p = 0.0087) and 1.16% for those 75 years or older (p = 0.0026). In patients younger than 65 years, the in-hospital mortality rate was 0.13% (3 deaths among 2241 patients). As analyzed using the chi-square test (for both 65 and 75 years as the age cutoff) and the Pearson rank correlation coefficient, the risk of cardiac, pulmonary, thromboembolic, and cerebrovascular complications was higher in older patients (that is, those 65 and older and those 75 and older), but the risks of wound complications and CNS infection were not. The risk of any in-hospital complication occurring in a patient 65 years and older was 7.36% (p < 0.0001) and 10.0% in those 75 years and older (p < 0.0001). There was no difference in the total hospital charges associated with age. The duration of the hospital stay was longer in older patients, and the likelihood of discharge home was lower in older patients. CONCLUSIONS: Microvascular decompression for TN in the elderly population remains a reasonable surgical option. However, based on data from a large national database, authors of the present study suggest that complications do tend to gradually increase in tandem with an advanced age. While age does not act as a risk factor in isolation, it may serve as a convenient surrogate for complication rates. The authors hope that this information can be of use in guiding older patients through decisions for the surgical treatment of TN.

Induction of HSPA4 and HSPA14 by NBS1 overexpression contributes to NBS1-induced in vitro metastatic and transformation activity.

BACKGROUND: Nijmegen breakage syndrome (NBS) is a chromosomal-instability syndrome associated with cancer predisposition, radiosensitivity, microcephaly, and growth retardation. The NBS gene product, NBS1 (p95) or nibrin, is a part of the MRN complex, a central player associated with double-strand break (DSB) repair. We previously demonstrated that NBS1 overexpression contributes to transformation through the activation of PI 3-kinase/Akt. NBS1 overexpression also induces epithelial-mesenchymal transition through the Snail/MMP2 pathway. METHODS: RT-PCR, Western blot analysis, in vitro migration/invasion, soft agar colony formation, and gelatin zymography assays were performed. RESULTS: Here we show that heat shock protein family members, A4 and A14, were induced by NBS1 overexpression. siRNA mediated knockdown of HSPA4 or HSPA14 decreased the in vitro migration, invasion, and transformation activity in H1299 cells overexpressing NBS1. However, HSPA4 or HSPA14 induced activity was not mediated through MMP2. NBS1 overexpression induced the expression of heat shock transcription factor 4b (HSF4b), which correlated with the expression of HSPA4 and HSPA14. CONCLUSION: These results identify a novel pathway (NBS1-HSF4b-HSPA4/HSPA14 axis) to induce migration, invasion, and transformation, suggesting the activation of multiple signaling events induced by NBS1 overexpression.

Pineal parenchymal tumor of intermediate differentiation: imaging spectrum of an unusual tumor in 11 cases.

INTRODUCTION: Pineal parenchymal tumor of intermediate differentiation (PPTID) was recognized in the 2007 World Health Organization (WHO) classification as a new pineal parenchymal neoplasm, intermediate in malignancy (WHO grade II or III) between pineocytoma (grade I) and pineoblastoma (grade IV). The imaging spectrum of this new tumor has not been previously delineated. We describe the imaging spectrum in 11 pathologically proven PPTIDs and identify findings that may suggest the preoperative diagnosis of this newly recognized entity. METHODS: Electronic medical records over the last 9 years and teaching files between the years 1985 and 1995 were searched for atypical pineal lesions. Additional cases were added from the teaching files of contributing authors. RESULTS: Imaging studies in nine patients (9/11) showed bulky, aggressive pineal region masses with local brain invasion; two patients (2/11) demonstrated circumscribed pineal masses. Two patients had spinal metastases at presentation. On computed tomography (CT), five patients had classic "exploded" calcifications characteristic of pineal parenchymal tumors. All tumors were heterogeneously hypointense on T1WIs and heterogeneously hyperintense on T2WIs. Post-contrast scans showed marked heterogeneous (10/11) or uniform (1/11) enhancement. Cystic foci were identified in eight cases. Intratumoral hemorrhage was present in one case. CONCLUSION: While no singular neuroimaging feature is pathognomonic of PPTID, these tumors are usually larger, demonstrate local invasion, and appear much more heterogeneous than pineocytoma. Because PPTIDs have a higher grade and increased potential for recurrence as compared to pineocytomas, it is important to consider this diagnosis as shorter follow-up, and adjuvant therapy may be indicated in selected cases.

Myxedema associated with cardiac tamponade.

Pericardial effusion is frequently found in patients diagnosed with hypothyroidism, yet it is rarely associated with cardiac tamponade. This report presents an atypical case concerning a 60-year-old Taiwanese female, with a history of thyroidectomy surgery due to thyroid cancer, who was later diagnosed with myxedema and cardiac tamponade. Treatment included an immediate pericardiocentesis followed by thyroxine hormone replacement therapy. Postoperative and recovery phases progressed favorably, and the patient's prognosis is good.