The efficacy of slow-rate ventriculolumbar perfusion chemotherapy for leptomeningeal carcinomatosis: a phase II study.

PURPOSE: This study aimed to evaluate the symptomatic response and side effects of ventriculolumbar perfusion (VLP) methotrexate chemotherapy with a low perfusion rate in patients with leptomeningeal metastasis. METHODS: Patients in a single-arm, two-stage phase II trial based on Simon's minimax design received VLP with a reduced (15 cc/h) perfusion rate with the purpose of decreasing constitutional side effects such as nausea/vomiting, insomnia, and confusion. The primary outcome was control of increased intracranial pressure (ICP). The secondary outcome was an occurrence of side effects. The results were compared with those of a previous trial of VLP with a 20-cc/h perfusion rate. RESULTS: Total 90 patients were enrolled. Out of 65 patients with increased ICP, 32 achieved normalized ICP after VLP chemotherapy (bias-adjusted response rate = 51%). The incidence of moderate-to-severe nausea/vomiting was reduced to 46% from 64% in the previous study, and that of sleep disturbance was increased to 13% from 9%, but both failed to reach statistical significance. The incidence of moderate-to-severe confusion was significantly reduced to 12% from 23% in the previous study (p = 0.04). Median overall survival was better among patients with controlled ICP than among those who remained with increased ICP (193 days vs. 94 days, p = 0.013). CONCLUSION: Compared with a higher perfusion rate, the low perfusion rate failed to provide non-inferior ICP control or improved side effects, except for confusion. The relationship between VLP perfusion rate and ICP control needs to be evaluated in future trials adjusting for bias from uncompleted protocol due to poor general condition.

Extracellular Vesicles from Cerebrospinal Fluid of Leptomeningeal Metastasis Patients Deliver MiR-21 and Induce Methotrexate Resistance in Lung Cancer Cells.

Leptomeningeal metastasis (LM) is a common and fatal complication of advanced non-small cell lung cancer (NSCLC) caused by the spread of malignant cells to the leptomeninges and cerebrospinal fluid (CSF). While intra-CSF methotrexate (MTX) chemotherapy can improve prognosis, eventual MTX resistance deters continued chemotherapy. Recent studies have shown that increased miRNA-21 (miR-21) expression in the CSF of patients with LM after intraventricular MTX-chemotherapy is associated with poor overall survival; however, the molecular mechanisms underlying this resistance are poorly understood. Here, we confirm, in 36 patients with NSCLC-LM, that elevated miR-21 expression prior to treatment correlates with poor prognosis. MiR-21 overexpression or sponging results in a corresponding increase or decrease in MTX resistance, demonstrating that cellular miR-21 expression correlates with drug resistance. MiR-21-monitoring sensor and fluorescent extracellular vesicle (EV) staining revealed that EV-mediated delivery of miR-21 could modulate MTX resistance. Moreover, EVs isolated from the CSF of LM patients containing miR-21 could enhance the cell proliferation and MTX resistance of recipient cells. These results indicate that miR-21 can be transferred from cell-to-cell via EVs and potentially modulate MTX sensitivity, suggesting that miR-21 in CSF EVs may be a prognostic and therapeutic target for overcoming MTX resistance in patients with NSCLC-LM.

Coronary CTA With AI-QCT Interpretation: Comparison With Myocardial Perfusion Imaging for Detection of Obstructive Stenosis Using Invasive Angiography as Reference Standard.

BACKGROUND. Deep learning frameworks have been applied to interpretation of coronary CTA performed for coronary artery disease (CAD) evaluation. OBJECTIVE. The purpose of our study was to compare the diagnostic performance of myocardial perfusion imaging (MPI) and coronary CTA with artificial intelligence quantitative CT (AI-QCT) interpretation for detection of obstructive CAD on invasive angiography and to assess the downstream impact of including coronary CTA with AI-QCT in diagnostic algorithms. METHODS. This study entailed a retrospective post hoc analysis of the derivation cohort of the prospective 23-center Computed Tomographic Evaluation of Atherosclerotic Determinants of Myocardial Ischemia (CREDENCE) trial. The study included 301 patients (88 women and 213 men; mean age, 64.4 ± 10.2 [SD] years) recruited from May 2014 to May 2017 with stable symptoms of myocardial ischemia referred for nonemergent invasive angiography. Patients underwent coronary CTA and MPI before angiography with quantitative coronary angiography (QCA) measurements and fractional flow reserve (FFR). CTA examinations were analyzed using an FDA-cleared cloud-based software platform that performs AI-QCT for stenosis determination. Diagnostic performance was evaluated. Diagnostic algorithms were compared. RESULTS. Among 102 patients with no ischemia on MPI, AI-QCT identified obstructive (≥ 50%) stenosis in 54% of patients, including severe (≥ 70%) stenosis in 20%. Among 199 patients with ischemia on MPI, AI-QCT identified nonobstructive (1-49%) stenosis in 23%. AI-QCT had significantly higher AUC (all p < .001) than MPI for predicting ≥ 50% stenosis by QCA (0.88 vs 0.66), ≥ 70% stenosis by QCA (0.92 vs 0.81), and FFR < 0.80 (0.90 vs 0.71). An AI-QCT result of ≥ 50% stenosis and ischemia on stress MPI had sensitivity of 95% versus 74% and specificity of 63% versus 43% for detecting ≥ 50% stenosis by QCA measurement. Compared with performing MPI in all patients and those showing ischemia undergoing invasive angiography, a scenario of performing coronary CTA with AIQCT in all patients and those showing ≥ 70% stenosis undergoing invasive angiography would reduce invasive angiography utilization by 39%; a scenario of performing MPI in all patients and those showing ischemia undergoing coronary CTA with AI-QCT and those with ≥ 70% stenosis on AI-QCT undergoing invasive angiography would reduce invasive angiography utilization by 49%. CONCLUSION. Coronary CTA with AI-QCT had higher diagnostic performance than MPI for detecting obstructive CAD. CLINICAL IMPACT. A diagnostic algorithm incorporating AI-QCT could substantially reduce unnecessary downstream invasive testing and costs. TRIAL REGISTRATION. Clinicaltrials.gov NCT02173275.

Association of MRI findings with clinical characteristics and prognosis in patients with leptomeningeal carcinomatosis from non-small cell lung cancer.

PURPOSE: Magnetic resonance imagining (MRI) is helpful for diagnosis of leptomeningeal carcinomatosis (LMC) and localizing LMC symptoms. Goal of this study is how MRI findings of LMC are associated with clinical characteristics or prognosis in patients with non-small cell lung cancer (NSCLC). METHODS: We retrospectively collected data on 283 patients with LMC from NSCLC, adenocarcinoma based on cerebrospinal fluid cytology. All patients had brain MRI with gadolinium enhancement at LMC diagnosis, and spinal MRI was performed at the physician's discretion. We evaluated the prognostic factors for overall survival (OS) of all patients and subgroup of patients with central nervous system cause of death. RESULTS: Two-hundred sixteen patients (76%) had definite or suggestive LMC findings and 67 had negative findings on brain MRI. Of the 37 patients who presented with cauda equina syndrome, 35 (95%) exhibited typical spinal MRI findings. Median OS of all patients was 3.65 months (95% confidence interval, 3.06-4.18). There was no significant difference in median OS between MRI-negative and MRI-positive groups (4.31 vs. 3.48 months, p = 0.711), whereas negative MRI finding showed longer median OS significantly in a subgroup of 77 patients with a central nervous system cause of death (p = 0.035). Considering clinical characteristics, progressive systemic disease, and altered mentality were significant prognostic factors associated with poor OS, whereas presenting symptom of headache with nausea/vomiting, intra-CSF chemotherapy, WBRT after LMC diagnosis, and concurrent RTKi treatment were significant for favorable OS in multivariable analysis. CONCLUSIONS: Positive MRI findings suggests heavier disease burden than negative MRI findings in patients with LMC who died of a central nervous system cause. Spinal MRI findings in patients with LMC correlate with cauda equina symptoms.

Magnetic-field-controlled reconfigurable semiconductor logic.

Logic devices based on magnetism show promise for increasing computational efficiency while decreasing consumed power. They offer zero quiescent power and yet combine novel functions such as programmable logic operation and non-volatile built-in memory. However, practical efforts to adapt a magnetic device to logic suffer from a low signal-to-noise ratio and other performance attributes that are not adequate for logic gates. Rather than exploiting magnetoresistive effects that result from spin-dependent transport of carriers, we have approached the development of a magnetic logic device in a different way: we use the phenomenon of large magnetoresistance found in non-magnetic semiconductors in high electric fields. Here we report a device showing a strong diode characteristic that is highly sensitive to both the sign and the magnitude of an external magnetic field, offering a reversible change between two different characteristic states by the application of a magnetic field. This feature results from magnetic control of carrier generation and recombination in an InSb p-n bilayer channel. Simple circuits combining such elementary devices are fabricated and tested, and Boolean logic functions including AND, OR, NAND and NOR are performed. They are programmed dynamically by external electric or magnetic signals, demonstrating magnetic-field-controlled semiconductor reconfigurable logic at room temperature. This magnetic technology permits a new kind of spintronic device, characterized as a current switch rather than a voltage switch, and provides a simple and compact platform for non-volatile reconfigurable logic devices.

Local recurrence of brain metastasis reduced by intra-operative hyperthermia treatment.

PURPOSE: Brain metastasis is a common complication in cancer patients. Local recurrence after total resection of metastatic brain tumor has been frequently reported. In this study, we developed a new hyperthermia device and applied it to metastatic brain tumor patients intra-operatively to study if hyperthermia treatment could reduce local tumor recurrence. MATERIALS AND METHODS: A total of 63 metastatic brain patients were enrolled in the study with an informed consent obtained from every patient. After total resection of the tumor, the hyperthermia device was applied intra-operatively to the resection cavity. The surrounding brain tissue at 5 mm in depth from the tumor resection margin was raised to 42.5 °C for a total of 60 minutes (Clinical Research Information Service Registration Number: KCT0001308). RESULTS: A total of 10 local recurrences were observed in 63 patients who received hyperthermia treatment showing a local recurrence rate of 15.8%. It was significantly lower than the local recurrence rate of those who received conventional treatment (34%) when analyzed with one tailed z-test (p value: .001). Kaplan-Meier analysis also showed a significantly lower recurrence rate in the hyperthermia treatment group (p value: .0003). Complications included two cases of seizures and two cases of wound infection. CONCLUSIONS: Results of this study suggest that intra-operative hyperthermia treatment after total resection of metastatic brain tumor could reduce local recurrence of tumor. We believe that intra-operative hyperthermia treatment could be used as an adjuvant therapy to surgery and post-operative radiotherapy, or as a salvage treatment in patients who cannot receive further radiotherapy.

Clinical outcome of cerebrospinal fluid shunts in patients with leptomeningeal carcinomatosis.

BACKGROUND: Leptomeningeal carcinomatosis (LMC) is frequently associated with hydrocephalus, which quickly devastates the performance of the patient. Cerebrospinal fluid (CSF) shunt is a widely accepted treatment of choice, but the clinical outcomes in patients with LMC are not well studied. This study aimed to examine the efficacy of a CSF shunt in patients with LMC. METHODS: Seventy patients with LMC confirmed by cytology or magnetic resonance imaging (MRI) underwent ventriculoperitoneal (VP) or lumboperitoneal (LP) shunt surgery. We retrospectively analyzed the clinical characteristics of patients, symptom improvement after the shunt, rate of complications associated with the surgery, and overall survival. RESULTS: Fifty-five patients had systemic cancer as a preceding disease, including lung cancer (45), breast cancer (6), and others (4). Primary brain tumors were mainly glioma (7) and medulloblastoma (5). Fifty-one patients had VP shunt, and 19 had LP shunt. After surgery, preoperative symptoms "improved" in 35 patients (50%) and were "normalized" in 24 of those patients (34%). Shunt malfunction occurred in eight patients, and infection occurred in eight patients. Seventeen patients underwent revision due to infection, shunt malfunction, or over-drainage. There were no complications associated with peritoneal seeding during a median follow-up of 3.3 months after surgery. The median overall survival was 8.7 months (95% confidence interval, 6.0-11.4) from LMC diagnosis and 4.1 months from shunt surgery. CONCLUSION: VP or LP shunt is effective for patients with hydrocephalus from LMC in terms of symptom improvement and prolonging of overall survival with an acceptable rate of procedure-related complications. TRIAL REGISTRATION: This study was approved by the Institutional Review Board (IRB) of the National Cancer Center (retrospectively registered, NCC2018-0051 ).

Discordances in ER, PR, and HER2 between primary breast cancer and brain metastasis.

When distant metastases are discovered, it is important to determine receptor profiles of these lesions through histologic examination. However, brain metastasis sites are difficult to reach to be routinely biopsied. The purpose of this study was to determine expression profiles of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) in breast cancer brain metastasis (BCBM) and the existence of discordance between primary breast cancer and brain metastasis. A total of 37 patients who underwent craniotomies for metastatic brain tumors arising from breast cancer at National Cancer Center (NCC) of Korea between 2002 and 2014 were retrospectively reviewed. Clinicopathologic data were collected from electronic medical records. Receptor profiles of primary breast cancer and brain metastasis in each patient were identified. Data of ER, PR, and HER2 expression in brain metastasis were available in electronic medical records for 21 (56.8%) of 37 cases. Results of ER, PR, and HER2 expression were positive in 47.6, 42.9, and 38.1% of patients with brain metastasis, respectively. Receptor conversion occurred in 11 (52.4%) of 21 patients (for ER, 9.5%; for PR, 38.1%; for HER2, 23.8%). Overall survival was longer in patients with concordant receptor expression patterns between primary breast cancer and brain lesion compared to that in patients with discordant patterns. However, such difference was not statistically significant (discordant vs. concordant median survival: 19.2 versus 31.1 months, p = 0.181). Receptor conversion in BCBMs was observed in over 50% of Korean patients used in this study. HER2 conversion was observed in 23.8% of patients in this study. Therefore, if resistance to anti-HER2 treatment is suspected in patients with BCBM, biopsy is needed to determine receptor profiles of brain lesion.

Treatment Results and Prognostic Factors of Brain Metastases From Ovarian Cancer: A Single Institutional Experience of 56 Patients.

OBJECTIVES: The most appropriate treatments for brain metastases from ovarian cancer have not been established mainly because of its rarity. The objective of this study was to describe clinical results of treatment and prognostic factors of patients with brain metastases from ovarian cancer treated at a single institution. MATERIALS AND METHODS: We retrieved information from the electronic medical records of 56 consecutive patients (2.8%) with brain metastases, from a total of 2008 patients with ovarian cancer. Endpoints were the pattern of treatment failure, progression-free survival, and overall survival (OS). RESULTS: Radiation was the most common initial treatment for brain metastases (59%), followed by surgery (23%). The median progression-free survival was 9.8 months. Radiological progression was confirmed in 20 patients: 7 had leptomeningeal carcinomatosis (37%), 8 had local recurrence, and 5 had distant recurrence. Median OS was 11.25 months, and the 1-year OS rate was 48.2%. Patients received surgery for single metastasis as initial treatment showed median OS of 24.1 months, which was significantly prolonged compared with the other patients (P = 0.0002). Of the 48 patients who died, 29 (60%) died of systemic disease and 7 (15%) died of central nervous system progression. Karnofsky Performance Status greater than or equal to 70, control of systemic cancer, serous histology, and surgery for brain metastases were associated with improved OS in multivariable analysis (P < 0.05). CONCLUSIONS: Surgical resection for single or symptomatic brain metastases from ovarian cancer prolonged OS significantly. Multimodality treatment, including control of systemic cancer, appeared to be an important factor in prolonging OS.

A porencephalic cyst formation in a 6-year-old female with a functioning ventriculoperitoneal shunt: a case-based review.

INTRODUCTION: Porencephalic cysts and cerebrospinal fluid (CSF) edema around the intracranial shuntcatheter are rare complications of ventriculoperitoneal shunt (VPS) surgery. Possible mechanisms leading to a porencephalic cyst formation in a patient with a VPS include taut ventricle, dysfunction of distalcatheters, and irreversible damage to the brain parenchyma caused by shunt insertion, chemotherapy, or radiation. Most of the previous reports were due to shunt malfunction and treatment consisted of shunt revision or removal. CASE REPORT: We present a case of porencephalic cyst formation in a 6-year-old female as a result ofcerebrospinal fluid under-drainage that was promptly improved with shunt valve adjustment. COCLUSIONS: A heightened index of suspicion is required to prevent misdiagnosis of porencephalic cysts astumors or abscesses that may lead to unnecessary surgical explorations. Further research is needed toelucidate the pathophysiological mechanism that causes a porencephalic cyst formation.

Clinical characteristics and follow-up of intracranial metastases from thyroid cancer.

BACKGROUND: Intracranial metastasis from thyroid cancer is extremely rare. However, less is known about the risk factors for intracranial metastasis and its treatment from few retrospective studies. The aim of this study was to contribute to the understanding of this disease by analyzing patients with intracranial metastases from thyroid cancer. METHODS: Between 2001 and 2014, the database of the National Cancer Center of Korea was searched for thyroid cancer patients. The clinical characteristics and site of distant metastasis according to the histological type were evaluated in the thyroid cancer cohort. Among the patients with intracranial metastases, the characteristics, histological type of primary cancer and metastatic brain tumor, additional synchronous or previous distant metastasis, treatment modalities, locations and characteristics on radiologic findings, time interval between the first diagnosis of the primary thyroid cancer and brain metastasis, thyroglobulin level at the first detection of intracranial metastasis and survival were reviewed. RESULTS: A total of 10 (0.032 %) out of 3,090 thyroid cancer patients in the National Cancer Center database were identified as having intracranial metastases. The histological types of the primary thyroid cancers were papillary for six patients, follicular for three, and poorly differentiated carcinoma for one. Six of these ten patients underwent surgical resection for intracranial lesions. Whole-brain radiotherapy or tyrosine kinase inhibitors were applied to the patients as postoperative adjuvant treatment, and stereotactic radiosurgery was considered for recurrent or surgically inoperable lesions. The overall median survival time was 33 months (range, 0.5-78 months) after diagnosis of intracranial metastasis. CONCLUSIONS: Surgical resection and adjuvant treatments in the contemporary era seem to result in improved survival after intracranial metastases compared with what has been reported in past studies. Considering the grave course of intracranial metastasis, the early detection and aggressive treatment of patients with a good performance status are crucial.

Ventriculolumbar perfusion chemotherapy with methotrexate for treating leptomeningeal carcinomatosis: a Phase II Study.

BACKGROUND: The efficacy of ventriculolumbar perfusion (VLP) chemotherapy with methotrexate (MTX) was evaluated for treatment of leptomeningeal carcinomatosis (LMC). METHODS: The primary outcome was the response rate of increased intracranial pressure (ICP), which was available for comparison from historical data on conventional intraventricular chemotherapy. Secondary endpoints were response rates of other LMC symptoms and overall survival of patients. Artificial cerebrospinal fluid (CSF) premixed with MTX was continuously perfused intraventricularly through a preinstalled intraventricular reservoir and drained via lumbar catheter for 72 hours. The VLP was repeated twice at 3-day intervals for each cycle. RESULTS: Forty-five of 65 patients had increased ICP, and 32 patients (71%) showed response after VLP chemotherapy, including 31 patients with normalization of ICP. Altered mentation improved in 7 of 21 patients (33%). Cauda equina symptoms responded in 5 of 27 patients (19%), including 4 patients who became ambulatory from a bedridden state. Median overall survival was 187 days, and the 1-year survival rate was 27%. All side effects, including nausea, vomiting, confusion, and sleep disturbance, were tolerable and transient except for two cases of CSF infection. CONCLUSION: VLP chemotherapy with MTX provided better control of increased ICP, improved symptom response, and prolonged survival at a cost of acceptable toxicity in patients with LMC.

Proton beam therapy reduces the incidence of acute haematological and gastrointestinal toxicities associated with craniospinal irradiation in pediatric brain tumors.

BACKGROUND: The benefits of proton beam craniospinal irradiation (PrBCSI) in children have been extensively reported in dosimetric studies. However, there is limited clinical evidence supporting the use of PrBCSI. We compared the acute toxicity of PrBCSI relative to that of conventional photon beam CSI (PhBCSI) in children with brain tumours. MATERIAL AND METHODS: We prospectively evaluated the haematological and gastrointestinal toxicities in 30 patients who underwent PrBCSI between April 2008 and December 2012. As a reference group, we retrospectively evaluated the medical records of 13 patients who underwent PhBCSI between April 2003 and April 2012. The median follow-up time from starting CSI was 22 months (range 2-118 months). The mean irradiation dose was 32.1 Gy (range 23.4-39.6 Gy) and 29.4 CGE (cobalt grey equivalents; range 19.8-39.6), in the PrBCSI and PhBCSI groups, respectively (p = 0.236). RESULTS: There was no craniospinal fluid space relapse after curative therapy in either group of patients. Thrombocytopenia was less severe in the PrBCSI group than in the PhBCSI group (p = 0.012). The recovery rates of leukocyte and platelet counts measured one month after treatment were significantly greater in the PrBCSI group than in the PhBCSI group (p = 0.003 and p = 0.010, respectively). Diarrhoea was reported by 23% of patients in the PhBCSI group versus none in the PrBCSI group (p = 0.023). CONCLUSIONS: The incidence rates of thrombocytopenia and diarrhoea were lower in the PrBCSI group than in the PhBCSI group. One month after completing treatment, the recovery from leukopenia and thrombocytopenia was better in patients treated with PrBCSI than in those treated with PhBCSI.

Disseminating Necrotizing Leukoencephalopathy Associated With Intra-CSF Methotrexate Chemotherapy: A Retrospective Observational Study.

BACKGROUND AND OBJECTIVES: Leptomeningeal metastases (LMs) are neoplasms that proliferate to membranes lining the brain and spinal cord. Intra-CSF methotrexate (MTX) chemotherapy is a prevalent treatment option. However, resultant long-term neurotoxicity can lead to irreversible disseminated necrotizing leukoencephalopathy (DNL). This study aims to determine the incidence, characteristics, risk factors, and outcomes of DNL following intra-CSF MTX chemotherapy for LM. METHODS: We retrospectively reviewed patients with LM who received intra-CSF MTX between 2001 and 2021 at the National Cancer Center of Korea. Patients with a follow-up duration of <3 months and those without follow-up MRI after MTX administration were excluded. The primary outcome was the development of DNL, evaluated based on the clinical and radiologic definitions of DNL. Logistic and Cox proportional regression models were used to assess the risk of DNL in patients with LM receiving intra-CSF MTX chemotherapy. RESULTS: Of the 577 patients included in the DNL investigation, 13 (2.3%) were identified to have irreversible DNL. The MRI features of DNL typically include necrotic changes in the bilateral anterior temporal region, extensive white matter, and/or brainstem lesions. All patients with DNL experienced fatal clinical course despite MTX cessation. Logistic regression analysis revealed that a cumulative dose of MTX significantly affected DNL occurrence. Multivariable analysis showed that the factor of ≥10 MTX rounds was significant for DNL development after adjusting for route of MTX administration and prior brain radiotherapy (odds ratio 7.32, 95% CI 1.42-37.77 at MTX rounds ≥10 vs < 10). In the Cox proportional hazards model considering time to occurrence of DNL, ≥10 rounds of MTX were identified as an independent predictor of DNL (hazard ratio 12.57, 95% CI 1.62-97.28, p = 0.015), even after adjusting for the synergistic effect of brain radiotherapy. DISCUSSION: DNL is a rare but fatal complication of intra-CSF MTX chemotherapy, and its progression cannot be prevented despite early recognition. The cumulative dose of intra-CSF MTX was an independent risk factor for DNL occurrence. Thus, intra-CSF MTX treatment for patients with LM should be administered with caution considering the possibility of the cumulative irreversible neurotoxicity.

JNK signaling plays an important role in the effects of TNF-α and IL-1ß on in vitro osteoblastic differentiation of cultured human periosteal-derived cells.

The purpose of this study was to examine the effects of TNF-α and IL-1ß on in vitro osteoblastic differentiation of cultured human periosteal-derived cells. To examine the effects of TNF-α and IL-1ß on in vitro osteoblastic differentiation of cultured human periosteal-derived cells, the cells cultured in the osteogenic induction medium were treated with 0.1-10 ng/ml TNF-α and 0.01-1 ng/ml IL-1ß. TNF-α and IL-1ß enhanced the alkaline phosphatase (ALP) activity and alizarin red S staining in cultured human periosteal-derived cells. However, these cytokines did not stimulate the Runt-related transcription factor (Runx) 2 activity and osteocalcin secretion. The ALP activity was decreased in the periosteal-derived cells pretreated with mitogen activated protein kinase (MAPK) inhibitors and then treated with TNF-α or IL-1ß. Among the periosteal-derived cells pretreated with MAPK inhibitors, the ALP activity was markedly decreased in the cells pretreated with SP 600125, the specific inhibitor of C-Jun N-terminal kinase (JNK). The periosteal-derived cells treated with TNF-α and IL-1ß showed an increase in extracellular signal-regulated kinase (ERK) and JNK phosphorylation. Among the ERK and JNK phosphorylation, JNK phosphorylation was strongly observed in the cells. These results suggest that TNF-α and IL-1ß increased the in vitro osteoblastic differentiation of cultured human periosteal-derived cells by enhancing the ALP activity and mineralization process, but not by Runx2 activation. The functional role of TNF-α and IL-1ß in increasing the ALP activity and mineralization of periosteal-derived cells primarily depends on the JNK signaling among the MAPK pathways.

An infant with prenatally diagnosed congenital anaplastic astrocytoma who remains disease-free after proton therapy.

The authors present a rare of prenatally diagnosed congenital anaplastic astrocytoma. A 9-month-old boy had three recurrences despite two surgical resections and various chemotherapeutic regimens. He underwent the 3rd gross tumor removal at 11 months of age, followed by proton therapy, and now he remains disease-free for 3 yr without a significant neurocognitive dysfunction. This is the 1st case of a pediatric tumor treated by proton therapy in Korea, and proton therapy may be a treatment of choice for a congenital anaplastic astrocytoma in infants and young children, considering limitation of radiation therapy.

Pancreatic arteriovenous malformation treated with transcatheter arterial embolization: Two case reports and review of literature.

BACKGROUND: Various treatment methods are available for the treatment of pancreatic arteriovenous malformation (P-AVM); however, there are no established treatment options for asymptomatic P-AVM. CASE SUMMARY: A 47-year-old and a 50-year-old male patients sought treatment for P-AVM in the pancreas, which was incidentally detected during routine abdominal computed tomography and magnetic resonance imaging conducted as part of a health check-up. They underwent transcatheter arterial embolization (TAE), and over the course of a 9-year follow-up period, the AVM did not worsen and was asymptomatic. CONCLUSION: TAE can be considered as an alternative treatment option for P-AVM in selective cases where patients are asymptomatic or have a high surgical risk.

Clinical Safety and Efficiency of the H-Port for Treatment of Leptomeningeal Metastasis.

Objective: To evaluate the usefulness of a cranial implantable chemoport, the H-port, as an alternative to the Ommaya reservoir for intraventricular chemotherapy/cerebrospinal fluid (CSF) access in patients with leptomeningeal metastasis (LM). Methods: One hundred fifty-two consecutive patients with a diagnosis of LM and who underwent H-port installation between 2015 and 2021 were evaluated. Adverse events associated with installation and intraventricular chemotherapy, and the rate of increased intracranial pressure (ICP) control via the port were evaluated for safety and efficacy. These indices were compared with published data of Ommaya (n=89), from our institution. Results: Time-to-install and installation-related complications of intracranial hemorrhage (n=2) and catheter malposition (n=5) were not significantly different between the two groups. Intraventricular chemotherapy-related complications of CSF leakage occurred more frequently in the Ommaya than in the H-port group (13/89 vs. 3/152, respectively, p<0.001). Intracranial hemorrhage during chemotherapy occurred only in the Ommaya group (n=4). The CSF infection rate was not statistically different between groups (14/152 vs. 12/89, respectively). The ICP control rate according to reservoir type revealed a significantly higher ICP control rate with the H-port (40/67), compared with the Ommaya result (12/58, p<0.001). Analyzing the ICP control rate based on the CSF drainage method, continuous extraventricular drainage (implemented only with the H-port), found a significantly higher ICP control rate than with intermittent CSF drainage (33/40 vs. 6/56, respectively, p<0.0001). Conclusion: The H-port for intraventricular chemotherapy in patients with LM was superior for ICP control; it had equal or lower complication rates than the Ommaya reservoir.

Leptomeningeal Metastasis in Gliomas : Clinical Characteristics and Risk Factors.

OBJECTIVE: Our objective is to analyze the occurrence, clinical course and risk factors for glioma patients with leptomeningeal metastasis (LM) according to different metastasis patterns and clinical variables. METHODS: We retrospectively reviewed data from 376 World Health Organization (WHO) grade II-IV adult glioma patients who were treated in the National Cancer Center from 2001 to 2020. Patients who underwent surgery at other institutions, those without initial images or those with pathologically unconfirmed cases were excluded. LM was diagnosed based on magnetic resonance imaging (MRI) findings or cerebrospinal fluid (CSF) cytology. The metastasis pattern was categorized as nodular or linear according to the enhancement pattern. Tumor proximity to the CSF space was classified as involved or separated, whereas location of the tumor was dichotomized as midline, for tumors residing in the thalamus, basal ganglia and brainstem, or lateral, for tumors residing in the cerebral and cerebellar hemispheres. RESULTS: A total of 138 patients were enrolled in the study. A total of 44 patients (38%) were diagnosed with LM during a median follow-up of 9 months (range, 0-60). Among the clinical variables, tumor proximity to CSF space, the location of the tumor and the WHO grade were significant factors for LM development in univariate analysis. In multivariate analysis, the midline location of the tumor and WHO grade IV gliomas were the most significant factor for LM development. The hazard ratio was 2.624 for midline located gliomas (95% confidence interval [CI], 1.384-4.974; p=0.003) and 3.008 for WHO grade IV gliomas (95% CI, 1.379-6.561; p=0.006). CONCLUSION: Midline location and histological grading are an important factor for LM in glioma patients. The proximity to the CSF circulation pathway is also an important factor for WHO grade IV glioma LM. Patients carrying high risks should be followed up more thoroughly.

Production and engineering of nanobody-based quenchbody sensors for detecting recombinant human growth hormone and its isoforms.

Due to athletes' misuse of recombinant human growth hormone (rhGH) for performance improvement, the World Anti-Doping Agency has designated rhGH as a prohibited substance. This study focuses on the development and improvement of a simple and fast rhGH detection method using a fluorescence-incorporated antibody sensor "Quenchbody (Q-body)" that activates upon antigen binding. Camelid-derived nanobodies were used to produce stable Q-bodies that withstand high temperatures and pH levels. Notably, pituitary human growth hormone (phGH) comprises two major isoforms, namely 22 and 20 kDa GH, which exist in a specific ratio, and the rhGH variant shares the same sequence as the 22 kDa GH isoform. Therefore, we aimed to discriminate rhGH abuse by analyzing its specific isoform ratio. Two nanobodies, NbPit (recognizing phGH) and NbRec (preferentially recognizing 22 kDa rhGH), were used to develop the Q-bodies. Nanobody production in Escherichia coli involved the utilization of a vector containing 6xHis-tag, and Q-bodies were obtained using a maleimide-thiol reaction between the N-terminal of the cysteine tag and a fluorescent dye. The addition of tryptophan residue through antibody engineering resulted in increased fluorescence intensity (FI) (from 2.58-fold to 3.04-fold). The limit of detection (LOD) was determined using a fluorescence response, with TAMRA-labeled NbRec successfully detecting 6.38 ng/ml of 22 kDa rhGH while unable to detect 20 kDa GH. However, ATTO520-labeled NbPit detected 7.00 ng/ml of 20 kDa GH and 2.20 ng/ml 22 kDa rhGH. Q-bodies successfully detected changes in the GH concentration ratio from 10 to 40 ng/ml in human serum within 10 min without requiring specialized equipment and kits. Overall, these findings have potential applications in the field of anti-doping measures and can contribute to improved monitoring and enforcement of rhGH misuse, ultimately enhancing fairness and integrity in competitive sports.