Preliminary Investigation of a Rapid and Feasible Therapeutic Drug Monitoring Method for the Real-Time Estimation of Blood Pazopanib Concentrations.

Pazopanib is a multi-kinase inhibitor used to treat advanced/metastatic renal cell carcinoma and advanced soft tissue tumors; however, side effects such as diarrhea and hypertension have been reported, and dosage adjustment based on drug concentration in the blood is necessary. However, measuring pazopanib concentrations in blood using the existing methods is time-consuming; and current dosage adjustments are made using the results of blood samples taken at the patient's previous hospital visit (approximately a month prior). If the concentration of pazopanib could be measured during the waiting period for a doctor's examination at the hospital (in approximately 30 min), the dosage could be adjusted according to the patient's condition on that day. Therefore, we aimed to develop a method for rapidly measuring blood pazopanib concentrations (in approximately 25 min) using common analytical devices (a tabletop centrifuge and a spectrometer). This method allowed for pazopanib quantification in the therapeutic concentration range (25-50 µg/mL). Additionally, eight popular concomitant medications taken simultaneously with pazopanib did not interfere with the measurements. We used the developed method to measure blood concentration in two patients and obtained similar results to those measured using the previously reported HPLC method. By integrating it with the point of care and sample collection by finger pick, this method can be used for measurements in pharmacies and patients' homes. This method can maximize the therapeutic effects of pazopanib by dose adjustment to control adverse events.

Clinical Features and Treatment of Patients Infected With SARS-CoV-2 Omicron Variant While Hospitalized Due to Stroke: A Single Center Study in Japan.

BACKGROUND AND OBJECTIVE: In December 2019, COVID-19 spread rapidly across the globe. Throughout the pandemic, SARS-CoV-2 repeatedly mutated, transitioning from the alpha variant to the omicron variant. The severity and mortality of COVID-19 have been linked to age, sex, and the presence of underlying diseases (respiratory, cerebrovascular, cardiovascular, metabolic, and immune diseases, as well as cancer). The clinical features of patients infected with COVID-19 following a stroke, however, are fully unknown. Therefore, it is significant to explore the appropriate treatment for these patients based on their clinical features. METHODS: Of the 6175 patients who visited Asahi Hospital (Tokyo, Japan) between November 2022 and February 2023, 206 were admitted. Of these 206 patients, the 44 that contracted COVID-19 while hospitalized for strokes were retrospectively analyzed. RESULTS: Six (13.6%) of these patients died; four expired due to coagulopathy associated with ischemic heart failure and recurrent ischemic cerebrovascular disease. The mean D-dimer level increased to 3.53 in the deceased patients, while it was 1.64 in all patients. The platelet count was low in three of the deceased patients, while it was high in two patients. The severity of COVID-19 was significantly correlated with a high modified Rankin Scale (mRS) score and a high National Institute of Health Stroke Scale (NIHSS) score. The timing of vaccination is inversely correlated with COVID-19 severity. CONCLUSION: Patients with COVID-19 after a stroke have high mortality rates due to coagulopathy. Stroke patients with high mRS scores and high NIHSS scores are more likely to develop severe COVID-19. Anticoagulant therapy should be administered to COVID-19 patients with high mRS scores following a stroke.

OPTIMAL PLASMA CONCENTRATION OF THROMBOMODULIN ALFA TO TREAT SEPSIS-INDUCED DISSEMINATED INTRAVASCULAR COAGULATION.

ABSTRACT: Thrombomodulin alfa (TM alfa) has been shown effective for treatment of disseminated intravascular coagulation (DIC) associated with sepsis, although the optimal therapeutic plasma concentration has not been clarified. In the present study, the plasma trough concentration of TM alfa in septic patients with DIC was determined, then the cutoff value for that concentration showing influence on treatment outcome was calculated using a receiver operating characteristic curve. With a cutoff value of 1,010, the area under the curve of the receiver operating characteristic was 0.669 (95% confidence interval, 0.530-0.808), with sensitivity of 0.458 and specificity of 0.882. To evaluate its accuracy, patients were divided into those above or below the cutoff value, and 90-day survival rates were compared. The above-cutoff group showed a significantly higher 90-day survival rate (91.7%) as compared with the below-cutoff group (63.4%) ( P = 0.017), with a hazard ratio of 0.199 (95% confidence interval, 0.045-0.871). Interestingly, the incidence of hemorrhagic adverse effects was not significantly different between the groups. Based on these results, the recommended plasma trough concentration of TM alfa for treatment of septic DIC is 1,010 ng/mL, which should minimize the risk of severe bleeding while maximizing the therapeutic effect.

Role of SOCS and VHL Proteins in Neuronal Differentiation and Development.

The basic helix-loop-helix factors play a central role in neuronal differentiation and nervous system development, which involve the Notch and signal transducer and activator of transcription (STAT)/small mother against decapentaplegic signaling pathways. Neural stem cells differentiate into three nervous system lineages, and the suppressor of cytokine signaling (SOCS) and von Hippel-Lindau (VHL) proteins are involved in this neuronal differentiation. The SOCS and VHL proteins both contain homologous structures comprising the BC-box motif. SOCSs recruit Elongin C, Elongin B, Cullin5(Cul5), and Rbx2, whereas VHL recruits Elongin C, Elongin B, Cul2, and Rbx1. SOCSs form SBC-Cul5/E3 complexes, and VHL forms a VBC-Cul2/E3 complex. These complexes degrade the target protein and suppress its downstream transduction pathway by acting as E3 ligases via the ubiquitin-proteasome system. The Janus kinase (JAK) is the main target protein of the E3 ligase SBC-Cul5, whereas hypoxia-inducible factor is the primary target protein of the E3 ligase VBC-Cul2; nonetheless, VBC-Cul2 also targets the JAK. SOCSs not only act on the ubiquitin-proteasome system but also act directly on JAKs to suppress the Janus kinase-signal transduction and activator of transcription (JAK-STAT) pathway. Both SOCS and VHL are expressed in the nervous system, predominantly in brain neurons in the embryonic stage. Both SOCS and VHL induce neuronal differentiation. SOCS is involved in differentiation into neurons, whereas VHL is involved in differentiation into neurons and oligodendrocytes; both proteins promote neurite outgrowth. It has also been suggested that the inactivation of these proteins may lead to the development of nervous system malignancies and that these proteins may function as tumor suppressors. The mechanism of action of SOCS and VHL involved in neuronal differentiation and nervous system development is thought to be mediated through the inhibition of downstream signaling pathways, JAK-STAT, and hypoxia-inducible factor-vascular endothelial growth factor pathways. In addition, because SOCS and VHL promote nerve regeneration, they are expected to be applied in neuronal regenerative medicine for traumatic brain injury and stroke.

Real-time intelligent classification of COVID-19 and thrombosis via massive image-based analysis of platelet aggregates.

Microvascular thrombosis is a typical symptom of COVID-19 and shows similarities to thrombosis. Using a microfluidic imaging flow cytometer, we measured the blood of 181 COVID-19 samples and 101 non-COVID-19 thrombosis samples, resulting in a total of 6.3 million bright-field images. We trained a convolutional neural network to distinguish single platelets, platelet aggregates, and white blood cells and performed classical image analysis for each subpopulation individually. Based on derived single-cell features for each population, we trained machine learning models for classification between COVID-19 and non-COVID-19 thrombosis, resulting in a patient testing accuracy of 75%. This result indicates that platelet formation differs between COVID-19 and non-COVID-19 thrombosis. All analysis steps were optimized for efficiency and implemented in an easy-to-use plugin for the image viewer napari, allowing the entire analysis to be performed within seconds on mid-range computers, which could be used for real-time diagnosis.

Quantitative determination of plasma cabozantinib concentration using HPLC-UV and its application to patients with renal cell carcinoma.

Cabozantinib is an oral small-molecule tyrosine kinase inhibitor that has become a standard of care for advanced renal cell carcinoma (RCC). However, cabozantinib is associated with a high rate of adverse events. Therefore, individualised cabozantinib administration and monitoring could help maximise its therapeutic efficacy and avoid serious adverse events. This study developed and validated a method to determine cabozantinib concentration in plasma using HPLC-UV. Sorafenib, an internal standard, was added to the plasma sample containing cabozantinib. A calibration curve for cabozantinib showed good linearity (R2 = 1.00), between 25 and 4,000 ng/ml. The recovery rate was above 92.1%, and the intra- and inter-day coefficients of variation were smaller than 5.2 and 6.8%, respectively. Then, we applied the method for monitoring cabozantinib blood levels in three patients with advanced RCC who were taking cabozantinib at a dose of 20, 40 or 60 mg/day. Grade 3 adverse events were more likely to occur in patients with high dosing and blood level of cabozantinib. Owing to its simplicity, the developed method can be used in general hospitals, and is expected to help maximise drug efficacy and minimise serious adverse events in many patients with RCC undergoing cabozantinib treatment.

SOCS7-Derived BC-Box Motif Peptide Mediated Cholinergic Differentiation of Human Adipose-Derived Mesenchymal Stem Cells.

Adipose-derived mesenchymal stem cells (ADMSCs) are a type of pluripotent somatic stem cells that differentiate into various cell types such as osteoblast, chondrocyte, and neuronal cells. ADMSCs as donor cells are used to produce regenerative medicines at hospitals and clinics. However, it has not been reported that ADMSCs were differentiated to a specific type of neuron with a peptide. Here, we report that ADMSCs differentiate to the cholinergic phenotype of neurons by the SOCS7-derived BC-box motif peptide. At operations for patients with neurological disorders, a small amount of subcutaneous fat was obtained. Two weeks later, adipose-derived mesenchymal stem cells (ADMSCs) were isolated and cultured for a further 1 to 2 weeks. Flow cytometry analysis for characterization of ADMSCs was performed with CD73, CD90, and CD105 as positive markers, and CD14, CD31, and CD56 as negative markers. The results showed that cultured cells were compatible with ADMSCs. Immunocytochemical studies showed naïve ADMSCs immunopositive for p75NTR, RET, nestin, keratin, neurofilament-M, and smooth muscle actin. ADMSCs were suggested to be pluripotent stem cells. A peptide corresponding to the amino-acid sequence of BC-box motif derived from SOCS7 protein was added to the medium at a concentration of 2 µM. Three days later, immunocytochemistry analysis, Western blot analysis, ubiquitination assay, and electrophysiological analysis with patch cramp were performed. Immunostaining revealed the expression of neurofilament H (NFH), choline acetyltransferase (ChAT), and tyrosine hydroxylase (TH). In addition, Western blot analysis showed an increase in the expression of NFH, ChAT, and TH, and the expression of ChAT was more distinct than TH. Immunoprecipitation with JAK2 showed an increase in the expression of ubiquitin. Electrophysiological analysis showed a large holding potential at the recorded cells through path electrodes. The BC-box motif peptide derived from SOCS7 promoted the cholinergic differentiation of ADMSCs. This novel method will contribute to research as well as regenerative medicine for cholinergic neuron diseases.

Long-term effects of Pfizer-BioNTech COVID-19 vaccinations on platelets.

There is a global concern about the safety of COVID-19 vaccines associated with platelet function. However, their long-term effects on overall platelet activity remain poorly understood. Here we address this problem by image-based single-cell profiling and temporal monitoring of circulating platelet aggregates in the blood of healthy human subjects, before and after they received multiple Pfizer-BioNTech (BNT162b2) vaccine doses over a time span of nearly 1 year. Results show no significant or persisting platelet aggregation trends following the vaccine doses, indicating that any effects of vaccinations on platelet turnover, platelet activation, platelet aggregation, and platelet-leukocyte interaction was insignificant.

Usefulness of criteria for intraoperative Management of Postoperative Nausea and Vomiting.

BACKGROUND: Postoperative nausea and vomiting (PONV) delays postoperative recovery, prolongs hospital stays, and hinders patients' return to society, thus making it a major cause of increased healthcare costs. It is also the most troubling postoperative complication in female patients undergoing surgery. However, in Japan, guidelines for the management of PONV have not been established, and the management protocol for PONV is left to each institution and anesthesiologist. Therefore, we developed criteria for intraoperative management of PONV. METHODS: In female surgical patients, the usefulness of the criteria was evaluated by comparing the implementation rate of intraoperative management and PONV incidence before and after the establishment of the criteria. An Apfel simplified score (Apfel score) ≥2 was set as an indication for intraoperative management of PONV. RESULTS: The implementation rate of intraoperative management increased from 91.2 to 96.0% after the introduction of the criteria. In patients with an Apfel score of 2, the intraoperative management implementation rate significantly increased from 81.1 to 94.7% (p = 0.016), while PONV incidence significantly decreased from 44.6 to 34.1% after the introduction of the criteria (p = 0.040). CONCLUSIONS: The criteria for intraoperative management of PONV increased the implementation rate of intraoperative management and decreased PONV incidence, indicating the usefulness of the criteria.

Massive image-based single-cell profiling reveals high levels of circulating platelet aggregates in patients with COVID-19.

A characteristic clinical feature of COVID-19 is the frequent incidence of microvascular thrombosis. In fact, COVID-19 autopsy reports have shown widespread thrombotic microangiopathy characterized by extensive diffuse microthrombi within peripheral capillaries and arterioles in lungs, hearts, and other organs, resulting in multiorgan failure. However, the underlying process of COVID-19-associated microvascular thrombosis remains elusive due to the lack of tools to statistically examine platelet aggregation (i.e., the initiation of microthrombus formation) in detail. Here we report the landscape of circulating platelet aggregates in COVID-19 obtained by massive single-cell image-based profiling and temporal monitoring of the blood of COVID-19 patients (n = 110). Surprisingly, our analysis of the big image data shows the anomalous presence of excessive platelet aggregates in nearly 90% of all COVID-19 patients. Furthermore, results indicate strong links between the concentration of platelet aggregates and the severity, mortality, respiratory condition, and vascular endothelial dysfunction level of COVID-19 patients.

Anaplastic myxopapillary ependymoma: A case report and review of literature.

BACKGROUND: Myxopapillary ependymoma (MPE) is a pathological grade I tumor that arises in the filum terminale. MPE with anaplastic features is extremely rare, and only 5 cases have shown malignancy at the time of recurrence. CASE SUMMARY: The patient (a 46-year-old woman) had undergone a MPE operation 30 years ago. After subtotal resection of the tumor located in L4-S1, it had a solid component that extended to the adjacent subcutaneous region. Histologically, the tumor consisted of a typical MPE with anaplastic features. The anaplastic areas of the tumor showed hypercellularity, a rapid mitotic rate, vascular proliferation, and connective tissue proliferation. Pleomorphic cells and atypical mitotic figures were occasionally observed. The MIB-1 index in this area was 12.3%. The immunohistochemical study showed immunoreactivity for vimentin, glial fibrillary acidic protein and S100. The morphological pattern and immunohistochemical profile were consistent with anaplastic MPE. The patient tolerated surgery well without new neurological deficits. She underwent local irradiation for the residual tumor and rehabilitation. CONCLUSION: Although extremely rare, anaplastic MPE occurs in both pediatric and adult patients, similar to other ependymomas. At a minimum, close monitoring is recommended, given concerns about aggressive biological potential. In the future, further study is needed to determine the WHO classification criteria and genetic indicators of tumor progression. The possibility of malignant transformation of MPE should be taken into account, and patients with MPE should be treated with care and follow-up.

Efficacy of Supraclavicular Scalenotomy Followed by External Neurolysis without Rib Resection for Post-traumatic Neurogenic Thoracic Outlet Syndrome.

MINI: Most patients with neurogenic thoracic outlet syndrome (NTOS) have a history of trauma. Scar tissue formation within the scalene muscle and around the nerves after injury cause arm and hand symptoms. We report that supraclavicular scalenotomy followed by external neurolysis without rib resection is very effective as the surgical treatment.

Consecutive case series. Our aim was to evaluate the outcomes of patients who underwent supraclavicular scalenotomy followed by external neurolysis without rib resection for post-traumatic NTOS. Neurogenic thoracic outlet syndrome (NTOS) comprises over 95% of all TOS patients, and most patients with NTOS have a history of trauma before the onset of their symptoms. Patients treated with supraclavicular scalenotomy and neurolysis without rib resection from September 2014 to December 2019 were retrospectively reviewed by using the medical records and operative notes. Patient's characteristics, clinical symptoms before treatment, operative findings, and short- and long-term outcomes were assessed. To assess clinical outcomes at 2 months after surgery (short-term outcomes) and 12 months later (long-term outcomes), we used a 4-grade categorization (Excellent, Good, Fair, and Poor) of patients' subjective evaluations after surgery on the basis of modified Odom's criteria. Excellent and Good were defined as a successful outcome. Ninety-six supraclavicular scalenotomies without rib resection were performed on patients with post-traumatic NTOS. The most common intraoperative observation was the fibrous bands within the anterior scalene muscle in 86 cases (89.6%). The short-term outcome with patients' subjective evaluation in 96 operations at 2 months after surgery showed a 96.9% success rate (Excellent + Good). In 85 cases followed for more than 12 months after surgery, the success rate based on patients' subjective evaluation at the last clinic follow-up appointment as a long-term outcome was 74.1%. In post-traumatic NTOS, it has been reported the arm and hand symptoms are due to pressure on the brachial plexus, which can stem from the swollen muscle following injuries and later from tightness of the scarred muscle. Considering this mechanism and our results, we concluded that supraclavicular scalenotomy and external neurolysis without rib resection made sense, as they were very effective and adequate to improve symptoms of NTOS. Level of Evidence: 5.

BC-Box Motif in SOCS6 Induces Differentiation of Epidermal Stem Cells into GABAnergic Neurons.

The BC-box motif in suppressor of cytokine signaling 6 (SOCS6) promotes the neuronal differentiation of somatic stem cells, including epidermal stem cells. SOCS6 protein belongs to the group of SOCS proteins and inhibits cytokine signaling. Here we showed that epidermal stem cells were induced to differentiate into GABAnergic neurons by the intracellular delivery of a peptide composed of the amino-acid sequences encoded by the BC-box motif in SOCS6 protein. The BC-box motif (SLQYLCRFVI) in SOCS6 corresponded to the binding site of elongin BC. GABAnergic differentiation mediated by the BC-box motif in SOCS6 protein was caused by ubiquitination of JAK2 and inhibition of the JAK2-STAT3 pathway. Furthermore, GABAnergic neuron-like cells generated from epidermal stem cells were transplanted into the brain of a rodent ischemic model. Then, we demonstrated that these transplanted cells were GAD positive and that the cognitive function of the ischemic model rodents with the transplanted cells was improved. This study could contribute to not only elucidating the mechanism of GABAnergic neuronal differentiation but also to neuronal regenerative medicine utilizing GABAnergic neurons.

Role of VHL-JAK-STAT signaling pathway in central nervous system hemangioblastoma associated with von Hippel-Lindau disease.

INTRODUCTION: Central nervous system hemangioblastoma is a benign tumor associated with or without von Hippel-Lindau (VHL) disease which is an autosomal dominant hereditary disease that results from a germline mutation in the VHL gene. A main axis of signaling pathways in central nervous system hemangioblastoma is VHL-HIF signaling pathway. Here, we propose an alternative VHL-JAK-STAT signaling pathway in hemangioblastoma and discuss the role. METHODS: Using MACS method, Scl+ hemangioblast-like cells were isolated from multipotent nestin-expressing stem cells. Then, ubiquitination of JAK2 in those cells and immunoprecipitation between JAK2 and VHL were examined. Then, expressions of JAK2 and STAT3 in those cells and expressions of VHL-associated hemangioblastoma tissues were examined. In addition, the VHL genes of patients bearing hemangioblastoma were analyzed. RESULTS: JAK2 and STAT3 in Scl+ hemangioblast-like cells were ubiquitinated after VHL- expression vector was transferred to those cells. Expressions of JAK2 and STAT3 in those cells were well recognized before the transfer, but those disappeared after the transfer. Expressions of both JAK2 and STAT3 in hemangioblastoma tissues were well shown. The VHL gene analysis revealed that patients bearing hemangioblastoma carried missense mutations in 5, small deletions in 2, large deletions in 4, and nonsense mutation in 1 CONCLUSIONS: VHL-JAK-STAT signaling pathway might play an important role in proliferation, angiogenesis, and maintenance of stem-cell-nature in hemangioblastoma as an alternative signaling pathway to supplement VHL-HIF signaling pathway.

High-speed single-pixel imaging by frequency-time-division multiplexing.

We propose and experimentally demonstrate high-speed single-pixel imaging by integrating frequency-division multiplexing and time-division multiplexing (techniques used widely in telecommunications) and applying the combined technique, namely, frequency-time-division multiplexing (FTDM), to optical imaging. Specifically, FTDM single-pixel imaging uses an array of broadband, spatially distributed, dual-frequency combs (i.e., spatial dual combs) for multidimensional illumination and detects an image-encoded time-domain signal with a single-pixel photodetector in a FTDM manner. As a proof-of-principle demonstration, we use the method to show ultrafast two-color (bright-field and fluorescence) single-pixel microscopy of breast cancer cells at a high frame rate of 32,000 fps and ultrafast image velocimetry of fluorescent particles flowing at a high speed of ${ \gt }{2}\;{\rm m/s}$>2m/s.

Predictors of the Response to an Epidural Blood Patch in Patients with Spinal Leakage of Cerebrospinal Fluid.

BACKGROUND AND PURPOSE: An epidural blood patch (EBP) is a highly effective therapy for spinal cerebrospinal fluid (CSF) leakage. However, the factors predicting the response to an EBP have not been fully elucidated. The aim of this study was to elucidate factors predicting the response to an EBP. METHODS: We retrospectively examined the relationship between the response to an EBP and clinical variables of 118 patients with spinal CSF leakage, such as patient age, sex, etiology, interval from the onset to EBP application, CSF opening pressure (OP), radioisotope (RI) cisternography findings, rate of RI remaining in the CSF space, computed tomography (CT) myelography findings, magnetic resonance imaging (MRI) findings, and subjective symptoms (headache, vertigo/dizziness, visual disturbance, nausea, numbness, nuchal pain, back pain/lumbago, fatigability, photophobia, and memory disturbance). The correlations between these variables and the responses to EBPs were analyzed statistically. RESULTS: A positive response to an EBP was significantly (p<0.05) correlated with the following variables: <1.5 years from the onset to EBP application, age <40 years, CSF OP <7 cm H2O, epidural CSF leakage in RI cisternography, epidural CSF collection in MRI, <20% RI remaining after 24 hours, orthostatic headache, nausea, nuchal pain, and photophobia. The other variables did not show significant correlations with the responses to EBPs. CONCLUSIONS: It might be prudent to take the following variables into account when applying an EBP to treat spinal CSF leakage: the interval from the onset to EBP application, age, CSF OP, epidural CSF leakage in RI, epidural CSF collection in MRI, rate of remaining RI, orthostatic headache, nuchal pain, photophobia, and nausea.

Therapeutic and Adverse Effects of Thrombomodulin Alfa to Treat Sepsis-Induced Disseminated Intravascular Coagulation.

In the treatment of disseminated intravascular coagulation (DIC), which is a complication of underlying diseases such as infections and malignant tumors, effective plasma concentrations of thrombomodulin (TM) alfa range from 300 to 900 ng/mL; however, appropriate concentrations when treating sepsis-induced DIC are unknown. Thus, our aim was to determine the relationship between plasma concentrations of TM alfa and its therapeutic effects, and hemorrhagic adverse events. First, we calculated the plasma trough concentrations of TM alfa in septic DIC patients. Next, we divided patients into two groups according to their plasma concentrations into a low- and high-concentration group based on a cut-off value of 600 ng/mL. Fourteen and 35 patients were included in the low- and high-concentration groups, respectively. The Japanese Association for Acute Medicine DIC diagnostic criteria score 4 days after TM alfa administration decreased significantly by 2.06 points from baseline in the high-concentration group compared with 0.71 points in the low-concentration group. The 90-day survival rate was significantly higher in the high-concentration group (85.4%) than in the low-concentration group (49.0%) (hazard ratio, 0.27; 95% confidence interval: 0.09-0.86). In contrast, the incidence of serious hemorrhage was not significantly different between the groups. The recommended plasma concentration of TM alfa in the treatment of septic DIC was determined to be higher than 600 ng/mL, and a dose of 380 U/kg (0.06 mg/kg) was necessary to achieve this concentration.

Simple, stable, compact implementation of frequency-division-multiplexed microscopy by inline interferometry.

Frequency-division-multiplexed (FDM) imaging is a powerful method for high-speed imaging that surpasses the speed limit of conventional imaging constrained by the frame rate of image sensors. However, its complexity, instability, and bulkiness deriving from the implementation with a Mach-Zehnder interferometer hamper its practical applications. Here we demonstrate a simple, stable, and compact implementation of FDM imaging by inline interferometry that makes the method readily available to practical situations. As a proof-of-concept demonstration, we demonstrate 2D bright-field and fluorescence image acquisition of fluorescent beads, microalgal cells, and breast cancer cells within 65.5 µs, corresponding to 15,300 frames per second.

[Efficacy and Safety of Salvage ESHAP Chemotherapy for Recurrent/Refractory PCNSLs].

BACKGROUND: Primary central nervous system lymphoma(PCNSL)is a primary brain tumor, which appears commonly and occupies around 4.6% of all primary brain tumors. The standard therapy for this tumor is high-dose methotrexate chemotherapy(HD-MTX)and whole-brain irradiation. No salvage therapies for HD-MTX therapy-refractory or recurrent PCNSLs have been standardized. In our institution, ESHAP therapy(high-dose cytarabine:2,000mg, cisplatin:25mg/m2, etoposide:40mg/m2, methylprednisolone:500mg)was administered as a secondary chemotherapy, and the efficiency was examined. METHODS: We administered ESHAP therapy as secondary chemotherapy for patients with refractory/recurrent PCNSL after HD-MTX therapy. Patients with PCNSL who were diagnosed and treated at our institute since 1996 were retrospectively studied. Clinical evaluations were performed based on Karnofsky Performance Status and overall survival, and the effect of ESHAP therapy was evaluated using the Response Assessment in Neuro-Oncology criteria. RESULTS: The number of patients with refractory/recurrent PCNSLs were 18(28-77 years of age, median age of 58.5 years). The response rate(RR)after the first course of salvage ESHAP therapy was 77.8%(14 cases), and complete response(CR)was achieved in 6 cases. The RR after the final course of ESHAP therapy was as high as 61.1%(11 cases), and 4 patients retained CR status. In patients with refractory PCNSL who were treated with HD-MTX, the RR in the final course of salvage ESHAP therapy was as high as 77.8%(7 cases), and 3 patients retained CR status during the periods. The occurrence rate of Grade 3 or higher adverse events, according to the Common Terminology Criteria for Adverse Events version 4.0, was 66.7%(12 cases);all events that were associated with blood and lymphatic system disorders were quickly alleviated, and no fatal adverse events occurred. CONCLUSION: In this study, we retrospectively examined the efficacy of ESHAP therapy as a secondary chemotherapy for patients with refractory/recurrent PCNSL after receiving HD-MTX therapy. Based on our findings, we suggest that ESHAP therapy should be considered as an encouraging secondary chemotherapy for patients with refractory/recurrent PCNSL.

VHL-Associated Optic Nerve Hemangioblastoma Treated with Stereotactic Radiosurgery.

Central nervous system hemangioblastomas are generally restricted to the cerebellum, spinal cord, and brainstem. Supratentorial hemangioblastomas are uncommon, and optic nerve hemangioblastomas are extremely rare, with fewer than 25 reports including this case. In this report, we present the case of a 36-year-old woman with von Hippel-Lindau (VHL) disease who presented with progressive diminution of vision in the left eye due to a retrobulbar optic nerve hemangioblastoma. The patient had a history of cerebellar/spinal hemangioblastomas and pancreatic cysts, and her father and brother were patients with VHL disease. Gadolinium-enhanced magnetic resonance imaging showed intraorbital retrobulbar-enhanced mass on the left optic nerve. The optic nerve hemangioblastoma was treated with fractionated stereotactic radiosurgery using Novalis. Eighteen months after the stereotactic radiosurgery, the tumor volume decreased although the patient lost vision. This report presents an extremely rare case of optic nerve hemangioblastoma, which is the first case treated with stereotactic radiosurgery.