Pulvinar quantitative susceptibility mapping predicts visual hallucinations post-deep brain stimulation in Parkinson's disease.

PURPOSE: We have reported the relationship between low pulvinar nuclei (PN) intensity in susceptibility-weighted imaging and the appearance of visual hallucinations and cognitive function. The aim of the study was to examine the changes in the quantitative susceptibility mapping (QSM) in patients with Parkinson's disease (PD) who underwent deep brain stimulation (DBS) and verify whether the PN susceptibility value (SV) on QSM can predict visual hallucination and cognitive changes after DBS. METHODS: This study examined 24 patients with PD who underwent DBS along with QSM imaging on magnetic resonance imaging (MRI). All MRIs were performed within 3 months before surgery. The PN SV was further assessed based on the QSM. Then, associations were examined among cognitive changes, hallucination, and PN SV. The cognitive function of the patient was compared immediately before surgery and at 1 year postoperatively. RESULTS: Visual hallucinations were observed in seven patients during the follow-up period. The PN SV was ≥0.045 ppm in nine patients with PD, and six of them had visual hallucinations, whereas only one of 15 patients with PD with SV of <0.045 ppm had visual hallucinations (Fisher's exact test, p = .0037). CONCLUSIONS: The SV of >0.045 ppm at the PN in QSM in patients with PD may provide useful information suggesting visual hallucination and cognitive deterioration after DBS treatment.

Prediction of Postoperative Delirium after Gastrointestinal Surgery Using the Mie Constructional Apraxia Scale.

BACKGROUND: Postoperative delirium (POD) is a transient postoperative complication that occurs after surgical procedures. Risk factors reported for POD include dementia and cognitive decline. The purpose of this study was to identify predictors of POD by examining the use of preoperative neuropsychological tests, including the Mie Constructional Apraxia Scale (MCAS), and patient background factors. METHOD: The study was performed as a retrospective cohort study. The subjects were 33 patients (mean age, 75.8 ± 10.9 years; male:female ratio, 26:7) who underwent gastrointestinal surgery at Matsusaka City Hospital between December 2019 and April 2021. Data were collected retrospectively from medical records. The study was started after receiving approval from the institution's ethics committee. The survey items included general patient information, nutritional assessment, surgical information, and neuropsychological tests. Subjects were classified into 2 groups according to the presence or absence of POD. If a significant difference was observed between the 2 groups, the sensitivity, specificity, and area under the curve were calculated using a receiver operating characteristic (ROC) curve. RESULT: There were 10 patients in the POD group (male:female ratio, 6:4) and 23 patients in the non-POD group (20:3). The POD group had a shorter education history (p = 0.047) and significantly higher MCAS scores (p = 0.007) than the non-POD group. The ROC curve showed a sensitivity of 90%, a specificity of 69%, and an area under the curve of 0.798 when the MCAS cutoff value was set at 3 points. CONCLUSION: Preoperative MCAS results were capable of predicting the occurrence of POD after gastrointestinal surgery. In addition, a relatively short education background was also considered a risk factor for POD.

Low Pulvinar Intensity in Susceptibility-Weighted Imaging May Suggest Cognitive Worsening After Deep Brain Stimulation Therapy in Patients With Parkinson's Disease.

Purpose: Deep brain stimulation (DBS) is an established therapy for Parkinson's disease (PD). However, deteriorating cognitive function after DBS is a considerable problem for affected patients. This study was undertaken to assess whether pulvinar findings in susceptibility-weighted imaging (SWI) can suggest cognitive worsening. Methods: We examined 21 patients with PD who underwent DBS along with SWI and neuromelanin-sensitive MR imaging (NMI). We further assessed pulvinar hypointensity based on the SWI findings and also the area of the substantia nigra (SN) pars compacta in NMI. We then examined associations among cognitive changes, pulvinar hypointensity, and SN area. The cognitive function of the patient immediately before surgery was compared with function at 1 year postoperatively. Results: Pulvinar hypointensity in SWI was found in 11 of 21 patients with PD at baseline. One year postoperatively, six of the 21 patients demonstrated a Mini-Mental State Examination score that was ≥3 points lower than the baseline score. We observed pulvinar hypointensity in SWI before DBS surgery in five of these six patients (p = 0.072). During the first postoperative year, six of 21 patients reported both transient or permanent hallucinations; we observed pulvinar hypointensity in these six patients, while 10 patients without pulvinar hypointensity had no hallucinations. Conclusion: Pulvinar hypointensity in SWI in patients with PD may provide information that is useful for suggesting cognitive deterioration after DBS treatment.

Dementia IT screening system (DITS): Practical use of local social resources for early diagnosis of dementia with collaboration between family physicians and dementia specialists.

AIM: To build a dementia screening system in the community to facilitate collaboration among patients/caregiver(s), family clinic physicians and memory clinic specialists. METHODS: We placed a Dementia Network Promoter (DNP) in four cities in Mie prefecture, Japan. Based on requests from patients/caregiver(s), family clinic physicians ordered dementia screening from the DNP. The DNP carried out screenings at the clinic using an IT device (iPad), and sent the results to a dementia specialist at the Mie University Hospital Dementia Center. The dementia specialist assessed the results of the screening tests, and made a treatment recommendation for a follow-up consultation with a memory clinic or continuing observation by the family clinic. The DNP reported the recommendation of the dementia specialist to the family clinic physician, who provided this information to the patients/caregiver(s). We investigated the characteristics of the patients referred for consultation with the memory clinic. RESULTS: A total of 158 patients participated in the screening. The majority of patients were in vulnerable living situations characterized by minimal social and family support. The mean score on the Mini-Mental State Examination was 24.1 ± 5.2. Of patients screened, 62% were referred for consultation at the memory clinic, and 57% of those referred completed a consultation at the memory clinic. Patients referred to the memory clinic showed significantly worse cognitive function and ability to complete activities of daily living. CONCLUSIONS: A dementia screening system might facilitate early consultation and intervention for patients with dementia, and build a more effective network to connect families and memory clinics. Geriatr Gerontol Int 2018; 18: 599-606.

The effectiveness of istradefylline for the treatment of gait deficits and sleepiness in patients with Parkinson's disease.

PURPOSE: Istradefylline is useful in treating the wearing-off state in Parkinson's disease (PD). We investigated the effectiveness of istradefylline (ISD) in improving arousal, sleep, and gait deficits in patients with PD. METHODS: We examined 14 patients with PD treated with ISD. We assessed the patients using the Unified Parkinson's Disease Rating Scale, Parkinson's Disease Questionnaire, Timed Up-and-Go test (TUG), Freezing of Gait Questionnaire (FOG-Q), Epworth Sleepiness Scale (ESS), and Parkinson's Disease Sleep Scale (PDSS) before and 1 month after ISD use. RESULTS: ESS scores were significantly lower 1 month after the start of ISD treatment (6.79±6.50) than before the intervention (8.14±6.15, Wilcoxon signed-rank test, p=0.0033). PDSS scores were not significantly different 1 month after beginning the treatment (112±23mm) when compared to those before the intervention (110±27mm, Wilcoxon signed-rank test, p=0.40). TUG scores were not changed after 1 month of ISD use (14.9±8.3s) when compared to those before the intervention (21.3±30.0s, Wilcoxon signed-rank test, p=0.59). Although these measures were not significantly affected by ISD treatment, some patients remarkably improved after the treatment. FOG-Q scores were significantly lower 1 month after the beginning of treatment (9.79±7.16) than those before the intervention (12.14±5.82, Wilcoxon signed-rank test, p=0.030). CONCLUSIONS: ISD may improve daytime sleepiness and FOG in patients with PD.

Background and distribution of lobar microbleeds in cognitive dysfunction.

Objectives: Cerebral microbleeds (CMBs) are often observed in memory clinic patients. It has been generally accepted that deep CMBs (D-CMBs) result from hypertensive vasculopathy (HV), whereas strictly lobar CMBs (SL-CMBs) result from cerebral amyloid angiopathy (CAA) which frequently coexists with Alzheimer's disease (AD). Mixed CMBs (M-CMBs) have been partially attributed to HV and also partially attributed to CAA. The aim of this study was to elucidate the differences between SL-CMBs and M-CMBs in terms of clinical features and regional distribution. Materials: We examined 176 sequential patients in our memory clinic for clinical features and CMB location using susceptibility-weighted images obtained on a 3T-MRI. The number of lobar CMBs in SL-CMBs and M-CMBs was counted in each cerebral lobe and their regional density was adjusted according to the volume of each lobe. Results: Of the total 176 patients, 111 patients (63.1%) had CMBs. Within the patients who had CMBs, M-CMBs were found in 54 patients (48.6%), followed by SL-CMBs in 35 (31.5%) and D-CMBs in 19 (17.1%). The SL-CMB group showed a significantly higher prevalence of family history of dementia, whereas the M-CMB group showed an increasing trend toward hypertension and smoking. The prevalence of AD was significantly higher in the SL-CMBs group, whereas the prevalence of AD with cerebrovascular disease was higher in the M-CMBs group. The regional density of lobar CMBs was significantly higher in the occipital lobe in the M-CMB group, whereas the SL-CMB group showed higher regional density between regions an increasing tendency in the parietal and occipital lobe. Conclusion: The between-group differences in clinical features and regional distribution indicate there to be an etiological relationship of SL-CMBs to AD and CAA, and M-CMBs to both HV and CAA.

Drug delivery of oral anti-cancer fluoropyrimidine agents.

INTRODUCTION: Sixty years since its introduction, 5-FU still forms the core of chemotherapy regimens for many types of malignancies. 5-FU is a time-dependent drug but is rapidly degraded in plasma by dihydropyrimidine dehydrogenase (DPD). Although originally developed in an intravenous form, 5-FU oral prodrugs were developed with the goal of improving efficacy and minimizing toxicity as well as to capitalize on the advantages of oral drug administration. The inactive 5-FU prodrug is gradually converted into the active form in the systemic circulation. UFT, S-1, and capecitabine are oral 5-FU prodrugs currently in clinical use. However, the efficacy of 5-FU can be further improved by its combination with DPD inhibitors and biochemical modulators, such as uracil and leucovorin, in addition to modifying administration schedules. Areas covered: We focused on the drug delivery of oral 5-FU prodrugs, their pharmacokinetics, and the development of DPD inhibitors. Since oral 5-FU prodrugs have been formulated into combination drugs, we also discussed the regulatory approval of combination drugs. Expert opinion: Many regimens that include intravenously administered 5-FU can be replaced by oral 5-FU prodrugs. Patients would benefit from development of combination 5-FU oral prodrug formulations and its associated path through the combination drug regulatory approval process.

The use of natural products in colorectal cancer drug discovery.

INTRODUCTION: Natural products (NPs) are evolutionarily designed and contain more complex and challenging structures than synthetic compounds. Since the 1980s, the pharmaceutical industry has gradually shifted to a strategy of developing targeted agents by screening libraries of synthetic compounds. However, NPs have recently received renewed focus as a rich repository for drug discovery. Irinotecan was developed as a derivative of camptothecin and was applied in standard regimens for metastatic colorectal cancer (CRC) worldwide. Additionally, polysaccharide K is approved for CRC in Japan and Taiwan in combination with cytotoxic agents. However, after the approval of irinotecan in 1996, no anti-cancer agents derived from NPs have been approved for CRC. AREAS COVERED: This review discusses NPs that are currently under investigation for the treatment of CRC. In addition, other NPs derived as purified ingredients and crude extracts are listed and also discussed. EXPERT OPINION: The use of NPs for the discovery of anti-cancer agents has not been fully investigated. New technologies that are currently applied for synthetic compounds may be utilized for anti-cancer drug discovery including NPs for CRC.

The preclinical development of regorafenib for the treatment of colorectal cancer.

INTRODUCTION: The RAS-RAF-MEK-ERK pathway is one of the best characterized kinase cascades. During the exploration of small molecules that inhibit RAF1 kinase, regorafenib (BAY 73-4506) was discovered as a multikinase inhibitor which demonstrated anti-cancer, anti-angiogenic, and apoptotic activities in metastatic colorectal cancer. This was not the first multikinase inhibitor discovered for the disease; indeed, before regorafenib was approved by FDA as a multikinase inhibitor for metastatic colorectal cancer in 2012, sorafenib (BAY 43-9006) had already been developed to be the first in the world as a multikinase inhibitor for malignancy. Indeed, the only difference between the two compounds is fluorine bound to its proximal phenyl ring although the end result is a considerably different profile, both as a kinase inhibitor as well as in its clinical application. AREAS COVERED: In this drug discovery case history, the authors review the design, discovery, and development of both regorafenib and sorafenib from back in the 1990s. Furthermore, the authors highlight the drug's anti-cancer and anti-angiogenic properties as well as its efficacy, safety pharmacology and toxicology based on FDA documents. EXPERT OPINION: In order to better predict the efficacy of kinase inhibitors and to utilize them more efficiently, our understanding of drug discovery, the approaches for kinase profiling, and technologies needed for their development are paramount. Indeed, the authors believe that the field should better explore the use of predictive biomarkers that might be able to better assess these therapeutics. Pharmaceutical scientists must also consider the cost effectiveness of the targeted agents developed as a number of the drugs developed are very expensive.

Case of singing seizure using syllable names.

We report a case of a patient with singing seizures, who was able to sing familiar songs by syllable name with no earlier practice. The patient was a 56-year-old musically naive woman who developed singing seizures when she was in her early 20s. She suddenly began singing familiar sacred songs by syllable name, even though she had never practiced the songs using a musical score or had earlier sung them by syllable name. An electroencephalogram showed bilateral low-voltage spikes that were significantly pronounced in the right temporal lobe. Technetium-99m-bicisate ethyl cysteinate dimer single photon emission computed tomography also showed hypoperfusion in the medial right temporal lobe. The right temporal lobe may be involved in singing, and there may be an automatic and unconscious analytical system of music perception that arranges each tone into its syllable name.

Successful islet transplantation to two recipients from a single donor by targeting proinflammatory cytokines in mice.

BACKGROUND: Currently, the inability to achieve successful islet transplantation from one donor to one recipient is a major obstacle facing clinical islet transplantation. We herein determined whether this limitation could be overcome by targeting pro-inflammatory cytokines with the prevention of immediate islet graft loss in association with engraftment in mice. METHODS: Isolated islets were grafted into the liver of streptozotocin-induced diabetic mice and the role of proinflammatory cytokines in the engraftment of islets was evaluated with the use of interferon (IFN)-gamma-/- mice and monoclonal antibodies against proinflammatory cytokines. RESULTS: Hyperglycemia in streptozotocin-induced diabetic mice receiving 200 syngenic islets, which were isolated from a single mouse pancreas, was ameliorated when IFN-gamma-/-, but not wild-type mice, were used as recipients. The treatment with anti-IFN-gamma antibody produced normoglycemia in diabetic wild-type mice receiving 200, but not 100 islets. However, when anti-tumor necrosis factor-alpha and anti-interleukin-1beta antibodies were administered in conjunction with anti-IFN-gamma antibody, wild-type diabetic mice receiving 100 islets became normoglycemic after transplantation. In addition, the favorable effect of the combined use of antibodies was similarly achieved in mice receiving islet allografts when rejection was prevented with anti-CD4 antibody treatment. CONCLUSIONS: These findings clearly demonstrate that successful islet transplantation from one donor to two recipients is feasible by targeting pro-inflammatory cytokines in mice, thus suggesting a potential application in clinical islet transplantation if similar mechanisms of islet graft loss could be mediated in humans.

[A case of complete response after neoadjuvant chemotherapy for advanced esophageal cancer with low-dose FP therapy].

The patient was a 58-year-old man complaining of vomit and body-weight loss of 10 kg with advanced lower thoraco-abdominal esophageal cancer, which was 9 cm in length and with a maximum diameter of 5.5 cm on thoracic CT examination. Moderately differentiated squamous cell carcinoma diagnosed by pre-operative endoscopic biopsy. Low-dose FP therapy (continuous 5-FU div of 500 mg/day with intermittent CDDP div of 5 mg/day) was performed during 4 weeks as neoadjuvant chemotherapy. The side effect was little, and the tumor size was remarkably reduced. A histological complete response was diagnosed with no carcinoma cells evident in the resected specimen. The patient is alive and healthy with no relapse of the carcinoma 30 months after operation. We are first planning neoadjuvant chemotherapy, and then considering the additional radiotherapy after estimating the effect of chemotherapy. Low-dose FP therapy with low-dose cisplatin as a modulator does not show much side effect and is useful for esophageal cancer. We consider that the chemotherapy is more effective preoperatively than postoperatively because it preserves the feeding vessels for transporting the medicine to the focus of the disease.

Interleukin-12 administration is more effective for preventing metastasis than for inhibiting primary established tumors in a murine model of spontaneous hepatic metastasis.

PURPOSE: The effect of interleukin-12 (IL-12) on tumor growth at the primary site and its therapeutic efficacy against metastasis were examined using a model of spontaneous hepatic metastasis. METHODS: IL-12 was peritumorally injected into RL male1 tumor-bearing BALB/c male mice at the different tumor stage. RESULTS: Striking inhibition of hepatic metastasis in both athymic and euthymic mice was induced by the administration of IL-12 irrespective of the stage of tumor progression. In contrast, IL-12 failed to produce any antitumor effect in athymic mice which lack conventional T cells. These results suggest that the antitumor effect of IL-12 is mediated mainly by T cells, and that the antimetastatic effect is mediated mainly by natural killer (NK) and/or NKT cells. Next we examined the direct effect of IL-12 on these cells. IL-12-induced T-cell proliferation was remarkably augmented in the early stage, then decreased dramatically in the advanced stage, while IL-12-induced cytotoxic activity, mediated by NK and NKT cells, was not attenuated even in the advanced stage. This dissociation in IL-12 responsiveness appeared to be the reason for the remarkable antimetastatic effect but insufficient antitumor effect of IL-12 in the advanced stage. CONCLUSION: The findings of this study support the clinical use of IL-12 for immunotherapy against either occult or evident liver metastasis.