David Pisapia

Coronary Artery Calcification: From Mechanism to Molecular Imaging

Vascular calcification is a hallmark of atherosclerosis. The location, density, and confluence of calcification may change portions of the arterial conduit to a noncompliant structure. Calcifications may also seed the cap of a thin cap fibroatheroma, altering tensile forces on the cap and rendering the lesion prone to rupture. Many local and systemic factors participate in this process, including hyperlipidemia, ongoing inflammation, large necrotic cores, and diabetes. Vascular cells can undergo chondrogenic or osteogenic differentiation, causing mineralization of membranous bone and formation of endochondral bone. Calcifying vascular cells are derived from local smooth muscle cells and circulating hematopoietic stem cells (especially in intimal calcification). Matrix vesicles in the extracellular space of the necrotic core serve as a nidus for calcification. Although coronary calcification is a marker of coronary atheroma, dense calcification (>400 HU) is usually associated with stable plaques. Conversely, microcalcification (often also referred to as spotty calcification) is more commonly an accompaniment of vulnerable plaques. Recent studies have suggested that microcalcification in the fibrous cap may increase local tissue stress (depending on the proximity of one microcalcific locus to another, and the orientation of the microcalcification in reference to blood flow), resulting in plaque instability. It has been proposed that positron emission tomography imaging with sodium fluoride may identify early calcific deposits and hence high-risk plaques.

Endoscopic endonasal versus transcranial approach to tuberculum sellae and planum sphenoidale meningiomas in a similar cohort of patients

OBJECTIVE Planum sphenoidale (PS) and tuberculum sellae (TS) meningiomas cause visual symptoms due to compression of the optic chiasm. The treatment of choice is surgical removal with the goal of improving vision and achieving complete tumor removal. Two options exist to remove these tumors: the transcranial approach (TCA) and the endonasal endoscopic approach (EEA). Significant controversy exists regarding which approach provides the best results and whether there is a subset of patients for whom an EEA may be more suitable. Comparisons using a similar cohort of patients, namely, those suitable for gross-total resection with EEA, are lacking from the literature. METHODS The authors reviewed all cases of PS and TS meningiomas that were surgically removed at Weill Cornell Medical College between 2000 and 2015 (TCA) and 2008 and 2015 (EEA). All cases were shown to a panel of 3 neurosurgeons to find only those tumors that could be removed equally well either through an EEA or TCA to standardize both groups. Volumetric measurements of preoperative and postoperative tumor size, FLAIR images, and apparent diffusion coefficient maps were assessed by 2 independent reviewers and compared to assess extent of resection and trauma to the surrounding brain. Visual outcome and complications were also compared. RESULTS Thirty-two patients were identified who underwent either EEA (n = 17) or TCA (n = 15). The preoperative tumor size was comparable (mean 5.58 ± 3.42 vs 5.04 ± 3.38 cm3 [± SD], p = 0.661). The average extent of resection achieved was not significantly different between the 2 groups (98.80% ± 3.32% vs 95.13% ± 11.69%, p = 0.206). Postoperatively, the TCA group demonstrated a significant increase in the FLAIR/edema signal compared with EEA patients (4.15 ± 7.10 vs -0.69 ± 2.73 cm3, p = 0.014). In addition, the postoperative diffusion-weighted imaging signal of cytotoxic ischemic damage was significantly higher in the TCA group than in the EEA group (1.88 ± 1.96 vs 0.40 ± 0.55 cm3, p =0.008). Overall, significantly more EEA patients experienced improved or stable visual outcomes compared with TCA patients (93% vs 56%, p = 0.049). Visual deterioration was greater after TCA than EEA (44% vs 0%, p = 0.012). While more patients experienced postoperative seizures after TCA than after EEA (27% vs 0%, p = 0.038), there was a trend toward more CSF leakage and anosmia after EEA than after TCA (11.8% vs 0%, p = 0.486 and 11.8% vs 0%, p = 0.118, respectively). CONCLUSIONS In this small single-institution study of similarly sized and located PS and TS meningiomas, EEA provided equivalent rates of resection with better visual results, less trauma to the brain, and fewer seizures. These preliminary results merit further investigation in a larger multiinstitutional study and may support EEA resection by experienced surgeons in a subset of carefully selected PS and TS meningiomas.

VZV, temporal arteritis, and clinical practice: False positive immunohistochemical detection due to antibody cross-reactivity

Varicella Zoster Virus (VZV) antigen has been reported to be present in the majority of temporal artery biopsies with implications for antiviral treatment in patients with giant cell arteritis. Using immunohistochemistry with VZV antibodies we found reactivity present in diverse myocyte types (smooth, skeletal and cardiac), diverse arteries (including temporal, coronary, and vertebral) and diverse clinical settings. This phenomenon is likely due to shared epitopes between VZV proteins and muscle elements and not due to actual VZV infection. We conclude that VZV immunohistochemistry should be used with caution for screening of VZV infection in the setting of temporal artery biopsies.

The cancer precision medicine knowledge base for structured clinical-grade mutations and interpretations

Objective: This paper describes the Precision Medicine Knowledge Base (PMKB; https://pmkb.weill.cornell.edu), an interactive online application for collaborative editing, maintenance, and sharing of structured clinical-grade cancer mutation interpretations. Materials and Methods: PMKB was built using the Ruby on Rails Web application framework. Leveraging existing standards such as the Human Genome Variation Society variant description format, we implemented a data model that links variants to tumor-specific and tissue-specific interpretations. Key features of PMKB include support for all major variant types, standardized authentication, distinct user roles including high-level approvers, and detailed activity history. A REpresentational State Transfer (REST) application-programming interface (API) was implemented to query the PMKB programmatically. Results: At the time of writing, PMKB contains 457 variant descriptions with 281 clinical-grade interpretations. The EGFR, BRAF, KRAS, and KIT genes are associated with the largest numbers of interpretable variants. PMKB’s interpretations have been used in over 1500 AmpliSeq tests and 750 whole-exome sequencing tests. The interpretations are accessed either directly via the Web interface or programmatically via the existing API. Discussion: An accurate and up-to-date knowledge base of genomic alterations of clinical significance is critical to the success of precision medicine programs. The open-access, programmatically accessible PMKB represents an important attempt at creating such a resource in the field of oncology. Conclusion: The PMKB was designed to help collect and maintain clinical-grade mutation interpretations and facilitate reporting for clinical cancer genomic testing. The PMKB was also designed to enable the creation of clinical cancer genomics automated reporting pipelines via an API.

Toxicity evaluation of convection-enhanced delivery of small-molecule kinase inhibitors in naïve mouse brainstem

PurposeDiffuse intrinsic pontine gliomas (DIPGs) are inoperable and lethal high-grade gliomas lacking definitive therapy. Platelet-derived growth factor receptor (PDGFR) and its downstream signaling molecules are the most commonly overexpressed oncogenes in DIPG. This study tested the effective concentration of PDGFR pathway inhibitors in cell culture and then toxicity of these small-molecule kinase inhibitors delivered to the mouse brainstem via convection-enhanced delivery (CED) for potential clinical application.MethodsEffective concentrations of small-molecule kinase inhibitors were first established in cell culture from a mouse brainstem glioma model. Sixteen mice underwent CED, a local drug delivery technique, of saline or of single and multidrug combinations of dasatinib (2 M), everolimus (20 M), and perifosine (0.63 mM) in the pons. Animals were kept alive for 3 days following the completion of infusion.ResultsNo animals displayed any immediate or delayed neurological deficits postoperatively. Histological analysis revealed edema, microgliosis, acute inflammation, and/or axonal injury in the experimental animals consistent with mild acute drug toxicity.ConclusionsBrainstem CED of small-molecule kinase inhibitors in the mouse did not cause serious acute toxicities. Future studies will be necessary to evaluate longer-term safety to prepare for potential clinical application.

Heterotopic Pancreatic Neoplasm Presenting as an Obstructing Mass at the Fourth Portion of the Duodenum

CONTEXT Heterotopic pancreatic adenocarcinoma is a rare finding at laparotomy. Herein we present the case of a patient with malignant transformation of a heterotopic pancreas located in the fourth portion of the duodenum. CASE REPORT A 79-year-old woman was admitted to the surgery service with complaints of early satiety and abdominal fullness progressively worsening over the previous two years. A computed tomography scan of the abdomen and an upper endoscopy revealed an obstructing mass in the fourth portion of the duodenum, biopsies were negative for carcinoma. A segmentectomy of the third and fourth portions of the duodenum was performed. Post-operative histology revealed malignant transformation of a heterotopic pancreas. The patient had an unremarkable postoperative recovery and was discharged home. CONCLUSION In evaluation of patients with distal duodenal masses, we report that heterotopic pancreatic neoplasms should be considered in the differential diagnosis.

A proangiogenic signaling axis in myeloid cells promotes malignant progression of glioma

Tumors are capable of coopting hematopoietic cells to create a suitable microenvironment to support malignant growth. Here, we have demonstrated that upregulation of kinase insert domain receptor (KDR), also known as VEGFR2, in a myeloid cell sublineage is necessary for malignant progression of gliomas in transgenic murine models and is associated with high-grade tumors in patients. KDR expression increased in myeloid cells as myeloid-derived suppressor cells (MDSCs) accumulated, which was associated with the transformation and progression of low-grade fibrillary astrocytoma to high-grade anaplastic gliomas. KDR deficiency in murine BM-derived cells (BMDCs) suppressed the differentiation of myeloid lineages and reduced granulocytic/monocytic populations. The depletion of myeloid-derived KDR compromised its proangiogenic function, which inhibited the angiogenic switch necessary for malignant progression of low-grade to high-grade tumors. We also identified inhibitor of DNA binding protein 2 (ID2) as a key upstream regulator of KDR activation during myeloid differentiation. Deficiency of ID2 in BMDCs led to downregulation of KDR, suppression of proangiogenic myeloid cells, and prevention of low-grade to high-grade transition. Tumor-secreted TGF-&bgr; and granulocyte-macrophage CSF (GM-CSF) enhanced the KDR/ID2 signaling axis in BMDCs. Our results suggest that modulation of KDR/ID2 signaling may restrict tumor-associated myeloid cells and could potentially be a therapeutic strategy for preventing transformation of premalignant gliomas.

The Current Status of Research on Chronic Traumatic Encephalopathy

Chronic traumatic encephalopathy (CTE) evolved from the term dementia pugilistica describing the dementia found in many boxers to its current use in describing the dementia and depression sometimes found in athletes subjected to multiple concussions or subconcussive blows to the head. Concurrently, the neuropathology evolved to specify a unique type of tauopathy found in perivascular spaces at the depth of sulci and other features not typically seen in neurodegenerative tauopathies. Four stages of CTE have been proposed, with 4 corresponding clinical syndromes of traumatic encephalopathy syndrome. However, it remains unclear whether this is a syndrome unique to repetitive head trauma, especially in contact sports, because the epidemiology has been difficult to establish. In particular, research to date has had a denominator problem in not establishing the total number of potential cases at risk for developing CTE. The current review examines the evidence to date for these syndromes and contributing or complicating factors affecting the neuropathology, neuroimaging, and clinical presentations associated with them.

Biomarker based PET Imaging of Diffuse Intrinsic Pontine Glioma in Mouse Models.

Diffuse intrinsic pontine glioma (DIPG) is a childhood brainstem tumor with a universally poor prognosis. Here, we characterize a positron emission tomography (PET) probe for imaging DIPG in vivo In human histological tissues, the probes target, PARP1, was highly expressed in DIPG compared to normal brain. PET imaging allowed for the sensitive detection of DIPG in a genetically engineered mouse model, and probe uptake correlated to histologically determined tumor infiltration. Imaging with the sister fluorescence agent revealed that uptake was confined to proliferating, PARP1-expressing cells. Comparison with other imaging technologies revealed remarkable accuracy of our biomarker approach. We subsequently demonstrated that serial imaging of DIPG in mouse models enables monitoring of tumor growth, as shown in modeling of tumor progression. Overall, this validated method for quantifying DIPG burden would serve useful in monitoring treatment response in early phase clinical trials. Cancer Res; 77(8); 2112-23. ©2017 AACR.

The Precision Medicine Knowledge Base: an online application for collaborative editing, maintenance and sharing of structured clinical-grade cancer mutations interpretations

Objective This paper describes the Precision Medicine Knowledge Base (PMKB; https://pmkb.weill.cornell.edu), an interactive online application for collaborative editing, maintenance and sharing of structured clinical-grade cancer mutations interpretations. Materials and Methods PMKB was built using the Ruby on Rails Web application framework. Leveraging existing standards such as Human Genome Variation Society (HGVS) variant description format, we implemented a data model that links variants to tumor-specific and tissue-specific interpretations. Key features of PMKB include support for all major variant types, standardized authentication, distinct user roles including high-level approvers, detailed activity history. A REpresentational State Transfer (REST) application-programming interface (API) was implemented to query the PMKB programmatically. Results At the time of writing, PMKB contains 457 variant descriptions with 281 clinical-grade interpretations. The EGFR, BRAF, KRAS, and KIT genes are associated with the largest numbers of interpretable variants. The PMKB’s interpretations have been used in over 1,500 AmpliSeq tests and 750 whole exome sequencing tests. The interpretations are accessed either directly via the Web interface or programmatically via the existing API. Discussion An accurate and up-to-date knowledge base of genomic alterations of clinical significance is critical to the success of precision medicine programs. The open-access, programmatically accessible PMKB represents an important attempt at creating such a resource in the field of oncology. Conclusion The PMKB was designed to help collect and maintain clinical-grade mutation interpretations and facilitates reporting for clinical cancer genomic testing. The PMKB was also designed to enable the creation of clinical cancer genomics automated reporting pipelines via an API.