Lynch syndrome-associated chordoma with high tumor mutational burden and significant response to immune checkpoint inhibitors.

Chordoma is a rare malignant bone tumor arising from notochordal tissue. Conventional treatments, such as radical resection and high-dose irradiation, frequently fail to control the tumor, resulting in recurrence and re-growth. In this study, genetic analysis of the tumor in a 72-year-old male patient with refractory conventional chordoma of the skull base revealed a high tumor mutational burden (TMB) and mutations in the MSH6 and MLH1 genes, which are found in Lynch syndrome. The patient and his family had a dense cancer history, and subsequent germline genetic testing revealed Lynch syndrome. This is the first report of a chordoma that has been genetically proven to be Lynch syndrome. Chordomas usually have low TMB; however, this is an unusual case, because the TMB was high, and immune checkpoint inhibitors effectively controlled the tumor. This case provides a basis for determining the indications for immunotherapy of chordoma based on the genetic analysis. Therefore, further extensive genetic analysis in the future will help to stratify the treatment of chordoma.

Macrophage colony-stimulating factor potentially induces recruitment and maturation of macrophages in recurrent pituitary neuroendocrine tumors.

Although pituitary neuroendocrine tumors (PitNETs) are usually benign, some are highly invasive and recurrent. Recurrent PitNETs are often treatment-resistant and there is currently no effective evidence-based treatment. Tumor-associated macrophages (TAMs) promote tumor growth in many cancers, but the effect of TAMs on PitNETs remains unclear. This study investigated the role of TAMs in the incidence of recurrent PitNETs. Immunohistochemical analysis revealed that the densities of CD163- and CD204-positive TAMs tended to increase in recurrent PitNETs. Compared with TAMs in primary lesions, those in recurrent lesions were enlarged. To clarify the cell-cell interactions between TAMs and PitNETs, in vitro experiments were performed using a mouse PitNET cell line AtT20 and the mouse macrophage cell line J774. Several cytokines related to macrophage chemotaxis and differentiation, such as M-CSF, were elevated significantly by stimulation with macrophage conditioned medium. When M-CSF immunohistochemistry analysis was performed using human PitNET samples, M-CSF expression increased significantly in recurrent lesions compared with primary lesions. Although no M-CSF receptor (M-CSFR) expression was observed in tumor cells of primary and recurrent PitNETs, flow cytometric analysis revealed that the mouse PitNET cell line expressed M-CSFR. Cellular proliferation in mouse PitNETs was inhibited by high concentrations of M-CSFR inhibitors, suggesting that cell-to-cell communication between PitNETs and macrophages induces M-CSF expression, which in turn enhances TAM chemotaxis and maturation in the tumor microenvironment. Blocking the M-CSFR signaling pathway might be a novel therapeutic adjuvant in treating recurrent PitNETs.

Use of Paine's Technique: Projecting Puncture Point to the Skull and Skin.

OBJECTIVE: Ventriculostomy from Paine's point is an effective technique to ensure that the brain is relaxed for aneurysm surgery. This study aimed to use Paine's point for other neurosurgical procedures (except for those that require a pterional approach) by delineation of surface landmarks for identification of Paine's point on the cranium and scalp. METHODS: Based on the anatomical knowledge and examination of 3-dimensional computed tomography images of skull, we determined novel surface landmarks to identify Paine's point on the cranium and scalp. The new method was used in patients with intraventricular hemorrhage and aneurysmal subarachnoid hemorrhage caused by ruptured aneurysm of the anterior communicating artery. RESULTS: The puncture point was determined at a point located 2.5 cm superior to the supraorbital margin on linea temporalis on the skull and 2.5 cm superior to the eyebrow along the anterior edge of temporal muscle on the skin. Ventriculostomy was performed from Paine's point in patients with intraventricular hemorrhage or aneurysmal subarachnoid hemorrhage who underwent aneurysm surgery via an interhemispheric approach. No adverse events were observed in any of the patients. CONCLUSIONS: By accurate surface marking on skull and skin, the use of Paine's point for ventriculostomy performed via an interhemispheric approach or for simple burr-hole surgery was found to be safe and reliable.

Region specificity of chromosome III on gene expression in the yeast Saccharomyces cerevisiae.

A single copy of a reporter gene cassette, such as PGKP-lacZ-LEU2 (promoter-reporter-marker gene) cassette, was inserted into one of 32 positions along chromosome III in Saccharomyces cerevisiae with an interval of approximately 10 kb. The amounts of translational gene product (beta-galactosidase) synthesized by the cassette-transformed cells were then determined. The region specificity in chromosome III could be demonstrated in gene expression: two higher-expressed regions (hot regions), 133 and 199 (MAT) regions, and seven lower-expressed regions (cold regions). For the steady and high production of polypeptide, foreign gene products, by yeast, we would like to state that we hope for an insertion of the artificially prepared gene cassette [(promoter)-(foreign gene)-(marker gene) ] into a hot region, such as 199 (MAT) region of chromosome III.