Neutrophil extracellular trap formation and its implications in nonsteroidal anti-inflammatory drug-induced small intestinal injury.

BACKGROUND AND AIM: Nonsteroidal anti-inflammatory drugs (NSAIDs) damage the small intestine via neutrophil infiltration driven by the mucosal invasion of enterobacteria. The antimicrobial function of neutrophils is partially dependent on neutrophil extracellular traps (NETs). Excessive NET formation has been associated with several inflammatory diseases. Here, we aimed to investigate the role of NETs in NSAID-induced small intestinal damage using human samples and an experimental mouse model. METHODS: Human small intestine specimens were obtained from NSAID users during double-balloon enteroscopy. Wild-type, protein arginine deiminase 4 (PAD4) knockout, and antibiotic-treated mice were administered indomethacin to induce small intestinal injury. The expression of NET-associated proteins, including PAD4, citrullinated histone H3 (CitH3), cell-free DNA, and myeloperoxidase (MPO), was evaluated. RESULTS: The double-positive stained area with CitH3 and MPO, which is specific for neutrophil-derived extracellular traps, was significantly high in the injured small intestinal mucosa of NSAID users. In a mouse model, small intestinal damage developed at 6 h after indomethacin administration, accompanied by increased mRNA levels of interleukin-1ß and keratinocyte chemoattractant and elevated NET-associated protein levels of PAD4, CitH3, and MPO in small intestine and serum levels of cell-free DNA. Both genetic deletion and pharmacological inhibition of PAD4 attenuated this damage by reducing the mRNA expression of inflammatory cytokines and NET-associated proteins. Furthermore, mice pretreated with antibiotics showed resistance to indomethacin-induced small intestinal damage, with less NET formation. CONCLUSION: These results suggest that NETs aggravate NSAID-induced small intestinal injury. Therefore, NET inhibition could be a potential treatment for NSAID-induced small intestinal injury.

A rare case of concomitant Lambert-Eaton myasthenic syndrome and syndrome of inappropriate antidiuretic hormone secretion in a patient with small cell lung carcinoma.

Small cell lung carcinoma (SCLC) is a neuroendocrine carcinoma with a poor prognosis and is a common cause of paraneoplastic syndromes. Paraneoplastic syndromes are characterized by neurological and endocrinological problems in patients with malignancy and are often associated with difficulty in induction of chemotherapy. Here we report the case of a patient with SCLC concomitant with two paraneoplastic syndromes, syndrome of inappropriate antidiuretic hormone secretion (SIADH) and Lambert-Eaton myasthenic syndrome (LEMS), who was treated with a platinum-doublet chemotherapy regimen. A 66-year-old male patient presented with a 1-month history of progressive proximal muscle weakness, ataxia gait and 5 kg of body weight loss. The laboratory tests revealed hyponatremia due to SIADH and the existence of antibodies against P/Q-type voltage-gated calcium channels. The nerve conduction study showed a low amplitude of compound muscle action potential (0.38 mv), a 34% decrement on 3-Hz stimulation, and a 1939% increment after maximum voluntary contraction in 10 seconds (7.75 mv). The endobronchial ultrasound transbronchial needle aspiration biopsy revealed the pathological findings of SCLC. A 2-cycle chemotherapy regimen of irinotecan plus cisplatin resulted in temporary tumor shrinkage that lasted 2 months, but the improvement of proximal muscle weakness and hyponatremia were maintained over the tumor re-progression period after chemotherapy. Although paraneoplastic syndromes accelerate the decrease in performance status, chemotherapy for SCLC may improve symptoms related to paraneoplastic syndromes and could be considered in similar cases.

[Spinal Cerebrospinal Fluid Leak: Current Concepts and Management Policies].

In this article we provide an update on the recent developments in understanding the diagnosis and treatment of spinal cerebrospinal fluid(CSF)leaks. Patients with spinal CSF leak show an increasingly broad spectrum of clinical presentations including intractable whiplash-associated disorder(WAD)and orthostatic dysregulation in childhood, in addition to classical spontaneous intracranial hypotension(SIH). A simple understanding of the condition defined by the presence of low CSF pressure is no longer sufficient or accurate. Fat-suppressed T2-weighted magnetic resonance images and continuous epidural fluid infusion as a diagnostic therapy ensure accurate diagnosis. Accurate localization of the leak followed by targeted epidural blood patch(EBP)significantly improves the outcome of patients with spinal CSF leak. In addition to the known sites of CSF leakage, a newly identified CSF leak site, at the craniovertebral junction dural entry point of the vertebral artery(VA), is described.

Dural Entry Point of the Vertebral Artery: An Overlooked Route of Spinal CSF Leaks.

Spontaneous intracranial hypotension (SIH) is no longer considered rare. Its estimated annual incidence is 5 cases per 100,000 individuals, which is half the incidence of subarachnoid hemorrhage. Epidural blood patch (EBP) is indicated for SIH patients who do not improve with conservative treatment. Accurate determination of the cerebrospinal fluid (CSF) leak site is critical for a successfully targeted EBP. We report the case of a 43-year-old woman with SIH secondary to CSF leakage at the craniovertebral junction dural entry point of the vertebral artery (VA). We treated the patient 2 months after the onset of symptoms. Fat-suppressed T2-weighted spinal magnetic resonance (MR) images revealed a massive epidural fluid collection around the upper thoracic spine. Extravasation of contrast medium through the left VA-dural entry point was clearly visible on computed tomographic myelography. A cervical EBP was injected through the C1-2 interlaminar space. The patient had a smooth recovery and was asymptomatic, with normal spinal MR findings, 6 months after treatment. The possibility of CSF leakage from the dural entry point of the VA should be considered in SIH patients. EBP targeted at the VA entry point is proposed as a safe and effective treatment.

Clinical outcomes and predictive value of programmed cell death-ligand 1 expression in response to anti-programmed cell death 1/ligand 1 antibodies in non-small cell lung cancer patients with performance status 2 or greater.

BACKGROUND: Anti-programmed cell death protein-1/ligand-1 (anti-PD-1/PD-L1) therapy is promising for patients with non-small-cell lung cancer (NSCLC); however, clinical trials have focused on patients with a performance status (PS) 0 or 1. This study aimed to evaluate the clinical outcomes and correlation between PD-L1 expression status and tumor response to anti-PD-1/PD-L1 therapy among NSCLC patients with poor PS (i.e., PS ≥ 2). METHODS: In total, 130 patients with NSCLC and PS ≥ 2 treated with anti-PD-1/PD-L1 monotherapy at 12 institutions between January 2016 and August 2019 were retrospectively reviewed. PD-L1 expression status was divided into four groups: < 1%, 1-49%, ≥ 50%, and unknown. RESULTS: The objective response rate and PS improvement rate were 23 and 21% and were higher in the PD-L1 ≥ 50% group than in other groups (P < 0.01). Median progression-free survival (PFS) was 62 days and was longer in the PD-L1 ≥ 50% group than in other groups (P = 0.03). Multivariate analyses revealed that PD-L1 expression is significantly associated with prolonged PFS (PD-L1 < 1%; reference; 1-49%, hazard ratio [HR] 0.19, 95% confidence interval [CI] 0.04-0.99, P = 0.05; ≥ 50%, HR 0.12, 95% CI 0.02-0.71, P = 0.02; unknown, HR 0.30, 95% CI 0.08-1.22, P = 0.09). CONCLUSIONS: NSCLC patients with poor PS and PD-L1 ≥ 50% are expected to benefit from anti-PD-1/PD-L1 therapy, despite a modest overall response among NSCLC patients with poor PS. Accordingly, PD-L1 expression provides useful information regarding decision-making for anti-PD-1/PD-L1 therapy even in these populations.

[Three Cases of Intrathecal Chemotherapy with Ventricular Catheter for the Treatment of Leptomeningeal Metastasis from Breast Cancer].

Leptomeningeal metastasis(LM)is a rare complication in patients with breast cancer. We report 3 cases of LMs in patients with breast cancer who were treated with intrathecal methotrexate via an Ommaya reservoir. In 2 patients, a significant neurological improvement was observed, whereas in 1 patient there was no response. The overall survivals for the patients who experienced improvements were 22 and 9 months. Although we have no evidence for the efficacy of intrathecal chemotherapy for LMs in patients with breast cancer, its effects for some patients could be promising, after reservoir management and drug selection establishment.

Spinal cerebrospinal fluid leakage after motor vehicle accident.

Two patients presented with spinal cerebrospinal fluid (CSF) leakage manifesting as chronic disabling headache and other symptoms after motor vehicle accidents. Combined radioisotope cisternography and computed tomography myelography confirmed the presence of the spinal leaks in the lumbar spine. Radioisotope cisternography has limited spatial resolution, so there is persistent and probably unfair mistrust in its reliability. The present 2 cases confirmed the diagnosis and support the causal relationship between motor vehicle accidents and spinal CSF leakage.

Epidural blood patch therapy for chronic whiplash-associated disorder.

BACKGROUND: Despite the absence of objective neurological deficits, patients with chronic whiplash-associated disorder (WAD) complain of symptoms such as headache, dizziness, and nausea. These symptoms are also often experienced by patients with cerebrospinal fluid (CSF) leak. It was recently reported that radioisotope (RI) cisternography is useful in the diagnosis of intracranial hypotension due to CSF leak. We investigated the relation between chronic WAD and CSF leak by RI cisternography and evaluated whether epidural blood patch (EBP) administration is effective in the treatment of chronic WAD. METHODS: We studied 66 patients with chronic WAD with symptoms lasting longer than 3 mo. All patients underwent RI cisternography to determine the presence of CSF leak. In patients in whom CSF leak was identified, EBP was administered. Symptoms were assessed before, 1 wk after, and 6 mo after EBP. Work status was also assessed and follow-up RI cisternography was performed. RESULTS: Of the 66 patients, 37 showed CSF leak, and 36 of these patients received EBP 2.2 +/- 0.7 times. The mean duration of symptoms was 33 mo. One week after EBP, the percentage of patients with symptoms was decreased significantly compared with that before EBP; headache: 100% vs 17%, respectively, memory loss: 94% vs 28%, dizziness: 83% vs 47%, visual impairment: 81% vs 25%, nausea: 78% vs 42% (P < 0.01). These effects were also observed at the 6 month follow-up examination (P < 0.01). Work status was also significantly improved at follow-up. CONCLUSIONS: We conclude that CSF leak should be considered in some cases of chronic WAD and that EBP is an effective therapy for chronic WAD.

Interhemispheric multiloculated ependymal cyst with dysgenesis of the corpus callosum: a case in a preterm fetus.

INTRODUCTION: The authors report a case of interhemispheric ependymal cyst accompanied with agenesis of the corpus callosum in a fetus. DISCUSSION: Routine ultrasound and subsequent magnetic resonance imaging of a 20-year-old woman at 33 weeks and 1 day of gestation detected a large interhemispheric cystic lesion in the fetal cranial cavity. Caesarian section was carried out at 36 weeks because of the progressive enlargement of the fetal head. The cyst was multiloculated and a cyst peritoneal shunt placement resulted in collapse of the drained cyst components followed by enlargement of others. After wrack-a-mole-like shunt revisions, open surgery was performed at the age of 2 years. Cyst walls were fenestrated and the cavities were communicated with each other and eventually with the lateral ventricle. Pathological diagnosis of the cyst wall was ependymal cyst. The boy is now 3 years old, and growing without apparent developmental delay or recurrence. Current concept and management policy of the interhemispheric cyst accompanied with agenesis of the corpus callosum is reviewed.

Pharmacokinetics of amrubicin and its active metabolite amrubicinol in lung cancer patients.

Amrubicin, a synthetic 9-aminoanthracycline agent, was recently approved in Japan for treatment of small-cell lung cancer and non-small-cell lung cancer. Amrubicin is converted enzymatically to the C-13 hydroxy metabolite amrubicinol, which is active and possesses a cytotoxicity 10 to 100 times that of the parent drug. The purpose of this study was to characterize the pharmacokinetics of amrubicin and its active metabolite amrubicinol. Amrubicin was administered on days 1-3 in 16 patients with advanced lung cancer. The pharmacokinetics analysis of amrubicin and amrubicinol was performed by high-performance liquid chromatography. When 45 mg/m amrubicin was administered in a bolus injection once every 24 hours for 3 consecutive days, the areas under the curves (0 to 72 hours) for amrubicin and amrubicinol were 13,490 and 2585 ng . h/mL, respectively. The apparent total clearance (CLapp) of amrubicin was 15.4 L/h. The area-under-the-curve ratio of amrubicinol to amrubicin was 15.1 +/- 4.6% (mean +/- SD) at doses ranging from 30 to 45 mg/m. Interindividual variability in the enzymatic conversion of amrubicin to amrubicinol was small. In contrast, a large interindividual variability in the CLapp of amrubicin was observed (CV = 49.8%). The areas under the curves of amrubicin and amrubicinol seemed to be associated with the severity of hematologic toxicities. There is a possibility that monitoring of the plasma concentrations of amrubicin and amrubicinol may provide an efficient tool for establishing the optimal dosage of amrubicin in each patient.

Size and surface charge effect of 5-aminolevulinic acid-containing liposomes on photodynamic therapy for cultivated cancer cells.

5-Aminolevulinic acid (ALA)-containing liposomes having various average diameters and/or positive surface charges were prepared, and their photodynamic therapy (PDT) efficacy for murine thymic lymphoma cells, EL-4 cells, cultivated in vitro was investigated. The PDT efficacy for EL-4 cells and the accumulation of ALA-induced protoporphyrin IX (PpIX) in the cells increased with a decrease in the average diameter of liposomes. In particular, the ALA-containing liposomes smaller than 63.5 nm in diameter promoted the PDT efficacy in comparison with that of ALA alone. We also found no significant changes in PDT efficacy and PpIX accumulation with increasing positive surface charges of liposomes.

Solitary fibrous tumor of the thoracic spinal cord.

A 63-year-old woman presented with a rare case of primary solitary fibrous tumor (SFT) occurring in the extramedullary thoracic spinal cord. T1-weighted magnetic resonance (MR) imaging showed the tumor as a mildly hypointense area with homogeneous enhancement by gadolinium. T2-weighted MR imaging showed a hypointense mass with peritumoral edema. The tumor arose from one of the posterior spinal roots, with no attachment to the dura. The tumor was clearly circumscribed from the surrounding cord tissue and easily removed. Histological examination showed the tumor predominantly consisted of spindle cells separated by abundant collagen matrix fibers. Tumor cells were strongly positive for vimentin and CD34, but negative for glial fibrillary acidic protein, S-100 protein, epithelial membrane antigen, myelin basic protein, and keratin. SFT should be considered in the differential diagnosis of spindle cell central nervous system neoplasms, although SFT is extremely rare in the spinal cord.

Phase II study of carboplatin-paclitaxel combination chemotherapy in elderly patients with advanced non-small cell lung cancer.

BACKGROUND: More than 30% of cases of non-small cell lung cancer (NSCLC) arise in patients aged > or =70 years. The efficacy and safety of carboplatin-paclitaxel combination chemotherapy in elderly patients with advanced NSCLC were evaluated in a phase II trial. METHODS: Twenty-five patients aged > or =70 years (median, 76; range, 70-83) with chemotherapy-naive advanced NSCLC were enrolled between January 2001 and July 2003. Additional criteria included the presence of measurable lesions, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate organ function. Patients received carboplatin at an area under the curve of 5 mg/ml/min and paclitaxel at 180 mg/m(2) on the first day of consecutive 3 week periods. RESULTS: The patients included four with stage IIIB, 19 with stage IV and two with recurrent disease. The median number of treatment cycles was three (range, 1-4). One complete response and six partial responses, yielding an objective response rate of 28%, were obtained. The median survival time was 12.3 months and the 1-year survival rate was 52%. Hematological toxicities of grade 3 or 4 included leukopenia (40%), neutropenia (68%) and anemia (4%). Non-hematological toxicities of grade 3 included arthralgia-myalgia (16%) and neuropathy (12%). The objective response rate for patients aged > or =75 years (n = 15) was 26%, and no evidence of excessive toxicity in these patients was apparent compared with those aged <75 years. CONCLUSION: The combination carboplatin-paclitaxel at these doses is a feasible treatment option with a favorable toxicity profile for fit elderly patients with advanced NSCLC.

Quantitative analysis of radioisotope cisternography in the diagnosis of intracranial hypotension.

OBJECT: The authors attempted a quantitative analysis of conventional radioisotope cisternography for the purpose of more accurate diagnosis of intracranial hypotension. METHODS: Fifty-seven patients suspected of having intracranial hypotension underwent radioisotope cisternography. Whole-body images were obtained 2.5, 6, and 24 hours after intrathecal injection of 111In-diethylenetriamine pentaacetic acid. Radioactivity in the cerebrospinal fluid (CSF) space was counted during scanning, and radioisotope clearance was studied. Direct signs of radioisotope leakage into the spinal epidural space were found in 25 patients. Most leaks were located in the lumbosacral region. Analysis of the radioisotope clearance curve revealed two different patterns. In patients without a radiographically demonstrated radioisotope leak, absolutely exponential curves were observed (R2 > 0.99). The activity of the radioisotope decreased at a rate of e(-003) to e(-0.107) (mean +/- standard deviation, e(-0.056 +/- 0.018); 32 patients). Clearance in patients with an overt radioisotope leak was not a simple exponential curve; it could be divided into an early rapid phase and a late slow phase. The clearance rate during the first 6 hours was e(-0.219 +/- 0.127) (25 patients) and e(-0.076 +/- 0.021) thereafter. The authors speculated that the early escape of undiluted radioisotope solution through an aberrant CSF outlet, such as a traumatic spinal dural tear, was responsible for this phenomenon. CONCLUSIONS: The quantitative analysis featured in this study seems to be useful in the diagnosis of intracranial hypotension. A small CSF leak below the limit of radioisotope cisternography resolution might be detected using this technique.

[Epidural blood patch as a successful treatment of Barrè-Lièou syndrome: report of two cases].

Barrè-Lièou syndrome accompanies neurological symptoms after neck sprain, and is often difficult to treat. We describe two young men with various neurological symptoms after traffic accident, who were diagnosed with Barrè-Lièou syndrome. Both case 1 (41-year-old man) and case 2 (34-year-old man) showed no abnormal findings in head and cervical X-ray, CT-scan and MRI. Only radionuclide cisternography (RNC) showed cerebrospinal fluid (CSF) leak into epidural space at thoracolumbar level. Three months (case 1) and four years (case 2) had passed after each accident. Two patients underwent epidural blood patch (EBP) for total of three times. The average volumes of the blood used for EBP were 30 ml (case 1) and 24 ml (case 2). The procedure improved various symptoms except for neck stiffness and dizziness. EBP had led to low back pain, which disappeared within three days. CSF leak vanished in RNC after EBP. Severe complication, for example epidural infection or neurological disorders due to hematoma, was not noticed. While neural blockade did not relieve pain before EBP, we could get good effect from neural blockade for remaining symptoms after EBP. We consider that Barrè-Lièou syndrome is due to CSF leak and EBP may be one of the useful treatments.