Poor tolerability of lenvatinib in elderly patients ≥80 years old with hepatocellular carcinoma: A multicenter observational study.

INTRODUCTION: Management of elderly patients with cancer has become a global issue. We investigated the safety and tolerability of lenvatinib in hepatocellular carcinoma (HCC) patients ≥80 years old. METHODS: We retrospectively evaluated 61 HCC patients and divided them into 2 groups: an elderly group (n = 13, ≥80 years old) and a younger group (n = 48, <80 years old). We compared the adverse events (AEs), administration period, dose intensity, objective response, and progression-free survival (PFS) between the two groups. RESULTS: The discontinuation of lenvatinib due to AEs was more frequent in the elderly group (8/13, 61.5%) than in the younger group (10/48, 20.8%) (P = 0.0043). Fatigue and appetite loss accounted for half of the cases discontinued due to AEs in the elderly group. The elderly group had a significantly lower 8-week-delivered dose intensity/body surface area ratio (147.2) and 8-week-relative dose intensity (50.0%) than those in the younger group (267.4, 67%) (P = 0.003, 0.029). The objective response rate was significantly lower in the elderly group (15.4%) than in the younger group (61.5%) (P = 0.021). The PFS in the elderly group tended to be shorter than that in the younger group (P = 0.058, hazard ratio [HR] 1.98). The modified albumin-bilirubin (mALBI) grade (hepatic function) (HR, 2.60; P = 0.01) and objective response (HR, 0.41; P = 0.011) were independently associated with the PFS in the multivariate analysis. CONCLUSION: The management of AEs is crucial for adherence and maintaining the dose intensity of lenvatinib in elderly HCC patients.

The Geriatric Nutritional Risk Index Predicts Tolerability of Lenvatinib in Patients With Hepatocellular Carcinoma.

BACKGROUND/AIM: We aimed to investigate the association between The Geriatric Nutritional Risk Index (GNRI) and the tolerability of lenvatinib in patients with hepatocellular carcinoma (HCC). PATIENTS AND METHODS: We retrospectively evaluated 61 HCC patients treated with lenvatinib and compared those with low GNRI (≤98, n=26) to those with high GNRI (>98, n=35). RESULTS: The discontinuation of lenvatinib due to adverse events was more frequent in the low GNRI group (46.2%) than in the high GNRI group (17.1%) (p=0.014). Multivariate analysis revealed that low GNRI (p=0.014), hypothyroidism (model 1 p=0.021, model 2 p=0.013), and advanced age (p=0.026) were independently associated with the discontinuation of lenvatinib. The progression-free survival in the low GNRI group was significantly shorter than that in the high GNRI group (p=0.047). CONCLUSION: The GNRI might be independently associated with the tolerability of lenvatinib in patients with HCC.

Arterial Spin Labeling Magnetic Resonance Imaging for Differentiating Acute Ischemic Stroke from Epileptic Disorders.

BACKGROUND: Differential diagnosis between acute ischemic stroke (AIS) and epilepsy-related stroke mimics is sometimes difficult in the emergency department. We investigated whether a combination of diffusion-weighted imaging (DWI) and arterial spin labeling imaging (ASL) is useful in distinguishing AIS from epileptic disorders. METHODS: The study included suspected AIS patients who underwent emergency MRI including both DWI and ASL, and who exhibited DWI high-intensity lesions corresponding to neurological symptoms. We investigated the relationship between the ASL results from within and/or around DWI lesions and the final clinical diagnosis. RESULTS: Eighty-five cases were included (mean age, 71 ± 13 years; 47 men). The time from onset to the MRI examination was 493 ± 536 minutes. ASL showed hyperintensity in 13 patients, isointensity in 43, and hypointensity in 29. All ASL hyperintensities were observed in the cortex, with 4 patients (31%) presenting with AIS and 9 (69%) with an epileptic disorder. All of the AIS patients with ASL hyperintensity were diagnosed with cardioembolic stroke (4/4, 100%), with magnetic resonance angiography demonstrating recanalization of the occluded artery in all cases (4/4, 100%). In the 9 patients with an epileptic disorder, the area of ASL hyperintensity typically extended beyond the vascular territory (7/9, 78%) and involved the ipsilateral thalamus (7/9, 78%). All patients with ASL isointensity and hypointensity were diagnosed with AIS; none had epileptic disorders. CONCLUSIONS: Although cortical ASL hyperintensity can indicate cardioembolic stroke with recanalization, hyperintensity beyond the vascular territory may alternatively suggest an epileptic disorder in suspected AIS patients with DWI lesions.

Endoscopic submucosal dissection in a patient with esophageal adenoid cystic carcinoma.

We report the first use of endoscopic submucosal dissection (ESD) for the treatment of a patient with adenoid cystic carcinoma of the esophagus (EACC). An 82-year-old woman visited our hospital for evaluation of an esophageal submucosal tumor. Endoscopic examination showed a submucosal tumor in the middle third of the esophagus. The lesion partially stained with Lugol's solution, and narrow band imaging with magnification showed intrapapillary capillary loops with mild dilatation and a divergence of caliber in the center of the lesion. Endoscopic ultrasound imaging revealed a solid 8 mm × 4.2 mm tumor, primarily involving the second and third layers of the esophagus. A preoperative biopsy was non-diagnostic. ESD was performed to resect the lesion, an 8 mm submucosal tumor. Immunohistologically, tumor cells differentiating into ductal epithelium and myoepithelium were observed, and the tissue type was adenoid cystic carcinoma. There was no evidence of esophageal wall, vertical stump or horizontal margin invasion with pT1b-SM2 staining (1800 µm from the muscularis mucosa). Further studies are needed to assess the use of ESD for the treatment of patients with EACC.

Liver injury after aluminum potassium sulfate and tannic acid treatment of hemorrhoids.

We are reporting a rare case of acute liver injury that developed after an internal hemorrhoid treatment with the aluminum potassium sulfate and tannic acid (ALTA) regimen. A 41-year-old man developed a fever and liver injury after undergoing internal hemorrhoid treatment with a submucosal injection of ALTA with lidocaine. The acute liver injury was classified clinically as hepatocellular and pathologically as cholestastic. We could not classify the mechanism of injury. High eosinophil and immunoglobulin E levels characterized the injury, and a drug lymphocyte stimulation test was negative on postoperative day 25. Fluid replacement for two weeks after hospitalization improved the liver injury. ALTA therapy involves injecting chemicals into the submucosa, from the rectum to the anus, and this is the first description of a case that developed a severe liver disorder after this treatment; hence, an analysis of future cases as they accumulate is desirable.

A case of adenosquamous cell carcinoma of the gallbladder with markedly elevated PTHrP and G-CSF levels.

A 76-year-old woman was referred to our hospital with anorexia. Computed tomography revealed a tumor lesion measuring 110mm in the liver at S4/5 with calcification and swelling of a paraaortic lymph node. The gallbladder was not visualized. Histological examination of a biopsy specimen from the liver tumor revealed squamous cell and undifferentiated carcinomas, and several tumor markers were elevated. Therefore, we diagnosed the patient with gallbladder adenosquamous cell carcinoma T3N2M0 stage III. Because the serum parathyroid hormone-related protein (PTHrP) and granulocyte-colony stimulating factor (G-CSF) levels were significantly elevated, we suspected that PTHrP and G-CSF production occurred because of adenosquamous cell carcinoma in the gallbladder. We initiated chemotherapy with S-1.

Epileptic Ictal Hyperperfusion on Arterial Spin Labeling Perfusion and Diffusion-Weighted Magnetic Resonance Images in Posterior Reversible Encephalopathy Syndrome.

BACKGROUND: The hemodynamic state of the posterior dominant vasogenic edema in posterior reversible encephalopathy syndrome (PRES) is controversial. The aim of this retrospective study was to examine the contribution of epileptic ictal hyperperfusion in patients with PRES using combined magnetic resonance perfusion imaging with arterial spin labeling (ASL) and diffusion-weighted magnetic resonance imaging (MRI). METHODS: A detailed review of chronological MRI findings in 2 patients, including diffusion-weighted imaging (DWI) and ASL, with special reference to clinical and electroencephalographic findings, was performed. At the onset of PRES, both patients developed secondary generalized seizures. RESULTS: At the first PRES episode in Case 1, ASL and DWI clearly depicted "ictal hyperperfusion" and prolonged epilepsy-induced cytotoxic edema in the left parieto-occipital lobe cortex, located around the vasogenic edema of the PRES lesion in the left occipital lobe (hypoperfused area). At the second and third episodes (2 and 7 months after the first episode, respectively), although recurrent PRES was ruled out, ASL and DWI clearly demonstrated ictal hyperperfusion in the left posterior temporal and parieto-occipital lobes associated with partial nonconvulsive status epilepticus, which developed around the PRES-related old hematoma lesion. In Case 2, peri-ictal MRI findings of ictal ASL hyperperfusion and cortical hyperintensity on DWI were also noted in the left parieto-occipital lobe, but were mild compared with Case 1. CONCLUSIONS: Combined use of DWI and ASL can provide information on hemodynamic state associated with epileptic ictal hyperperfusion in the various phases of PRES.

[Infection Control Effect of Dietary Fluid with Whey Peptide in the Management of Patients with Severe Intracranial Hemorrhage During the Acute Stage].

UNLABELLED: Abstract BACKGROUND AND PURPOSE: Patients with severe intracranial hemorrhage (ICH) often develop infectious complications during the acute stage. Animal experiments have demonstrated that enteral immunonutrition with a dietary fluid containing whey peptide (WP) enhances immunoactivity and prevents infection. The aim of the current study was to investigate the infection control effect of WP in the clinical management of patients with severe ICH. METHODS: Fourteen patients with ICH were given enteral nutrition from January 2012 to December 2012. Nine patients were given WP (WP group) and the other five were given control dietary fluid (Non-WP group) for two weeks. We retrospectively analyzed the incidence of infectious complications and chronological changes in white blood cell (WBC) count, C-reactive protein (CRP), and total lymphocyte count. RESULTS: All patients in the Non-WP Group experienced infectious complications, whereas 5 out of 9 patients in the WP Group did not experience them. There was a tendency for a decrease in WBC count and CRP value in the WP group. In contrast, WBC and CRP increased in 3 patients in the Non-WP Group. Total lymphocyte count tended to increase earlier in the WP Group; however this tendency was not noted in the Non-WP Group. CONCLUSION: Although the number of cases was small, our study suggests that WP might have an infection control effect, capable of preventing infectious complications associated with severe ICH in the acute stage.

[Case of intravascular large B-cell lymphoma (IVLBCL) with central nervous system symptoms diagnosed by renal biopsy].

A 60-year-old man was admitted to our hospital complaining of fever, headache and vertigo. Neurological examination on admission showed mild ataxic gait. Brain magnetic resonance imaging showed linear high intensity in the left parietal lobe on diffusion-weighted imaging (DWI) and laboratory data revealed elevated serum lactate dehydrogenase and soluble interleukin-2 receptor. Although intravascular lymphoma was suspected from these findings, bone marrow and skin biopsies were negative. Two months later, he presented with sensory disturbance of the left upper limb, and new lesions in the right frontal and bilateral parietal lobes were detected on DWI. A systemic evaluation showed multiple low-density lesions in the bilateral kidneys on computed tomography. Based on the results of a renal biopsy, we made a histological diagnosis of intravascular large B-cell lymphoma (IVLBCL). As IVLBCL is quite rare and often has a poor prognosis, a systemic evaluation to determine the proper biopsy site is needed for early diagnosis.

[Case of CNS-limited ANCA-associated vasculitis presenting as recurrent ischemic stroke].

A 73-year-old man was admitted to our hospital because of a decrease in spontaneity. His medical history included two stroke episodes, probably related to hypertension. Brain MRI on admission demonstrated acute infarction in the right caudate nucleus and left putamen. Intravenous infusion of a low molecular-weight heparin added to oral antiplatelets was started. Following admission, he developed a low grade fever and severe inflammatory reaction. The focus of infection was not evident, and none of the antibiotics tried were effective. Ten days after admission, he developed right hemiparesis, and an additional brain MRI showed new multiple infarctions. We also determined the presence of a high MPO-ANCA titer (57 EU), and we diagnosed the patient's condition to be ANCA-associated vasculitis (AAV). Steroid therapy improved his inflammatory reaction and stroke recurrence was not observed. We suggest that vasculitis should be considered as a potential risk factor for repeated small infarctions with fever of unknown origin, especially those of perforating artery territories.

[Nutrition support team (NST) intervention for hip fracture in elderly patients over 90 years old - Validation effect using the Functional Independence Measure].

AIM: Malnutrition is common in the hospitalized elderly with hip fractures and has been linked to poorer recovery and increased complications. Hence, the aim of this study is to investigate whether nutrition support team (NST) intervention has a beneficial effect on rehabilitation outcome in the elderly, especially in the oldest-old patients with hip fracture using the Functional Independence Measure (FIM). METHOD: Patients were classified into two groups before and after NST intervention, and we evaluated FIM gain, FIM efficacy, and discharge outcomes. Every item was compared in low-ADL patients with an FIM of 54 or less on admission. RESULTS: The numbers of patients were 18 in the non-NST and 22 in the NST group. Although nutritional indicators on admission showed no significant difference in the groups, FIM gain and FIM efficacy were significantly higher (p<0.01) and walking ability at discharge was better in the NST group (p<0.05). In low-ADL patients, the same results were confirmed. CONCLUSION: Although the malnourished patients often have a poor prognosis, there was a significant improvement in rehabilitation effect and discharge outcome in the NST group. Thus, these results suggest the effectiveness of multidisciplinary NST intervention. Moreover, even in elderly patients with low ADL on admission, significant effect of rehabilitation can be expected by appropriate nutritional management.

Change in intracellular pH causes the toxic Ca2+ entry via NCX1 in neuron- and glia-derived cells.

Brain hypoxia or ischemia causes acidosis and the intracellular accumulation of Ca(2+) in neuron. The aims of the present study were to elucidate the interaction between intracellular pH and Ca(2+) during transient acidosis and its effects on the viability of neuronal and glial cells. Intracellular Ca(2+) and pH were measured using the fluorescence of fura-2 and 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein acetoxymethyl ester in neuroblastoma (IMR-32), glioblastoma (T98G), and astrocytoma (CCF-STTG1) cell lines. The administration of 5 mM propionate caused intracellular acidification in IMR-32 and T98G cells but not in CCF-STTG1 cells. After the removal of propionate, the intracellular pH recovered to the resting level. The intracellular Ca(2+) transiently increased upon the removal of propionate in IMR-32 and T98G cells but not in CCF-STTG1 cells. The transient Ca(2+) increase caused by the withdrawal of intracellular acidification was abolished by the removal of external Ca(2+), diminished by a reduction of external Na(+), and inhibited by benzamil. Transient acidosis caused cell death, whereas the cells were more viable in the absence of external Ca(2+). Benzamil alleviated cell death caused by transient acidosis in IMR-32 and T98G cells but not in CCF-STTG1 cells. These results suggest that recovery from intracellular acidosis causes a transient increase in cytosolic Ca(2+) due to reversal of Ca(2+) transport via Na(+)/Ca(2+) exchanger coactivated with Na(+)/H(+) exchanger, which can cause cell death.

Amiloride inhibits hydrogen peroxide-induced Ca2+ responses in human CNS pericytes.

The aims of the present study were to investigate the mechanisms of Ca(2+) signaling caused by hydrogen peroxide in CNS pericytes. In cultured human brain microvascular pericytes, cytosolic Ca(2+) concentration was measured by means of fura-2 fluorescence. Reverse transcription and polymerase chain reaction was performed to examine the expression of mRNA. Knockdown of Na(+)/H(+) exchanger (NHE) was done by transfecting the cells with specific double-strand siRNAs for NHE. Externally applied hydrogen peroxide dose-dependently (100 microM-10 mM) increased cytosolic Ca(2+) in human CNS pericytes. Cytosolic Ca(2+) remained high after wash-out of hydrogen peroxide. However, the addition of dithiothreitol rapidly reversed cytosolic Ca(2+) to the resting level. The hydrogen peroxide-induced Ca(2+) increase was not inhibited by nicardipine, Gd(3+), La(3+), or omission of external Ca(2+). Neither thapsigargin nor carbonyl cyanide 4-trifluoromethoxyphenylhydrazone attenuated the hydrogen peroxide-induced Ca(2+) rise. Amiloride and its derivatives, benzamil and hexamethylene amiloride reversed the hydrogen peroxide-induced Ca(2+) increase. Human CNS pericytes expressed acid sensing ion channel (ASIC) 1a, Na(+)/Ca(2+) exchanger (NCX) 1, Na(+)/H(+) exchanger (NHE) 1, and NHE7. However, the removal of external Na(+), treatment with KB-R 7943 and mibefradil, or knockdown of NHE1 and NHE7 did not affect the hydrogen peroxide-induced Ca(2+) increase. Hydrogen peroxide releases Ca(2+) from intracellular Ca(2+) pool via an amiloride-sensitive protein, which is controlled by oxidation of thiol group in human CNS pericytes.

Polymorphisms in the lymphotoxin alpha gene and the risk of ischemic stroke in the Japanese population. The Fukuoka Stroke Registry and the Hisayama Study.

BACKGROUND AND PURPOSE: Lymphotoxin alpha (LTA), one of the tumor necrosis factor family proteins, is an important proinflammatory cytokine and appears to play a putative role in the inflammatory process of atherosclerosis. Recent genetic studies have suggested that variations in the gene encoding LTA, which affect its expression and biological function, may contribute to the development of vascular diseases. We conducted a case-control study to clarify the association of LTA gene polymorphisms with ischemic stroke in a large Japanese population. METHODS: Genotyping for LTA A252G and C804A polymorphisms was achieved by a rapid-cycle polymerase chain reaction and melting curve analysis using fluorescent probes in 1,044 incident cases of ischemic stroke recruited from the Fukuoka Stroke Registry and 1,044 age- and sex-matched control subjects recruited from the Hisayama Study. RESULTS: The overall distribution of allele and genotype for each polymorphism was similar between stroke patients and control subjects. The allele frequencies of 252G and 804A were slightly lower in stroke patients than in control subjects; however, conditional logistic regression analysis adjusted for potential risk factors found no association between the risk of ischemic stroke and either polymorphism. In terms of stroke subtype, we also found no association of these polymorphisms with any subtypes of ischemic stroke. CONCLUSIONS: Neither the A252G nor C804A polymorphism of the LTA gene was associated with stroke overall and any subtypes of ischemic stroke in the Japanese population.

Role of NHE1 in calcium signaling and cell proliferation in human CNS pericytes.

The central nervous system (CNS) pericytes play an important role in brain microcirculation. Na(+)/H(+) exchanger isoform 1 (NHE1) has been suggested to regulate the proliferation of nonvascular cells through the regulation of intracellular pH, Na(+), and cell volume; however, the relationship between NHE1 and intracellular Ca(2+), an essential signal of cell growth, is still not known. The aim of the present study was to elucidate the role of NHE1 in Ca(2+) signaling and the proliferation of human CNS pericytes. The intracellular Ca(2+) concentration was measured by fura 2 in cultured human CNS pericytes. The cells showed spontaneous Ca(2+) oscillation under quasi-physiological ionic conditions. A decrease in extracellular pH or Na(+) evoked a transient Ca(2+) rise followed by Ca(2+) oscillation, whereas an increase in pH or Na(+) did not induce the Ca(2+) responses. The Ca(2+) oscillation was inhibited by an inhibitor of NHE in a dose-dependent manner and by knockdown of NHE1 by using RNA interference. The Ca(2+) oscillation was completely abolished by thapsigargin. The proliferation of pericytes was attenuated by inhibition of NHE1. These results demonstrate that NHE1 regulates Ca(2+) signaling via the modulation of Ca(2+) release from the endoplasmic reticulum, thus contributing to the regulation of proliferation in CNS pericytes.

Dissection of bilateral intracranial vertebral artery with basilar artery involvement: a case report of a patient free from neurological deficits.

We report a patient with dissection of the bilateral intracranial vertebral artery (VA) that did not present any symptoms other than occipital headache, which was probably associated with sleeping overnight in a car seat with unsteady head position. Although cerebral angiography revealed extensive dissection of the bilateral VA after branching of the posterior inferior cerebral artery, retrograde flow to the basilar artery (BA) via the right posterior communicating artery contributed to preserved posterior circulation. These findings indicate that even in patients without neurological deficits, the involvement of BA cannot be excluded and that accurate evaluation using radiological techniques should be considered.

Lack of association between infectious burden and carotid atherosclerosis in Japanese patients.

Several infectious agents, such as Chlamydia pneumoniae, cytomegalovirus (CMV), herpes simplex virus (HSV), and Helicobacter pylori, have been implicated in the pathogenesis of atherosclerosis; however, but the contribution of infection may vary among races and geographic conditions. The present study investigates the association between the presence of these pathogens and carotid atherosclerosis and examines the relevance of an infectious burden during atherogenesis in Japanese patients undergoing carotid endarterectomy. We investigated a total of 50 carotid atherosclerotic plaques resected during carotid endarterectomy by polymerase chain reaction (PCR) for C. pneumoniae, CMV, HSV, and H. pylori and by immunocytochemistry (ICC) for C. pneumoniae. We also examined the presence of antibodies to IgG and/or IgA for each pathogen in blood samples. We detected HSV DNA in 2 specimens (4%) and positive ICC for C. pneumoniae in 8 (16%). The results of PCR, ICC, or serum antibodies, as well as the number of seropositive antibodies, did not correlate with severely stenotic, ulcerative, or symptomatic plaques. Our findings indicate that the detection rate of infectious agents within atherosclerotic plaques was significantly lower in our patients than that in other studies. Thus, an inflammatory mechanism might not correlate with the pathogenesis of carotid atherosclerosis among Japanese patients with severe carotid artery stenosis.

Hydrogen peroxide-induced Ca2+ responses in CNS pericytes.

OBJECTIVE: The aims of the present study were to elucidate the interaction of reactive oxygen species (ROS) and Ca(2+) response in central nervous system (CNS) pericytes. METHODS: The intracellular Ca(2+) concentration was measured using fluorescent Ca(2+) indicator, fura-2, in cultured CNS pericytes. RESULTS: Hydrogen peroxide evoked a dose-dependent increase in cytosolic Ca(2+), which was completely inhibited by catalase. Removal of external Ca(2+) or addition of nicardipine (1 microM) during application of hydrogen peroxide did not affect Ca(2+) response. Incubation of the cells in Ca(2+) free solution did not abolish but slightly reduced Ca(2+) response by hydrogen peroxide. Ca(2+) response to hydrogen peroxide was not altered by the depletion of intracellular Ca(2+) by thapsigargin (1 microM). Pretreatment of the cells with tyrosine kinase inhibitor genistein (100 microM) or tyrphostin A47 (30 microM) significantly reduced Ca(2+) increase by hydrogen peroxide. CONCLUSIONS: These results indicate that hydrogen peroxide evokes Ca(2+) increase predominantly by release from intracellular Ca(2+) store, which may be regulated by tyrosine kinases.