Evaluation of molecular targeted cancer drug by changes in tumor marker doubling times

Background  

We evaluated the usefulness of tumor marker doubling time (DT) as an efficacy indicator of a molecular targeted anticancer agent.     

Acute effects of adaptive servo ventilation on hemodynamics, coronary flow, and flow reserve in a patient with idiopathic dilated cardiomyopathy

Adaptive servo ventilation (ASV) is reported to be effective for the treatment of heart failure. We treated a patient with idiopathic dilated cardiomyopathy using ASV and assessed the effects on hemodynamics, coronary flow, and flow reserve before and after ASV therapy. This case suggests that ASV might decrease myocardial oxygen demand, which was represented by the decreased resting coronary flow velocity (the improvement of coronary flow velocity reserve) on ASV.     

Role of Neurokinin B and Dynorphin A in pituitary gonadotroph and somatolactotroph cell lines

The role of Neurokinin B (NKB) and Dynorphin A (Dyn) in the regulation of the hypothalamic pituitary axis is an important area of recent investigation. These peptides are critical for the rhythmic release of GnRH, which subsequently stimulates the secretion of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The present study utilized the gonadotroph cell line LβT2 and the somatolactotroph GH3 cell line to examine the possible role of these peptides in pituitary hormone secretion. The NKB receptor (NK3R) and the Dyn receptor (the κ-opiate receptor (KOR)) were both detected in LβT2 cells and GH3 cells. NKB, by itself, failed to increase gonadotropin LHβ and FSHβ promoter activities and did not modulate the effects of GnRH on gonadotropin promoter activity. In GH3 cells, NKB significantly increased TRH-induced PRL promoter activity although NKB alone did not have an effect on basal PRL promoter activity. Dyn had no effect on gonadotropin promoters alone or in combination with GnRH stimulation. PRL promoters stimulated by TRH were not significantly changed by Dyn. TRH-induced PRL promoter activity was further increased in the presence of higher concentrations of NKB, whereas Dyn did not have a significant effect on the PRL promoter even at a high concentration. In addition, TRH-induced ERK (Extracelluar signal-regulated kinase) activation was enhanced in the presence of NKB. Our current study demonstrated that NKB had a stimulatory effect on PRL expression in a PRL-producing cell, but had no effect on gonadotropin secretion from a gonadotroph cell line.     

Phase I clinical trial of vaccination with URLC10-derived peptide for patients with advanced esophageal cancer

Background

Up-regulated gene in lung cancer 10 (URLC10), confirmed to be lymphocyte antigen 6 complex locus K and defined as an oncoantigen, has been identified as a tumor-associated antigen by systematic analysis of expression levels of thousands of genes in lung cancer tissues and esophageal squamous cell carcinoma tissues, which were compared with those of normal human tissues by use of cDNA microarray analysis. Human leukocyte antigen (HLA)-A*2402-positive dendritic cells pulsed with URLC10-derived epitope peptide induced CD8⁺ cytotoxic T lymphocytes to exert specific cytotoxicity against the HLA-A*2402-positive URLC10-expressing esophageal carcinoma cell lines.

Methods

In a phase I clinical trial we evaluated the safety and immunogenicity of a URLC10-177 peptide vaccine emulsified with Montanide ISA51 for patients with unresectable advanced esophageal cancer. One milligram of URLC10-177 peptide in 1 mL sterile saline was emulsified with 1 mL incomplete Freund’s adjuvant and administered subcutaneously to the inguinal region or axilla of the patients. One course of treatment comprised four vaccinations, which were performed every week in the first and second treatment courses and subsequently every 2 weeks after the first vaccination in the third treatment course.

Results

Redness and induration of the skin were the only adverse events at the injection site and were believed to be a delayed-type hypersensitivity (DTH) reaction against the peptide vaccine. A URLC10-177-specific immune reaction in the enzyme-linked immunospot assay was detected in three of four DTH-positive patients (75 %) and in one of three DTH-negative patients (33 %). Furthermore, patients who had a DTH reaction seemed to survive longer than those who had no DTH reaction.

Conclusion

URLC10-177 peptide/Montanide vaccine therapy was well tolerated and induced a URLC10-177 peptide-specific immune response. Therapeutic URLC10-177 peptide vaccination is expected to have clinical benefit in prolonging the survival of patients with unresectable advanced esophageal cancer.     

Developing a novel custom cutting guide for curved peri-acetabular osteotomy

Purpose

Curved peri-acetabular osteotomy (CPO) produces excellent clinical results, but the surgical procedure is technically demanding, and severe complications related to the osteotomy have been reported. To provide a safe, accurate surgical procedure, we have developed a novel method for setting the cutting line and direction. We have designed and made a custom cutting guide for individual patients. The purpose of the study was to evaluate the efficacy of this new method and cutting guide.

Methods

The cutting line was designed on a full-scale three-dimensional plaster model made from computed tomography (CT) data for each case. The surface of each plaster model was colour-coded according to the distance from the centre of the femoral head. A custom cutting guide was designed based on this cutting line on the workstation. A titanium custom cutting guide was fabricated using rapid prototyping technology. The cutting guide directed the cutting direction of the osteotome. We evaluated the outcomes for seven consecutive hips in seven patients who underwent CPO using the system between April and December 2011. All peri-operative complications were recorded. The accuracy of the cutting line was evaluated using CT data obtained two weeks after the operation.

Results

There were no major complications related to the osteotomy such as posterior column fracture or intra-articular osteotomy. The actual cutting line corresponded almost exactly to the planned cutting line in all cases.

Conclusions

The colour-coded plaster model and the custom cutting guide were effective for avoiding severe complications associated with a CPO.     

Brain perfusion asymmetry in patients with oral somatic delusions

Oral cenesthopathy is a somatic delusion or hallucination involving the oral area and is categorized as a delusional disorder, somatic type. The pathophysiology of this intractable condition remains obscure. In this study, we clarified the pathophysiology of oral cenesthopathy by evaluating regional brain perfusion. We performed single photon emission computed tomography (SPECT) using ^99mTc-ethylcysteinate dimer in 16 subjects (cenesthopathy:control = 8:8). The SPECT images were visually assessed qualitatively, and quantitative analyses were also performed using a three-dimensional stereotactic region-of-interest template. The visual assessment revealed a right > left perfusion asymmetry in broad areas of the brain among the patients. The quantitative analysis confirmed that the regional cerebral blood flow values on the right side were significantly larger than those on the left side for most areas of the brain in the patients. A comparison of the R/(R + L) ratios in both groups confirmed the significant brain perfusion asymmetry between the two sides in the callosomarginal, precentral, and temporal regions in the patients. Qualitative evaluation of the SPECT images revealed right > left brain perfusion asymmetry in broad regions of the brain. Moreover, the quantitative analyses confirmed the perfusion asymmetry between the two sides in the frontal and temporal areas. Those may provide the key for elucidation of the pathophysiology of oral cenesthopathy.