A randomized-controlled trial of blonanserin and olanzapine as adjunct to antipsychotics in the treatment of patients with schizophrenia and dopamine supersensitivity psychosis: The ROADS study.

Dopamine supersensitivity psychosis (DSP) is a key factor contributing to the development of antipsychotic treatment-resistant schizophrenia. We examined the efficacy and safety of blonanserin (BNS) and olanzapine (OLZ) as adjuncts to prior antipsychotic treatment in patients with schizophrenia and DSP in a 24-week, multicenter (17 sites), randomized, rater-blinded study with two parallel groups (BNS and OLZ add-on treatments) in patients with schizophrenia and DSP: the ROADS Study. The primary outcome was the change in the Positive and Negative Syndrome Scale (PANSS) total score from baseline to week 24. Secondary outcomes were changes in the PANSS subscale scores, Clinical Global Impressions, and Extrapyramidal Symptom Rating Scale (ESRS), and changes in antipsychotic doses. The 61 assessed patients were allocated into a BNS group (n = 26) and an OLZ group (n = 29). The PANSS total scores were reduced in both groups (mean ± SD: -14.8 ± 24.0, p = 0.0042; -10.5 ± 12.9, p = 0.0003; respectively) with no significant between-group difference (mean, -4.3, 95 %CI 15.1-6.4, p = 0.42). The BNS group showed significant reductions from week 4; the OLZ group showed significant reductions from week 8. The ESRS scores were reduced in the BNS group and the others were reduced in both groups. The antipsychotic monotherapy rates at the endpoint were 26.3 % (n = 6) for BNS and 23.8 % (n = 5) for OLZ. The concomitant antipsychotic doses were reduced in both groups with good tolerability. Our results suggest that augmentations with BNS and OLZ are antipsychotic treatment options for DSP patients, and BNS may be favorable for DSP based on the relatively quick responses to BNS observed herein.

Validation of Newly Proposed Time to Transarterial Chemoembolization Progression in Intermediate-Stage Hepatocellular Carcinoma Cases.

BACKGROUND/AIM: Determination of failure of transarterial chemoembolization (TACE) for treatment of Barcelona Clinic Liver Cancer stage B (BCLC-B) hepatocellular carcinoma (HCC) has become important because of the development of tyrosine kinase inhibitor (TKI) treatment. We evaluated the usefulness and efficacy of the newly proposed time to TACE progression (TTTP). PATIENTS AND METHODS: From 2006 to 2016, 192 BCLC-B HCC patients [median age 72 years, male/female ratio = 149/43, Child-Pugh score 5/6/7 = 106/56/30, albumin-bilirubin (ALBI) grade 1/2 = 64/128, Kinki criteria B1/B2 = 64/128] were enrolled. TTTP was defined based on a previous report and first imaging performed 3 months after initial TACE had been used to obtain baseline images. The patients were divided into three groups according to TTTP (<5, 5-10, and ≥10 months; group I, II, and III, respectively). We evaluated the relationship between TTTP and overall survival (OS) as well as the prognostic factors for death. RESULTS: The median number of TACE procedures was 4 (interquartile range 3-7). There was a moderate correlation between TTTP and OS (r = 0.527, 95% CI 0.416-0.622, p < 0.001). The median survival for group I (n = 78), II (n = 49), and III (n = 65) was 24.6, 34.7, and 49.5 months, respectively (group I vs. group II, p = 0.023; group I vs. group III, p < 0.001; group II vs. group III, p = 0.037; Holm's method). ALBI grade 2 (HR 1.548, 95% CI 1.004-2.388, p = 0.048), alpha-fetoprotein (>100 ng/mL) (HR 1.540, 95% CI 1.035-2.291, p = 0.033), and TTTP (<5 months) (HR 2.157, 95% CI 1.447-3.215, p < 0.001) were significant prognostic factors for death in multivariate Cox hazard analysis. CONCLUSION: In patients with reduced TTTP, especially <5 months, it might be difficult to improve prognosis with a repeated TACE procedures. In such cases, reconsideration of the therapeutic strategy might be needed when possible.

Prognosis and therapy for ruptured hepatocellular carcinoma: problems with staging and treatment strategy.

BACKGROUND: There are no clear criteria established for treating a ruptured hepatocellular carcinoma (HCC). To elucidate the clinical features of affected patients, we examined prognosis and therapy choices. MATERIALS/METHODS: We enrolled 67 patients treated for a ruptured HCC (HCV 44, HBV 5, HBV+HCV 1, alcohol 2, others 15; naïve HCC 34, recurrent 33) from 2000 to 2013, and investigated their clinical background and prognosis. RESULTS: Median survival time (MST) for all cases was 4 months. For patients who survived for more than 1 year after rupture, the percentages of Child-Pugh C and positive for portal vein tumor thrombosis (PVTT)/extrahepatic metastasis were less than for those who died within 1 year. Child-Pugh classification (A:B:C=14:15:5 vs. 4:9:20, P<0.001) was better, while the percentage of patients with multiple tumors was lower [19/34 (55.9%) vs. 29/33 (87.9%), respectively; P<0.001] in the naïve group. The 1- and 3-year survival rates were better in the naïve as compared to the recurrent group (60.6% and 33.3% vs. 12.6% and 0%, respectively; P<0.01). MST according to modified TNM stage (UICC 7th) calculated after exclusion of T4 factor of rupture, stage I was better than others (22.7 vs. (II) 2.2, (III) 1.2, and (IV) 0.7 months) (P=0.010). CONCLUSION: In patients with a ruptured HCC, especially those with a single tumor, and without decompensated liver cirrhosis and PVTT/extrahepatic metastasis, better prognosis can be expected with curative treatment. The present naïve group included more of such cases than the recurrent group, indicating the effectiveness of curative therapy.

PHYTOCHROME-DEPENDENT LATE-FLOWERING accelerates flowering through physical interactions with phytochrome B and CONSTANS.

In flowering plants, light is one of the major environmental stimuli that determine the timing of the transition from the vegetative to reproductive phase. In Arabidopsis, phytochrome B (phyB); phyA; cryptochrome 2; and flavin-binding, KELCH repeat, F-BOX 1 are major photoreceptors that regulate flowering. Unlike phyA; cryptochrome 2; and flavin-binding, KELCH repeat, F-BOX 1, phyB delays flowering mainly by destabilizing the CONSTANS (CO) protein, whose reduction leads to decreased expression of a florigen gene, flowering locus T. However, it remains unclear how the phyB-mediated CO destabilization is mechanistically regulated. Here, we identify a unique phytochrome-dependent late-flowering (PHL) gene, which is mainly involved in the phyB-dependent regulation of flowering. Plants with mutant phl exhibited a late-flowering phenotype, especially under long-day conditions. The late-flowering phenotype of the phl mutant was completely overridden by a phyB mutation, indicating that PHL normally accelerates flowering by countering the inhibitory effect of phyB on flowering. Accordingly, PHL physically interacted with phyB both in vitro and in vivo in a red light-dependent manner. Furthermore, in the presence of phyB under red light, PHL interacted with CO as well. Taken together, we propose that PHL regulates photoperiodic flowering by forming a phyB-PHL-CO tripartite complex.

Detection of lung cancer using single-exposure dual-energy subtraction chest radiography.

PURPOSE: The aim of this study was to evaluate the detectability of lung cancer by chest radiography with a single-exposure dual-energy subtraction (ES) method. MATERIALS AND METHODS: Five radiologists read two sets of chest radiographs from 77 patients (66.5 +/- 9.6 years old) with histologically proven lung cancer measuring or=50 but <100%; (3) solid: TDR was <50%. RESULTS: Overall, detectability with the ES method was significantly better than that without ES (mean Az value increased from 0.7673 to 0.8265, P < 0.05). In the subgroup analysis of the nonsolid group and the solid group detectability did not change using the ES method, whereas in the partly solid group detectability with the ES method was significantly better than that without ES (mean Az value increased from 0.7162 to 0.8209, P < 0.005). CONCLUSION: The ES method improves the detectability of lung cancer by chest radiography, especially of the partly solid group.

Can psychiatric intervention improve major depression in very near end-of-life cancer patients?

OBJECTIVE: Although depression is a prevalent and burdensome psychiatric problem in end-of-life cancer patients, little is known about its susceptibility to treatment, especially when patients reach very close to the end of life. This study was conducted to evaluate response rate of that end-of-life depression to psychiatric intervention and to assess the feasibility of conventional evidence-based pharmacological therapy for depression. METHODS: The medical records of 20 patients who were referred to the psychiatry division for major depressive disorder and died within 3 months after the referral were reviewed. The Clinical Global Impression-Improvement (CGI-I) Scale was used for each case, and responders were defined as patients whose scores were much or very much improved. All pharmacological treatments were extracted, and the doses of the antidepressant prescribed were compared to their evidence-based-defined therapeutic doses. RESULTS: Of the 20 patients, seven were responders, but no response was achieved when the survival time was less than 3 weeks. Most patients were treated with antidepressants, but the doses prescribed were far less than the defined doses, especially the doses of the tricyclic antidepreSsants (TCAs). SIGNIFICANCE OF RESULTS: These results suggested that patients' survival time largely determines susceptibility to psychiatric treatment, and it is hard to achieve response in patients whose survival time was less than about 1 month. Implementation of conventional evidence-based pharmacological treatment is difficult, especially with TCAs, and various antidepressants, which can be administrated by other routes, are needed when oral intake is impossible.

Preliminary statistical assessment of intervention by a palliative care team working in a Japanese general inpatient unit.

The effectiveness of intervention by the palliative care team at the University of Tokyo Hospital was assessed using the Support Team Assessment Schedule. During the study, 316 consecutive patients with malignant tumor disease were referred to the palliative care team, which assessed 11 physical symptoms. Results were tested by paired t test to calculate 95% confidence intervals comparing the mean Support Team Assessment Schedule scores for each symptom from the first time to the last time after palliative care intervention. The study concluded that (1) intervention by a palliative care team in general inpatient units can effectively control pain, nausea, and vomiting in patients up until the terminal stage; (2) it is likely that cough is controllable in the terminal stage with intervention by a palliative care team; (3) mouth dryness, anorexia, constipation, diarrhea, fatigue, and ascites are difficult to alleviate in the long term even with palliative intervention.

Arterial air embolism during percutaneous pulmonary marking under computed tomography guidance.

Percutaneous pulmonary marking under computed tomography (CT) guidance is often used to identify the location of small nodules prior to pulmonary wedge resection by video assisted thoracoscopic surgery. Although pneumothorax and pulmonary hemorrhage are known complications that accompany this method, arterial air embolism is an extremely rare and occasionally fatal complication. We report a case of arterial air embolism during percutaneous pulmonary marking under CT guidance. Percutaneous pulmonary marking was performed in the prone position in a 59-year-old male with a right lung nodule. The chest CT performed immediately after this procedure revealed an air-fluid level in the heart. The skin of the patient's back appeared cyanotic and neurological dysfunction was noted in his left thigh, although his vital signs were stable. Four hours later, the air in the heart and aorta disappeared, as observed by a chest CT. The patient underwent pulmonary resection 12 days later.

Clinical evaluation of pulmonary nodules with dual-exposure dual-energy subtraction chest radiography.

PURPOSE: The purpose of this study was to assess the effect of dual-exposure dual-energy (DE) subtraction chest radiography with flat-panel detector. MATERIALS AND METHODS: One hundred patients underwent dual-exposure DE subtraction chest radiography and chest CT for evaluation of pulmonary nodules. Fifty-two patients with pulmonary nodules and 48 patients with normal lungs were selected for receiver operating characteristic (ROC) curve analysis. Ten radiologists who were unaware of the CT results evaluated chest radiography alone and chest radiography with DE subtraction images in the detection of pulmonary nodules. For each radiologist, we calculated the areas under the ROC curve (Az) for chest radiography alone and chest radiography with DE subtraction images. RESULTS: The average detectability of dual-exposure DE subtraction chest radiography was statistically significantly higher than that of chest radiography without subtraction images (mean Az value increased from 0.784 to 0.815, p<0.001). CONCLUSION: Dual-exposure DE subtraction chest radiography improves diagnostic accuracy of pulmonary nodules.

Pulmonary lesions detected in population-based CT screening for lung cancer: reliable findings of benign lesions.

PURPOSE: To identify the characteristics of benign pulmonary lesions in order to reduce false-positive rates in screening computed tomography (CT) and in order to reduce frequency of follow-up high-resolution CT (HRCT). MATERIALS AND METHODS: We evaluated 238 screening-detected benign lesions and 23 screening-detected lung cancers for 12 characteristics: spiculation, well-defined margin, concave margin, polygonal shape, notch/lobulation, solid component, ground-glass opacity (GGO), air bronchogram, cavity, bubble-like appearance, pleural indentation, and vascular convergence. We also measured the lesion diameters to set a threshold for benign lesions. We tested combinations of these characteristics to differentiate benign lesions from lung cancers. RESULTS: By using certain combinations of the characteristics that showed statistically significant differences between benign lesions and lung cancers, benign lesions could be extracted without contamination by lung cancer in screening CT, when the combination included solid component as a positive finding. In HRCT, more than 80% of the benign lesions could be extracted without contamination by lung cancer when the combination included GGO as a negative finding. CONCLUSION: It seems possible to reduce the frequency of follow-up HRCT to establish a diagnosis of benign lesions using certain combinations of the characteristics of benign nodules.

Steep elevation of blood interleukin-6 (IL-6) associated only with late stages of cachexia in cancer patients.

Changes in blood cytokines of 28, consenting, terminally ill cancer patients were studied to determine a relationship between cachexia and changes in cytokine levels. Levels of PTHrP and five types of cytokines considered to be associated with cachexia, TNFalpha, IL-1beta, IL-6, IFNgamma and LIF, were measured during routine blood examination and were compared with clinical findings. With the exception of TNF-alpha, which was detected in one patient, only IL-6 was detected in all 28 patients recruited in this study. Ten patients showed a sharp elevation of IL-6 just before death, following a 40-day period in which IL-6 was continually detected in the blood. In six out of these ten patients, levels of 100 pg/mL or more of IL-6 were detected in the week prior to death. The average period between detection of these levels of IL-6 and death was 2.0 days. Progression of carcinoma is believed to induce a variety of cytokines, which cause loss of appetite, weight loss, tissue wasting, and finally patients may become cachectic. Of the six cytokines studied during this test, only the level of IL-6 was significantly elevated, and this sharp rise occurred approximately one week before patients died. We conclude that IL-6 increases only gradually during the early stages of cachexia but then shows a sudden and steep rise just before death.

Cellular pH regulators: potentially promising molecular targets for cancer chemotherapy.

One of the major obstacles to the successful treatment of cancer is the complex biology of solid tumour development. Although regulation of intracellular pH has been shown to be critically important for many cellular functions, pH regulation has not been fully investigated in the field of cancer. It has, however, been shown that cellular pH is crucial for biological functions such as cell proliferation, invasion and metastasis, drug resistance and apoptosis. Hypoxic conditions are often observed during the development of solid tumours and lead to intracellular and extracellular acidosis. Cellular acidosis has been shown to be a trigger in the early phase of apoptosis and leads to activation of endonucleases inducing DNA fragmentation. To avoid intracellular acidification under such conditions, pH regulators are thought to be up-regulated in tumour cells. Four major types of pH regulator have been identified: the proton pump, the sodium-proton exchanger family (NHE), the bicarbonate transporter family (BCT) and the monocarboxylate transporter family (MCT). Here, we describe the structure and function of pH regulators expressed in tumour tissue. Understanding pH regulation in tumour cells may provide new ways of inducing tumour-specific apoptosis, thus aiding cancer chemotherapy.

Structural and functional characterization of two human V-ATPase subunit gene promoters.

The vacuolar-ATPase (V-ATPase) is a multi-subunit enzyme that couples ATP hydrolysis to proton pumping across membranes. V-ATPase genes are considered to be housekeeping genes and are expressed in human neoplastic tissue and in cell lines. We have isolated and characterized several genomic clones containing the 5'-end of the human V-ATPase genes. DNA sequence analysis of the promoters of two V-ATPase subunit genes, encoding C (ATP6C) and c (ATP6F), reveals GC-rich regions in the region of the first exon. Neither TATA- nor CCAAT-boxes were found in these promoters, but both GC-boxes and E-boxes were identified. Transient transfection analysis, using a series of 5' nested deletions of promoter-luciferase constructs in human cancer cells, demonstrated that a positive cis-acting regulatory region was present in these TATA-less promoters. The regions between -79 and -40 of the ATP6C promoter and between -245 and -99 of the ATP6F promoter were identified as being likely to be extremely important for basal promoter activity. Electrophoretic mobility shift assays (EMSA) of these cis-regulatory regions revealed the basal promoter to be highly complex, with cooperative binding of several transcription factors, including Sp family members. These data identify the critical regulatory regions for both the ATP6C and ATP6F basal promoters and stress the functional importance of multiple protein complexes, involving the Sp family of transcription factors, in regulating gene expression.

The effects of benzodiazepines on event-related potential indices of automatic and controlled processing in schizophrenia: a preliminary report.

The effects of benzodiazepines on cognitive function in schizophrenic patients were investigated using event-related potential (ERP) measurement during an auditory selective attention task. In this study, the authors compared the mismatch negativity (MMN) and N2b components between two subgroups of schizophrenic patients: one is comprised of patients who received no benzodiazepines (NT group, n = 7) and the other is comprised of those administered benzodiazepines in the daytime (T group, n = 7). There were no significant differences in MMN and N2b amplitudes between the two subgroups, whereas the N2b latency was significantly prolonged in the T group relative to the NT group. This suggested that benzodiazepines induce delayed stimulus classification processing in schizophrenic patients.

Enhanced expression of the human vacuolar H+-ATPase c subunit gene (ATP6L) in response to anticancer agents.

We have isolated two overlapping genomic clones that contain the 5'-terminal portion of the human vacuolar H(+)-ATPase c subunit (ATP6L) gene. The sequence preceding the transcription initiation site, which is GC-rich, contains four GC boxes and one Oct1-binding site, but there is no TATA box or CCAAT box. In vivo footprint analysis in human cancer cells shows that two GC boxes and the Oct1-binding site are occupied by Sp1 and Oct1, respectively. We show here that treatment with anticancer agents enhances ATP6L expression. Although cisplatin did not induce ATP6L promoter activity, it altered ATP6L mRNA stability. On the other hand, the DNA topoisomerase II inhibitor, TAS-103, strongly induced promoter activity, and this effect was completely eradicated when a mutation was introduced into the Oct1-binding site. Treatment with TAS-103 increased the levels of both Sp1/Sp3 and Oct1 in nuclear extracts. Cooperative binding of Sp1 and Oct1 to the promoter is required for promoter activation by TAS-103. Incubation of a labeled oligonucleotide probe encompassing the -73/-68 GC box and -64/-57 Oct1-binding site with a nuclear extract from drug-treated KB cells yielded higher levels of the specific DNA-protein complex than an extract of untreated cells. Thus, the two transcription factors, Sp1 and Oct1 interact, in an adaptive response to DNA damage, by up-regulating expression of the vacuolar H(+)-ATPase genes. Furthermore, combination of the vacuolar H(+)-ATPase (V-ATPase) inhibitor, bafilomycin A1, with TAS-103 enhanced apoptosis of KB cells with an associated increase in caspase-3 activity. Our data suggest that the induction of V-ATPase expression is an anti-apoptotic defense, and V-ATPase inhibitors in combination with low-dose anticancer agents may provide a new therapeutic approach.

Human mitochondrial transcription factor A binds preferentially to oxidatively damaged DNA.

Mitochondrial transcription factor A (mtTFA) is necessary for both transcription and maintenance of mtDNA, and is also one of the high mobility group (HMG) proteins that preferentially binds to cisplatin-damaged DNA. In this study we confirmed the preferential binding of mtTFA to cisplatin-damaged DNA, and also discovered that mtTFA binds to oxidatively damaged DNA. The affinity for oxidatively damaged DNA of mtTFA is higher for A/8-oxo-dG and C/8-oxo-dG than for G/8-oxo-dG and T/8-oxo-dG. Our findings suggest that mtTFA plays an important role in the recognition of oxidative DNA damage.

Vacuolar H(+)-ATPase: functional mechanisms and potential as a target for cancer chemotherapy.

Tumor cells in vivo often exist in a hypoxic microenvironment with a lower extracellular pH than that surrounding normal cells. Ability to upregulate proton extrusion may be important for tumor cell survival. Such microenvironmental factors may be involved in the development of resistant subpopulations of tumor cells. In solid tumors, both intracellular and extracellular pH differ between drug-sensitive and -resistant cells, and pH appears critical to the therapeutic effectiveness of anticancer agents. Four major types of pH regulators have been identified in tumor cells: the sodium-proton antiporter, the bicarbonate transporter, the proton-lactate symporter and proton pumps. Understanding mechanisms regulating tumor acidity opens up novel opportunities for cancer chemotherapy. In this minireview, we describe the structure and function of certain proton pumps overexpressed in many tumors--vacuolar H(+)-ATPases--and consider their potential as targets for cancer chemotherapy.