Clinical utility of the Oncomine Dx Target Test multi-CDx system and the possibility of utilizing those original sequence data.

BACKGROUND: Companion diagnostic tests play a crucial role in guiding treatment decisions for patients with non-small cell lung cancer (NSCLC). The Oncomine Dx Target Test (ODxTT) Multi-CDx System has emerged as a prominent companion diagnostic method. However, its efficacy in detecting driver gene mutations, particularly rare mutations, warrants investigation. AIMS: This study aimed to assess the performance of the ODxTT in detecting driver gene mutations in NSCLC patients. Specifically, we aimed to evaluate its sensitivity in detecting epidermal growth factor receptor (EGFR) mutations, a key determinant of treatment selection in NSCLC. MATERIALS AND METHODS: We conducted a retrospective analysis of NSCLC patients who underwent testing with the ODxTT at Keio University Hospital between May 2020 and March 2022. Patient samples were subjected to both DNA and RNA tests. Driver gene mutation status was assessed, and instances of missed mutations were meticulously examined. RESULTS: Of the 90 patients, five had nucleic acid quality problems, while 85 underwent both DNA and RNA tests. Driver gene mutations were detected in 56/90 (62.2%) patients. Of the 34 patient specimens, driver mutations were not detected using the ODxTT; however, epidermal growth factor receptor (EGFR) mutations were detected using polymerase chain reaction-based testing in two patients, and a KRAS mutation was detected by careful examination of the sequence data obtained using the ODxTT in one patient. For the above three cases, carefully examining the gene sequence information obtained using the ODxTT could identify driver mutations that were not mentioned in the returned test results. Additionally, we confirmed comparable instances of overlook results for EGFR mutations in the dataset from South Korea, implying that this type of oversight could occur in other countries using the ODxTT. EGFR mutation was missed in ODxTT in Japan (6.3%, 2/32), South Korea (2.0%, 1/49), and overall (3.7%, 3/81). CONCLUSION: Even if sufficient tumor samples are obtained, rare EGFR mutations (which are excluded from the ODxTT's genetic mutation list) might not be detected using the current ODxTT system due to the program used for sequence analysis. However, such rare EGFR mutations can still be accurately detected on ODxTT's sequence data using next-generation sequencing.

Cat Scratch Disease-associated Encephalitis Followed by Parkinsonism.

Cat scratch disease (CSD) is a zoonotic infection caused by Bartonella henselae typically resulting in self-limited regional lymphadenopathy. Encephalitis is a complication with a supposedly benign prognosis, but we encountered an exceptional case. A 19-year-old Japanese woman presented with status epilepticus. She was diagnosed with CSD-associated encephalitis based on her history of contact with a kitten and a high titre of serum IgG to B. henselae. Multimodal treatment ameliorated her encephalitis, but neurological sequelae including spastic paraparesis, persisted. After several months, she developed age-disproportionate parkinsonism inconsistent with a neurodegenerative disease. In conclusion, CSD-associated encephalitis can result in severe neurological sequelae and post-encephalitic parkinsonism.

A Probable Case of Mirogabalin-Induced Neutropenia.

Mirogabalin is a novel ligand for the α2δ subunit of voltage-gated calcium channels and is used to treat neuropathic pain in a similar manner to pregabalin. Although the frequency of pregabalin-induced neutropenia has been reported as 0.3%-1%, mirogabalin-induced neutropenia has not previously been reported in the literature. Herein, we report what we believe is the first case of neutropenia induced by mirogabalin. A 77-year-old woman with squamous cell carcinoma of the lung had been taking mirogabalin at 10 mg/day for six weeks prior to admission to our hospital. She had received two courses of chemotherapy with carboplatin and nanoparticle albumin-bound (nab)-paclitaxel for lung cancer until four months before admission, followed by two courses of nivolumab until one month before admission. The patient was hospitalized for urinary tract infection (UTI), which improved with oral amoxicillin/clavulanic acid at 500/125 mg three times daily for five days (until the fifth hospital day). After that, she underwent rehabilitation to improve muscle strength. During rehabilitation, neutropenia (1,278/µL) was noted, acetaminophen and mexiletine were ceased, and filgrastim was started on hospital day 17. The neutrophil count was 755/µL on hospital day 18. Mirogabalin was discontinued on hospital day 19. The neutrophil count fell to 320/µL and 118/µL on hospital day 20 and day 21, respectively, and recovered to 1,064/µL on hospital day 24. Acetaminophen and mexiletine were resumed on hospital day 31 and neutropenia has not recurred since.

Sub-classification of apraxia of speech in patients with cerebrovascular and neurodegenerative diseases.

Some studies have hypothesized that primary progressive apraxia of speech (ppAOS) consists of heterogeneous symptoms that can be sub-classified; however, no study has classified stroke-induced AOS (sAOS) and ppAOS according to common criteria. The purpose of this study was to elucidate the symptoms and relevant brain regions associated with sAOS and ppAOS for sub-classification. Participants included 8 patients with sAOS following lesions in the left precentral gyrus and/or underlying white matter, and 3 patients with ppAOS. All patients with sAOS could be classified into three subtypes: type I, with prominent distorted articulation; type II, with prominent prosodic abnormalities or type III, with similarly distorted articulation and prosodic abnormalities. This sub-classification was consistent with the subtypes of ppAOS proposed in previous reports. All patients with ppAOS were classified as type III, and exhibited three characteristics distinguishable from those of sAOS. First, they showed prominent lengthened syllables compared with the segmentation of syllables. Second, they could not always complete the production of multi-syllabic single words in one breath. Finally, they showed dysfunctional lesions in the bilateral supplementary motor area. We conclude that sAOS and ppAOS can be sub-classified and are universal symptoms that are common between the English and Japanese populations.

Accuracy and validity of sentinel lymph node biopsy for breast cancer using a photosensitizer: 8-year follow-up.

BACKGROUND AND OBJECTIVE: We evaluated an alternative procedure for sentinel lymph node biopsy (SLNB) for breast cancer after approval of the study by the Ethics Committee of Tokyo Medical University Hospital in 2004. We examined the efficacy and safety of SLNB using the photosensitizer talaporfin sodium (Laserphyrin®, Meiji Seika Pharma, Tokoyo, Japan), compared with current methods. STUDY DESIGN/PATIENTS AND METHODS: The study included 21 breast cancer patients (Japanese women; median age, 54 years; range, 35-75). All patients received a breast cancer operation combined with SLNB between June 2004 and May 2005. Three milliliters of talaporfin solution was locally injected into the subareolar region just before the operation. We attempted to identify a sentinel lymph node (SLN) that exhibited fluorescence and was consistent with a radioisotope (RI) localization technique. Our purpose was to verify the accuracy and validity of the talaporfin fluorescence imaging method after 8 years of application. RESULTS: There was no consistent correlation between fluorescence and pathological SLN metastasis, although all four cases of pathological SLN metastasis revealed positive fluorescence. In some cases in which we could not identify SLNs by the RI technique, we could identify SLNs using talaporfin. The method using talaporfin did not adversely affect the patients after the operation, even the chronic renal failure patient. After 8 years, all patients are alive, and none had lymph node recurrence. Side effects were not observed. CONCLUSION: SLNB using the photosensitizer talaporfin sodium in breast cancer patients is considered to be useful as complementary to other current methods. We could evaluate the accuracy and validity of this method 8 years after all of the procedures were performed. In the future, a large-scale clinical study with statistical analyses should be conducted.

Concurrent use of Sr-89 chloride with zoledronic acid is safe and effective for breast cancer patients with painful bone metastases.

Our aim in this study was to examine the safety and efficacy of the concurrent use of the radiopharmaceutical strontium-89 (Sr-89) chloride with zoledronic acid in standard anticancer therapy for breast cancer patients with painful multifocal bone metastases. The study comprised 16 breast cancer patients with painful multifocal bone metastases detected by bone scintigraphy, computed tomography or magnetic resonance imaging. All patients were treated with Sr-89 and zoledronic acid concurrently between March 2007 and February 2011 as part of a standard therapeutic regimen comprising chemotherapy, endocrine therapy, molecular targeting therapy and targeted radiotherapy. Sr-89 was administered intravenously at 2 MBq/kg to a maximum of 141 MBq per person. Safety was evaluated according to myelotoxicity as measured by the Common Terminology Criteria for Adverse Events (v3.0). To assess treatment efficacy, we monitored changes in analgesic drug dosages. Furthermore, bremsstrahlung imaging after the administration of Sr-89 was utilized to examine the relationship between the accumulation of Sr-89 in metastatic sites and treatment efficacy. Based on the results, a total of 14 out of 16 patients (88%) reported bone pain relief, indicating a high efficacy of Sr-89 combined with zoledronic acid. In responsive cases, a strong uptake of Sr-89 was observed on bremsstrahlung imaging at the same sites indicated by (99m)Tc bone scintigraphy. Moreover, severe myelosuppression (> grade 3) was not observed, and adverse events were tolerable. In conclusion, the use of Sr-89 with zoledronic acid in breast cancer patients with painful bone metastases was safe and effective when administered concurrently with other standard therapies. In the future, the treatment with Sr-89 at the early stage should be considered, and a large-scale clinical study should be conducted.

[A case of combined glossopharyngeal and trigeminal neuralgia].

It is well-known that idiopathic neuralgias of the trigeminal and glossopharyngeal nerves are caused by vascular compression at the root entry zone of the cranial nerves. Because they are functional diseases, initial treatment is medical, especially with carbamazepine. However, if medical therapy fails to adequately manage the pain, microvascular decompression (MVD) is prescribed. Glossopharyngeal neuralgia is rare, and combined trigeminal and glossopharyngeal neuralgia is an extremely rare disorder. A 70-year-old woman presented herself to Hokkaido Neurosurgical Memorial Hospital because of paroxysms of lancinating pain in her left pharynx and another lancinating pain in her left cheek. Carbamazepine, which was prescribed at another hospital, favorably relieved the pain; however, drug eruption compelled her to discontinue the medication. The multi-volume method revealed that a root entry zone of the left glossopharyngeal nerve was compressed by the left posterior inferior cerebellar artery, and the left trigeminal artery was compressed by the left superior cerebellar artery. MVD for both nerves was performed employing a left lateral suboccipital craniotomy. She experienced complete relief of pain immediately after MVD. Combined trigeminal and glossopharyngeal neuralgia is extremely rare, but some groups noted a relatively high incidence of concurrent trigeminal neuralgia in patients with glossopharyngeal neuralgia up until the 1970's. Glossopharyngeal neuralgia includes pain near the gonion; therefore, there is an overlap of symptoms between glossopharyngeal and trigeminal neuralgias. By virtue of recent progress in imaging technology, minute preoperative evaluations of microvascular compression are possible. Until the 1970's, there might have been some misunderstanding regarding the overlap of symptoms because of lack of the concept of microvascular compression as a cause of neuralgia and rudimentary imaging technology. Minute evaluations of both symptoms and imaging are very important.

Comparative proteomic analysis of the ribosomes in 5-fluorouracil resistance of a human colon cancer cell line using the radical-free and highly reducing method of two-dimensional polyacrylamide gel electrophoresis.

Many auxiliary functions of ribosomal proteins (r-proteins) have received considerable attention in recent years. However, human r-proteins have hardly been examined by proteomic analysis. In this study, we isolated ribosomal particles and subsequently compared the proteome of r-proteins between the DLD-1 human colon cancer cell line and its 5-fluorouracil (5-FU)-resistant sub-line, DLD-1/5-FU, using the radical-free and highly reducing method of two-dimensional polyacrylamide gel electrophoresis, which has a superior ability to separate basic proteins, and we discuss the role of r-proteins in 5-FU resistance. Densitometric analysis was performed to quantify modulated proteins, and protein spots showing significant changes were identified by employing matrix-assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometry. Three basic proteins (L15, L37 and prohibitin) which were significantly modulated between DLD-1 and DLD-1/5-FU were identified. Two proteins, L15 and L37, showed down-regulated expression in DLD-1/5-FU in comparison to DLD-1. Prohibitin, which is not an r-protein and is known to be localized in the mitochondria, showed up-regulated expression in DLD-1/5-FU. These 3 proteins may be related to 5-FU resistance.

Entacapone, a catechol-O-methyltransferase inhibitor, improves the motor activity and dopamine content of basal ganglia in a rat model of Parkinson's disease induced by Japanese encephalitis virus.

Levodopa is the main medication used for the treatment of Parkinson's disease. However, dyskinesia and wearing-off appear after the administration of high-dose levodopa for a long period. To combat the dyskinesia and wearing-off, levodopa is used together with a dopamine (DA) receptor agonist, and the amount of levodopa is decreased. We have reported the monoamine oxidase (MAO)-B inhibitor selegiline to be effective for treating motor dysfunction in Parkinson's disease model rats. We analyzed the improvement in motor functions and catecholamine contents in various brain regions induced by a combination of the catechol-O-methyltransferase (COMT) inhibitor entacapone and a levodopa/dopadecarboxylase inhibitor (DDCI) in Japanese encephalitis virus (JEV) induced Parkinson's disease model rats. Entacapone (10 mg/kg) was administered via a single oral administration with levodopa/DDCI (10 mg/kg). The motor functions of the JEV model rats were significantly worsened, compared with those of the healthy control rats. The motor functions in the Parkinson's disease model rats were significantly recovered to the same levels as the healthy control rats by the combined administration of entacapone and levodopa/DDCI. A significant improvement in motor function was not demonstrated in the case of the administration of levodopa/DDCI alone. The striatal DA concentrations in the model rat brains were significantly increased by using levodopa/DDCI together with entacapone. Motor function was recovered by raising the striatum DA density in the model rats. Thus, COMT inhibitors are useful for decreasing the amount of levodopa administered to Parkinson's disease patients.

Morphology-dependent carrier and exciton generations in regioregular poly(3-hexylthiophene) polymer diodes as revealed by bleaching spectroscopy.

Bleaching probe spectroscopy performed for regioregular poly(3-hexylthiophene) diodes reveals that coexistent morphological phases determine the conducting and optical properties of conjugated polymer films. Photoinduced absorption measurements demonstrate that exciton migration occurs from lamella aggregates to morphological sites consisting of quasiuncoupled chains and that the latter sites determine steady-state photophysical properties. Spectroscopy synchronized with diode operation reveals that the morphological locations of injected carriers in polymer diodes vary with the applied bias.

[A case of subarachnoid hemorrhage presenting with supplementary motor aphasia as an initial symptom].

Supplementary motor aphasia results from impairment of the supplementary motor area in the left mesial frontal cortex. We report a rare case of subarachnoid hemorrhage presenting with supplementary motor aphasia as an initial symptom. A 52-year-old woman was brought to our hospital by ambulance due to sudden severe headache and supplementary motor aphasia. CT demonstrated subarachnoid hemorrhage that appeared to be particularly thick in the pericallosal cistern. She had undergone neck clipping of a left vertebral artery aneurysm for subarachnoid hemorrhage 14 years earlier. At that time, she underwent neck clipping of a de novo anterior communicating artery aneurysm. The postoperative course was uneventful and supplementary motor aphasia had disappeared in 4 weeks. To our knowledge, this is the first reported case of subarachnoid hemorrhage presenting with supplementary motor aphasia as an initial symptom. In this case, adhesion of the arachnoid membrane resulting from old subarachnoid hemorrhage might have prevented new subarachnoid hemorrhage from spreading diffusely. Hematomas spread mainly into the pericallosal cistern from ruptured aneurysm of the anterior communicating artery. Therefore, thick hematoma in this cistern might have compressed the supplementary motor area, resulting in supplementary motor aphasia. Aphasia disappeared as pressure from the hematoma dissipated. Neurosurgeons may be likely to encounter a patient showing a transient consciousness disturbance after the use of the anterior interhemispheric approach or within a period of vascular spasm. Supplementary motor aphasia might also be included in such consciousness disturbance. Supplementary motor aphasia might be a reversible symptom if there is no irreversible damage to the supplementary motor area by infarction or intraparenchymal hemorrhage.

Secretion of DJ-1 into the serum of patients with Parkinson's disease.

DJ-1 was initially identified by us as a novel oncogene and has later been found to be a causative gene for familial Parkinson's disease PARK7. DJ-1 plays role in transcriptional regulation and in oxidative stress function, and loss of its function is thought to be related to onset age, mode of progression and clinical severity of both familial and sporadic forms of Parkinson's disease (PD). DJ-1 is localized both in the cytoplasm and nucleus, and it has been reported to be secreted into the serum or plasma of patients with breast cancer, melanoma, familial amyloidotic polyneuropathy and stroke. In this study, levels of DJ-1 secreted into the serum of healthy controls and patients with sporadic PD were examined by using a DJ-1 ELISA kit, and the level of oxidative stress in the serum was also measured. The results showed that DJ-1 was secreted into the serum of both healthy controls and PD patients. There was no significant difference between the levels of secreted DJ-1 in two groups, and correlations of levels of secreted DJ-1 with age, clinical severity of PD and level of oxidative stress were not found.

[Antioxidant and anticancer properties of metalloporphyrins embedded in liposomes].

Reactive oxygen species (ROS) are implicated in many disease such as inflammation, arteriosclerosis, cancer. Therefore, a water-soluble cationic metalloporphyrins with SOD activity are studied widely as antioxidant drugs. Further, liposomes are applied to drug delivery system (DDS) as drug carriers and investigated for example disposition and stability. We designed PEG modified liposomes for avoiding reticuloendothelial system (RES) and embedded cationic metalloporphyrins for DDS, evaluated antioxidant and anticancer property. Preservation of these particle size measured DLS in an in vitro system, in order to simulate in vivo conditions of flow. Result of this measurement, we found Pluronic F-68/ liposomes have a long circulation property, and avoid fusion with plasma protein. SOD activity was determined by the stopped-flow analysis and cytochrome c assay, which allowed the evaluation of k(cat) and IC(50) for the reaction with a superoxide anion radical (.O(2)(-)). Anti cancer property was measured by cell viability test. We found that F-68/ liposomes were the most effective catalyst as antioxidant and anticancer. These results revealed that porphyrin-embedded PEG-liposomes had the property of long circulation in blood and that this compound was effective as a SOD model compound with a drug carrier capacity.

Ultraflex expandable stents for the management of air leaks.

Postoperative empyema and aspergillosis were diagnosed in a 66-year-old man. Since non-operative therapy was not effective, we performed surgery. On the 8th postoperative day, a covered Ultraflex expandable stent (Boston Scientific, Galway, Ireland) was implanted to make a one-way airway for blocking a major air leak from a bronchopleural fistula causing respiratory distress. His general condition improved gradually, and he was discharged 30 days after stenting. In conclusion, we used a covered Ultraflex expandable stent to make an airway to block an air leak. This may be a new application for this stent.

Early detection of subacute sclerosing panencephalitis by high b-value diffusion-weighted imaging: a case report.

The authors report a case of subacute sclerosing panencephalitis in which the diagnosis was suggested by high b-value diffusion-weighted imaging (DWI) findings. The signal abnormalities were located asymmetrically at bilateral cerebral corticosubcortical regions. High b-value DWI showed these signal abnormalities as marked hyperintensity with decreased apparent diffusion coefficient values. The signal abnormalities were difficult to identify on other magnetic resonance imaging sequences, including routine DWI. High b-value DWI could be valuable for earlier detection of subacute sclerosing panencephalitis.

[A possibility of overcoming local tumor immune tolerance by radiofrequency ablation in combination with intratumoral injection of naïve dendritic cell].

Recently we reported the systemic antitumor efficacy of intratumoral naive dendritic cell injection (IT-DC) in combination with local photodynamic therapy in Clinical Cancer Research 2006. In general, tumor cells secrete several immune suppression cytokines which could induce immune tolerance in a tumor microenvironment. The rationale and advantages of IT DC in combination with conventional antitumor therapy are as follows: (1) dying tumor cells release some tumor antigens, (2) sufficient number of DC recruiting occurs at tumor site, (3) there is naive DC capturing some tumor antigens in vivo, (4) DC activation by inflammatory cytokines are released from dying tumor cells, and (5) DC migration happens in regional lymph nodes and induces adoptive tumor immunity. Conventional antitumor therapy before IT DC could destroy the immune tolerance at a tumor site and induce durable DC vaccination. In this report, we demonstrated the mechanism of (4) and (5) by radiofrequency ablation plus IT DC using mouse tumor model.

Pathology of pure hippocampal sclerosis in a patient with dementia and Hodgkin's disease: the Ophelia syndrome.

An archive autopsy case of a 50-year-old man who died of Hodgkin's lymphoma had a 4-year, 4-month history of dementia. After radiochemotherapy, the lymphoma subsided except for involvement of the spleen, but the dementia remained. Neuropathological examination revealed that the pathology was confined to the hippocampus, both hippocampi showing sclerosis without inflammation. Neurons of sector cornu ammonis (CA) 1 were completely lost whereas moderate neuron loss was also observed in sectors CA3 and 4, and the dentate gyrus. Neurons of sector CA2 were relatively well preserved and the subiculum was intact. There was no evidence of global hypoxia, or of neurodegenerative disorders with pathological changes affecting the hippocampus. Although there was a long preneoplastic history, and no inflammatory changes were found at autopsy, the present case of hippocampal sclerosis could be included in the category of paraneoplastic limbic encephalitis associated with Hodgkin's lymphoma or the Ophelia syndrome.

Expression of macrophage migration inhibitory factor in rat skin during embryonic development.

We have previously shown that human epidermal keratinocytes express macrophage migration inhibitory factor (MIF) mRNA, and immunohistochemical studies showed that MIF is expressed in human epidermis. To explore the possible pathophysiological roles of MIF in skin during rat fetal development, we examined the expression patterns of MIF during rat epidermal development using Northern blot analysis and in situ hybridization. Expression of MIF mRNA was first detected by in situ hybridization in the developing epidermis and hair germ cells from embryonic day (ED) 16. From ED 19, moderate levels of MIF expression were detected in the epidermis and epithelial sheath cells of growing hair follicles. In postnatal rat skin, higher MIF expression was detected in the epidermis and hair follicles on postnatal day 3. These observations were also confirmed by Northern blot analysis. Immunohistochemical analysis with an anti-MIF antibody showed a similar distribution to that of the mRNA. Our results suggest that MIF is associated with epidermal and hair follicle development.