Coexisting lipomatous meningioma and glioblastoma in Cowden syndrome: A unique tumor association.

Cowden syndrome (CS) is a rare hereditary hamartoma-cancer disorder related to germline mutations in the tumor suppressor phosphatase and tensin homolog (PTEN) gene. Association of CS with intracranial tumors, apart from Lhermitte-Duclos disease (LDD), is not well recognized. We present an exceptional instance of concomitant meningioma and glioblastoma in CS, the first case ever reported. Following a new-onset seizure, a 62-year-old male harboring the PTEN gene germline mutation c.334C > G was diagnosed with multiple brain tumors, which were erroneously thought to correspond to metastases. Because no primary cancer was found, an operation was proposed for histopathological diagnosis. Examination of surgical specimens obtained from the two lesions removed, one extra-axial and the other intracerebral, demonstrated a metaplastic meningioma with a lipomatous appearance and an isocitrate dehydrogenase wild-type glioblastoma, respectively. Loss of the PTEN gene expression was demonstrated immunohistochemically in both lesions, a finding that supports their relation to CS. A thorough literature review revealed only 25 additional CS patients with intracranial tumors other than LDD. All of them corresponded to primary lesions, with meningiomas accounting for 76% of the cases (19 patients), followed by pituitary tumors (three cases) and glioblastomas (two patients from the same family). Our report and literature review highlight the association between CS and primary brain tumors rather than metastasis. For judicious management of a CS patient with multiple intracranial tumors, different primary brain pathological entities should also be suspected first before considering metastasis. Close neurological monitoring and brain magnetic resonance imaging are advocated as part of the cancer screening in CS patients, particularly in cases with a family history of intracranial tumors.

Trispecific T-cell engagers for dual tumor-targeting of colorectal cancer.

Retargeting of T lymphocytes toward cancer cells by bispecific antibodies has demonstrated its therapeutic potential, with one such antibody approved for the treatment of acute lymphoblastic leukemia (blinatumomab) and several other in clinical trials. However, improvement of their efficacy and selectivity for solid tumors is still required. Here, we describe a novel tandem T-cell recruiting trispecific antibody for the treatment of colorectal cancer (CRC). This construct, termed trispecific T-cell engager (TriTE), consists of a CD3-specific single-chain Fv (scFv) flanked by anti-epidermal growth factor receptor (EGFR) and anti-epithelial cell adhesion molecule (EpCAM) single-domain VHH antibodies. The TriTE was well expressed in mammalian and yeast cells, bound the cognate antigens of the three parental antibodies, and enabled the specific cytolysis of EGFR- and/or EpCAM-expressing cancer cells, without inducing T cell activation and cytoxicity against double-negative (EGFR-EpCAM-) cancer cells. Bivalent bispecific targeting of double-positive HCT116 cells by TriTE improved in vitro potency up to 100-fold compared to single-positive cells and significantly prolonged survival in vivo. In addition, it was less efficient at killing single-positive target cells than the corresponding bispecific controls, leading to potentially enhanced tumor specificity. Moreover, dual targeting of two tumor-associated antigens may contribute toward preventing the tumor escape by antigen loss caused by selective pressures from conventional single-targeting T-cell engagers, and may help to overcome antigenic heterogeneity.

TGF-ß-induced IGFBP-3 is a key paracrine factor from activated pericytes that promotes colorectal cancer cell migration and invasion.

The crosstalk between cancer cells and the tumor microenvironment has been implicated in cancer progression and metastasis. Fibroblasts and immune cells are widely known to be attracted to and modified by cancer cells. However, the role of pericytes in the tumor microenvironment beyond endothelium stabilization is poorly understood. Here, we report that pericytes promoted colorectal cancer (CRC) cell proliferation, migration, invasion, stemness, and chemoresistance in vitro, as well as tumor growth in a xenograft CRC model. We demonstrate that coculture with human CRC cells induced broad transcriptomic changes in pericytes, mostly associated with TGF-ß receptor activation. The prognostic value of a TGF-ß response signature in pericytes was analyzed in CRC patient data sets. This signature was found to be a good predictor of CRC relapse. Moreover, in response to stimulation by CRC cells, pericytes expressed high levels of TGF-ß1, initiating an autocrine activation loop. Investigation of secreted mediators and underlying molecular mechanisms revealed that IGFBP-3 is a key paracrine factor from activated pericytes affecting CRC cell migration and invasion. In summary, we demonstrate that the interplay between pericytes and CRC cells triggers a vicious cycle that stimulates pericyte cytokine secretion, in turn increasing CRC cell tumorigenic properties. Overall, we provide another example of how cancer cells can manipulate the tumor microenvironment.

Giant Dumbbell-Shaped Thoracic Schwannoma in an Elderly Patient Resected Through a Single-Stage Combined Laminectomy and Video-Assisted Thoracoscopy: Surgical Strategy and Technical Nuances.

BACKGROUND: Dumbbell-shaped schwannomas involving the spinal canal, the intervertebral foramen, and the thoracic cavity are rare lesions. Surgical treatment represents a challenge, and there is no consensus regarding ideal management. Two major surgical routes have been used: combined laminectomy and open thoracotomy or posterolateral extrapleural approach with wide bone removal. This report describes a relatively easy surgical strategy, combined laminectomy and thoracoscopy, which allows safe resection under an adequate view with low risk of spinal instability, pain, or respiratory problems. CASE DESCRIPTION: A 74-year-old man presented with rapidly progressing motor impairment caused by a dumbbell-shaped, 65-mm, Eden type III lesion at the T5 level. Magnetic resonance imaging showed an intraspinal-extradural mass extending into the chest cavity and causing severe spinal cord compression. The patient underwent single-stage surgery performed by a neurosurgical and thoracic team. The extradural and foraminal tumor components were first removed through a 1-level laminectomy with foraminotomy and without facetectomy. Subsequently, video-assisted thoracic surgery was performed to approach the anterior paraspinal component. Total tumor removal, confirmed with postoperative magnetic resonance imaging, was achieved. Pathologic diagnosis was schwannoma. The postoperative course was uneventful. The patient's neurologic deficits resolved, and he experienced minimal pain after the operation. CONCLUSIONS: A single-stage operation using combined laminectomy and video-assisted thoracic surgery is a safe and efficacious strategy for achieving total removal of dumbbell-shaped thoracic schwannomas, even in cases involving giant lesions and elderly patients.

Improved demonstration of immunohistochemical prognostic markers for survival in follicular lymphoma cells.

Follicular lymphoma (FL) is one of the most common forms of the low-grade non-Hodgkin's lymphoma in adults, with a characteristic translocation, t(14;18)(q32;q21) that deregulates the expression of the BCL2 gene. The clinical course of FL patients is variable, whereby a subset of patients survive for long periods even without relapses, whereas the majority have frequent relapses with shorter survival. We have analyzed a series of 186 FLs, studying the correlation between clinical outcome and the tumor cell expression of a set of immunohistochemical markers, using an automated procedure for tissue microarrays to reduce the subjectivity of scoring. The results identified several markers associated with differences in overall survival (OS) in univariate analyses, such as Cyclin E, Mdm2, CD10, p21, IgD, Bcl-xL, CD30, and E2F6. Cases with a higher level of expression of Cyclin E, Mdm2, p21, IgD, Bcl-xL, CD30, and E2F6 were associated with a significantly shorter OS. On the other hand, strong CD10 expression was linked to a significantly better outcome. A Cox model was then constructed, integrating the Follicular Lymphoma International Prognostic Index (FLIPI) score and a restricted selection of three immunohistochemical markers: Cyclin E, Mdm2, and CD10 expression. A potentially useful finding is that the integrated FLIPI plus immunohistochemical model can be used to identify a subset of 26 patients (almost 20% of the total series), with a survival probability of 100% at 5 years. This not only confirms that a group of FL cases may have a very good clinical course, but also indicates that this group can be identified using this integrated clinical and immunohistochemical approach.