CD98 heavy chain protein is overexpressed in non-small cell lung cancer and is a potential target for CAR T-cell therapy.

Chimeric antigen receptor (CAR) T cells are effective against hematological cancers, but are less effective against solid tumors such as non-small cell lung cancer (NSCLC). One of the reasons is that only a few cell surface targets specific for NSCLC cells have been identified. Here, we report that CD98 heavy chain (hc) protein is overexpressed on the surface of NSCLC cells and is a potential target for CAR T cells against NSCLC. Screening of over 10,000 mAb clones raised against NSCLC cell lines showed that mAb H2A011 bound to NSCLC cells but not normal lung epithelial cells. H2A011 recognized CD98hc. Although CAR T cells derived from H2A011 could not be established presumably due to the high level of H2A011 reactivity in activated T cells, those derived from the anti-CD98hc mAb R8H283, which had been shown to lack reactivity with CD98hc glycoforms expressed on normal hematopoietic cells and some normal tissues, were successfully developed. R8H283 specifically reacted with NSCLC cells in six of 15 patients. R8H283-derived CAR T cells exerted significant anti-tumor effects in a xenograft NSCLC model in vivo. These results suggest that R8H283 CAR T cells may become a new therapeutic tool for NSCLC, although careful testing for off-tumor reactivity should be performed in the future.

Awake surgery for a deaf patient using sign language: A case report.

Background: Although awake surgery is the gold standard for resecting brain tumors in eloquent regions, patients with hearing impairment require special consideration during intraoperative tasks. Case Description: We present a case of awake surgery using sign language in a 45-year-old right-handed native male patient with hearing impairment and a neoplastic lesion in the left frontal lobe, pars triangularis (suspected to be a low-grade glioma). The patient primarily communicated through sign language and writing but was able to speak at a sufficiently audible level through childhood training. Although the patient remained asymptomatic, the tumors gradually grew in size. Awake surgery was performed for tumors resection. After the craniotomy, the patient was awake, and brain function mapping was performed using tasks such as counting, picture naming, and reading. A sign language-proficient nurse facilitated communication using sign language and the patient vocally responded. Intraoperative tasks proceeded smoothly without speech arrest or verbal comprehension difficulties during electrical stimulation of the tumor-adjacent areas. Gross total tumor resection was achieved, and the patient exhibited no apparent complications. Pathological examination revealed a World Health Organization grade II oligodendroglioma with an isocitrate dehydrogenase one mutant and 1p 19q codeletion. Conclusion: Since the patient in this case had no dysphonia due to training from childhood, the task was presented in sign language, and the patient responded vocally, which enabled a safe operation. Regarding awake surgery in patients with hearing impairment, safe tumor resection can be achieved by performing intraoperative tasks depending on the degree of hearing impairment and dysphonia.

Identification of glioblastoma-specific antigens expressed in patient-derived tumor cells as candidate targets for chimeric antigen receptor T cell therapy.

Background: New therapies for glioblastoma (GBM) are urgently needed because the disease prognosis is poor. Chimeric antigen receptor (CAR)-T cell therapy that targets GBM-specific cell surface antigens is a promising therapeutic strategy. However, extensive transcriptome analyses have uncovered few GBM-specific target antigens. Methods: We established a library of monoclonal antibodies (mAbs) against a tumor cell line derived from a patient with GBM. We identified mAbs that reacted with tumor cell lines from patients with GBM but not with nonmalignant human brain cells. We then detected the antigens they recognized using expression cloning. CAR-T cells derived from a candidate mAb were generated and tested in vitro and in vivo. Results: We detected 507 mAbs that bound to tumor cell lines from patients with GBM. Among them, E61 and A13 reacted with tumor cell lines from most patients with GBM, but not with nonmalignant human brain cells. We found that B7-H3 was the antigen recognized but E61. CAR-T cells were established using the antigen-recognition domain of E61-secreted cytokines and exerted cytotoxicity in co-culture with tumor cells from patients with GBM. Conclusions: Cancer-specific targets for CAR-T cells were identified using a mAb library raised against primary GBM tumor cells from a patient. We identified a GBM-specific mAb and its antigen. More mAbs against various GBM samples and novel target antigens are expected to be identified using this strategy.

Growth risk classification and typical growth speed of convexity, parasagittal, and falx meningiomas: a retrospective cohort study.

OBJECTIVE: Meningiomas are the most common primary intracranial tumors, and their clinical and biological characteristics vary by location. Convexity, parasagittal, and falx meningiomas account for approximately 50%-65% of intracranial meningiomas. Focusing only on these locations, the aim of this study was to determine the typical speed of tumor growth, to assess the growth risk, and to show the possible tumor volume that many lesions can reach after 5 years. METHODS: Patients with radiologically suspected convexity, parasagittal, or falx meningiomas at the authors' institution were studied retrospectively. The relative growth rate (RGR) and annual volume change (AVC) were calculated from MRI at more than 3-month intervals. Based on sex, age, and signal intensity on T2-weighted MRI, the cases were classified into three groups: extremely high-growth, high-growth, and low-growth groups. RESULTS: The data of 313 cases were analyzed. The median RGR and AVC for this entire cohort were 6.1% (interquartile range [IQR] 2.4%-16.0%) and 0.20 (IQR 0.04-1.18) cm3/year, respectively. There were significant differences in sex (p = 0.018) and T2-weighted MRI signal intensity (p < 0.001) for RGR, and T2-weighted MRI signal intensity (p < 0.001), tumor location (p = 0.025), and initial tumor volume (p < 0.001) for AVC. The median RGR and AVC were 17.5% (IQR 8.3%-44.1%) and 1.05 (IQR 0.18-3.53) cm3/year, 8.2% (IQR 2.9%-18.6%) and 0.33 (IQR 0.06-1.66) cm3/year, and 3.4% (IQR 1.2%-5.8%) and 0.04 (IQR 0.02-0.21) cm3/year for the extremely high-growth, high-growth, and low-growth groups, respectively, with a significant difference among the groups (p < 0.001). A 2.24-times, or 5.24 cm3, increase in tumor volume over 5 years was typical in the extremely high-growth group, whereas the low-growth group showed little change in tumor volume even over a 5-year follow-up period. CONCLUSIONS: For the first time, the typical speed of tumor growth was calculated, focusing only on patients with convexity, parasagittal, and falx meningiomas. In addition, the possible tumor volume that many lesions in these locations can reach after 5 years was shown based on objective indicators. These results may allow clinicians to easily detect lesions that require frequent follow-up or early treatment by determining whether they deviate from the typical range of the growth rate, similar to a growth chart for children.

A case of meningolacrimal artery aneurysm associated with meningioma.

BACKGROUND: Intraorbital aneurysms are rare, and most of them originate from the ophthalmic arteries. Herein, we report a case of meningolacrimal artery aneurysm associated with a meningioma. CASE DESCRIPTION: A 55-year-old woman had a frontal convexity meningioma identified by brain magnetic resonance imaging during a checkup. Cerebral angiography revealed the middle meningeal artery as a feeding artery as well as the presence of an aneurysm associated with the meningolacrimal artery. Embolization of the feeding artery was performed before the removal of the meningioma. The meningioma was resected, and the aneurysm was removed with a bone flap. The patient was discharged without any complications. CONCLUSION: We report a meningolacrimal artery aneurysm associated with a meningioma. Embolizing the feeding artery of the aneurysm was helpful in safely resecting the meningioma.

Feasibility of Smart Metal Artifact Reduction Algorithm on Computed Tomography Angiography for Clipping of Recurrent Aneurysms After Coil Embolization.

BACKGROUND: The number of patients with a history of clipping of recurrent aneurysms after coil embolization has increased. The aim of this article was to report the feasibility of CT angiography using a commercial metal artifact reduction algorithm (Smart Metal Artifact Reduction [MAR]) for patients who underwent clipping of recurrent aneurysms after coil embolization. METHODS: Six cases of clipping of recurrent aneurysms after coil embolization were examined with CT angiography using MAR between 2015 and 2018 at a single institution. Conventional CT angiography and three-dimensional digital subtraction angiography data were compared, and depiction of the status of treated aneurysms using MAR was estimated. RESULTS: Conventional CT angiography was unable to depict the status of treated aneurysms in the patients with a history of clipping of recurrent aneurysms after coil embolization because of metal artifacts. With MAR, metal artifacts were greatly reduced, and the status of treated aneurysms was able to be depicted, although depiction was inferior to three-dimensional digital subtraction angiography. CONCLUSIONS: For patients with a history of clipping of recurrent aneurysms after coil embolization, CT angiography using MAR is feasible, although further development of imaging techniques is needed.

Freehand Technique of an Electromagnetic Navigation System Emitter to Avoid Interference Caused by Metal Neurosurgical Instruments.

BACKGROUND: Electromagnetic (EM) navigation has been reported to be a noninvasive and easy-to-use technique. However, the use of metal neurosurgical instruments (e.g., skin hooks, head frames, brain retractors systems) can interfere with the magnetic fields of such systems. We present the freehand technique, a new technique involving the manual manipulation of the emitter of an EM navigation system, which helps to prevent interference caused by metal instruments during surgery. METHODS: The AxiEM Electromagnetic StealthStation Navigation System (Medtronic) was used in this study. The emitter was placed in the sterilized surgical field, which allowed it to be moved freely during surgery. When navigation was necessary during the procedure, the assistant held the emitter at an appropriate angle to the sterile surgical field to avoid interference caused by the metal neurosurgical instruments. RESULTS: During surgery involving metal surgical instruments, all of the functions of the EM navigation system were available throughout the procedure. The accuracy of the navigation system was sufficient to allow craniotomy and intradural manipulation to be conducted. CONCLUSIONS: During the use of EM navigation systems, the freehand technique with the emitter can prevent interference caused by metal instruments.

Metastasis from a primary hepatic angiosarcoma to the colon: A case report and literature review.

Primary hepatic angiosarcoma is a rare type of tumor with a poor prognosis. To the best of our knowledge, curative surgery of a metastatic gastrointestinal angiosarcoma from a hepatic angiosarcoma has not been reported previously. In the present report, a case of colonic metastasis from a primary hepatic angiosarcoma is discussed. A rapidly growing mass was identified in the liver of an 84-year-old Japanese male who underwent a subsegmentectomy of the liver. Microscopic examination determined that the mass was an angiosarcoma composed of sheets of spindle cells. Immunohistochemical studies confirmed the diagnosis with positive CD31 staining, which indicated the endothelial nature of the malignancy. A total of 14 months following surgery, the patient did not exhibit any symptoms; however, follow-up positron emission tomography and computed tomography images revealed a mass in the cecum. The patient underwent an ileocolectomy, and the microscopic and immunohistochemical findings indicated that the mass was a metastasized colorectal angiosarcoma. At a 4-year post-surgery follow-up appointment the patient was alive with no evidence of recurrence or metastasis.

Estimation of Crystallinity of Nifedipine-Polyvinylpyrrolidone Solid Dispersion by Usage of Terahertz Time-Domain Spectroscopy and of X-Ray Powder Diffractometer.

Crystalline state of pharmaceutical materials is of great importance in preparation of pharmaceutics, because their physicochemical properties affect bioavailability, quality of products, therapeutic level and manufacturing process. In this study, we have estimated time-dependent changes of nifedipine in nifedipine-polyvinylpyrrolidone (PVP) solid dispersion by measuring terahertz time-domain spectroscopy (THz-TDS) and by X-ray powder diffractometry (XRPD), and compared their correlativity. Crystallinity of nifedipine-PVP solid dispersion was changed by storing the amorphous sample at 25°C-75°C and relative humidity of over 80% for 0.25-24.00 h. To compare the results of two types of measurements, we have used a general method of linear regression analysis. Crystallinities estimated using THz-TDS were plotted on the x-axis and that of XRPD were on the y-axis. From the result of the calculation, the correlativity of them was confirmed. THz-TDS has the capability of becoming the replacement of XRPD.

Estimation of crystallinity of trehalose dihydrate microspheres by usage of terahertz time-domain spectroscopy.

Crystalline state of pharmaceutical materials is of great importance in the preparation of pharmaceutics because their physicochemical properties affect bioavailability, quality of products, therapeutic level, and manufacturing process. In this study, we have estimated the crystallinity of trehalose dihydrate microspheres by measuring terahertz (THz) spectroscopy. The commercially available trehalose dihydrate takes in general a crystalline state, but trehalose dihydrate microspheres prepared by using spray-drying method are in an amorphous state. We have prepared amorphous anhydrous trehalose by using melt-quenched method from crystalline trehalose dihydrate. We have measured the absorbance of trehalose dihydrate containing amorphous anhydrous trehalose (0%, 25%, 50%, 75%, and 100%) using THz time-domain spectroscopy (THz-TDS) to prepare calibration curves. Using the calibration curves, we have estimated the crystallinity of trehalose dihydrate microspheres prepared by using spray-drying method. Our results suggest that THz-TDS is well suited to distinguish crystallinity differences in pharmaceutical compounds.

Trophinin is a potent prognostic marker of ovarian cancer involved in platinum sensitivity.

Ovarian cancer is the leading cause of death in women with gynecological malignancies, with prognosis of advanced stage tumors determined by chemotherapeutic response and the success of tumor resection. Since aberrant RAS pathway activation is frequent in ovarian cancer, study of in vitro RAS-induced transformation and accompanying genomic expression changes in ovarian surface epithelial cells is imperative for development of new therapeutic modalities and for understanding tumorigenesis. cDNA microarray analysis revealed TROPHONIN (TRO), a homophilic adhesion molecule involved in blastocyst implantation, was among the genes most downregulated by RAS induction. TRO expression is higher in cisplatin-sensitive cancer cell lines and positively correlates with prognoses in ovarian cancers. TRO knockdown by RNA interference conferred cisplatin resistance and led to increased invasiveness of cultured ovarian cancer cells. These findings underscore the importance of TRO in tumorigenesis, and suggest that TRO may be a useful biomarker for cisplatin sensitivity and invasive potential.

LH/hCG action and development of ovarian cancer--a short review on biological and clinical/epidemiological aspects.

A link between infertility therapy, especially ovulation induction therapy using gonadotropins, and the development of ovarian cancer has long been an issue of debate since an epidemiological report supporting the possibility appeared in 1992. A number of clinical/epidemiological and biological studies, including a few that we conducted, have revealed various facts regarding this issue. The aim of this short review was to summarize the last 10 years findings and to address the implications of the debates on this issue.