Treatment with K-18 (IgG-melphalan) in recurrent cases of hematopoietic malignancies

K 18, an IgG-Melphalan conjugate was administered to 30 patients, who had recurrent hematopoietic malignancy. Ten out of the 30 patients received single doses of 1 to 20 enteric tablets containing 10 mg of K 18, as a phase I study. No side effects were observed. K 18 was administered every day to the remaining 20 patients in order to evaluate the side effects and therapeutic effects, as a phase II study. One patient attained partial remission. Although no remission effect was obtained in 14 of the 20 patients, antitumor effects such as a decrease in leukemia cells, were observed in 4 of 20 patients. As to side effects, neither recurrence of tumor nor cumulative toxicity were shown in one patient with NHL who received only K 18 for 14 months as maintenance therapy. Evaluation of antitumor effect was difficult in the case of the remaining 4 patients. In the 20 cases who entered the phase II study, a decrease in neutrophils was observed in 2 patients, a slight decrease in platelets in 3 patients and increased transaminase activity in one patient as side effects of K 18. In brief, compared with Melphalan, K 18 has between 1.3 and 2 times a more potent therapeutic effect, with extremely low side effects.     

Effects of oral flecainide treatment of refractory tachyarrhythmias

Oral flecainide treatment was given to five patients who were refractory to conventional antiarrhythmic agents. The five patients included one with atrioventricular reentrant tachycardia (AVRT), one with non-sustained ventricular tachycardia (nsVT) and three with sustained VT (sVT). Flecainide produced favorable responses in patients of AVRT, nsVT and sVT with arrhythmogenic right ventricular dysplasia (ARVD). In the case of AVRT, flecainide exhibited a preventive effect on tachycardia induced by programmed electrical stimulation (PES). In the case of nsVT, flecainide markedly reduced the number of VPC and abolished the VT on the Holter ECG. In the case of sVT with ARVD, sVT was not induced by PES after the flecainide. Long-term treatment with flecainide on these three cases produced complete prevention of tachycardias. As an adverse effect of flecainide, an aggravation of congestive heart failure was recognized in one case with cardiac sarcoidosis. PQ interval and QRS interval in all the cases were prolonged after flecainide. The results indicate that flecainide is a useful antiarrhythmic agent for tachyarrhythmias refractory to treatment with conventional drugs.     

Antiproliferative property of sphingosine 1-phosphate in rat hepatocytes involves activation of Rho via Edg-5

BACKGROUND & AIMS: Sphingosine 1-phosphate (S1P), a ligand for G protein-coupled endothelial differentiation gene-1 (Edg-1), Edg-3, Edg-5, Edg-6, and Edg-8, elicits a variety of responses by cells. Prominent among these is cell proliferation. S1P is abundantly stored in platelets and released upon their activation, suggesting that S1P plays a pathophysiologic role in vivo. Because the major part of injected S1P was distributed into the liver in mice, we wondered whether the liver would be one of its targets. The effects of S1P on hepatocytes, the major constituent cells in the liver, were examined. METHODS & RESULTS: Northern blot analysis revealed the expression of Edg-1 and Edg-5 messenger RNA (mRNA) in cultured rat hepatocytes, in which S1P decreased DNA synthesis induced by hepatocyte growth factor (HGF) or epidermal growth factor (EGF) without affecting total protein synthesis. This inhibitory effect was attenuated by inactivation of small GTPase Rho with C3 exotoxin but not by inactivation of G(i) with pertussis toxin. Moreover, in the presence of JTE-013, a newly developed and specific binding antagonist for Edg-5, the inhibitory effect was also cancelled. Finally, the administration of S1P after 70% partial hepatectomy in rats reduced the peak of DNA synthesis in hepatocytes with increased Rho activity. Furthermore, Edg-5 but not Edg-1 mRNA expression was enhanced in hepatocytes 24-72 hours after partial hepatectomy, which coincides with decreasing hepatocyte proliferation. CONCLUSIONS: S1P has an antiproliferative property in rat hepatocytes by activating Rho via Edg-5. Our results raise the possibility that S1P is a negative regulator in liver regeneration.     

The landmark for removal of sialoliths using sialendoscopy alone in parotid gland sialolithiasis

Objective

To assess the general guidelines for removal of sialoliths in parotid gland sialolithiasis using sialendoscopy alone.

Fast diffusion kurtosis imaging (DKI) with Inherent COrrelation‐based Normalization (ICON) enhances automatic segmentation of heterogeneous diffusion MRI lesion in acute stroke

Diffusion kurtosis imaging (DKI) has been shown to augment diffusion‐weighted imaging (DWI) for the definition of irreversible ischemic injury. However, the complexity of cerebral structure/composition makes the kurtosis map heterogeneous, limiting the specificity of kurtosis hyperintensity to acute ischemia. We propose an Inherent COrrelation‐based Normalization (ICON) analysis to suppress the intrinsic kurtosis heterogeneity for improved characterization of heterogeneous ischemic tissue injury. Fast DKI and relaxation measurements were performed on normal (n = 10) and stroke rats following middle cerebral artery occlusion (MCAO) (n = 20). We evaluated the correlations between mean kurtosis (MK), mean diffusivity (MD) and fractional anisotropy (FA) derived from the fast DKI sequence and relaxation rates R₁ and R₂, and found a highly significant correlation between MK and R₁ (p < 0.001). We showed that ICON analysis suppressed the intrinsic kurtosis heterogeneity in normal cerebral tissue, enabling automated tissue segmentation in an animal stroke model. We found significantly different kurtosis and diffusivity lesion volumes: 147 ± 59 and 180 ± 66 mm³, respectively (p = 0.003, paired t‐test). The ratio of kurtosis to diffusivity lesion volume was 84% ± 19% (p < 0.001, one‐sample t‐test). We found that relaxation‐normalized MK (RNMK), but not MD, values were significantly different between kurtosis and diffusivity lesions (p < 0.001, analysis of variance). Our study showed that fast DKI with ICON analysis provides a promising means of demarcation of heterogeneous DWI stroke lesions.     

Prognostic significance of HLA class I expression in osteosarcoma defined by anti-pan HLA class I monoclonal antibody, EMR8-5

With the goal of establishing efficacious peptide-based immunotherapy for patients with bone and soft tissue sarcomas, we previously identified the cytotoxic T lymphocyte-defined osteosarcoma antigenic gene Papillomavirus binding factor. The present study was designed to determine the status of HLA class I expression in osteosarcoma and other bone and soft tissue sarcomas. Seventy-four formalin-fixed paraffin-embedded specimens of various bone and soft tissue sarcomas, including 33 osteosarcomas, were stained with the anti-HLA class I monoclonal antibody EMR8-5, which we recently generated. The expression of HLA class I was lost or downregulated in 46 of these specimens (62%). With respect to osteosarcoma, loss or downregulation of HLA class I expression was seen in 13 (52%) of 25 primary tumors and seven (88%) of eight metastatic tumors. In six of 11 HLA class I-negative osteosarcoma specimens, the expression of beta-2 microglobulin was also lost. Subsequently the prognostic significance of HLA class I expression was analyzed in 21 patients with osteosarcoma who had completed multidrug neoadjuvant chemotherapy and undergone adequate surgery. Patients with osteosarcoma highly expressing HLA class I showed significantly better overall and event-free survival than those with HLA class I-negative osteosarcoma. In contrast, such prognostic significance of HLA class I expression was not found in 15 patients with malignant fibrous histiocytoma of soft tissue. These findings suggest that the class I-restricted cytotoxic T lymphocyte pathway plays a major role in immune surveillance of patients with osteosarcoma.     

SYT-SSX breakpoint peptide vaccines in patients with synovial sarcoma: A study from the Japanese Musculoskeletal Oncology Group

In the present study, we evaluated the safety and effectiveness of SYT‐SSX‐derived peptide vaccines in patients with advanced synovial sarcoma. A 9‐mer peptide spanning the SYT‐SSX fusion region (B peptide) and its HLA‐A*2402 anchor substitute (K9I) were synthesized. In Protocols A1 and A2, vaccines with peptide alone were administered subcutaneously six times at 14‐day intervals. The B peptide was used in Protocol A1, whereas the K9I peptide was used in Protocol A2. In Protocols B1 and B2, the peptide was mixed with incomplete Freund's adjuvant and then administered subcutaneously six times at 14‐day intervals. In addition, interferon‐α was injected subcutaneously on the same day and again 3 days after the vaccination. The B peptide and K9I peptide were used in Protocols B1 and B2, respectively. In total, 21 patients (12 men, nine women; mean age 43.6 years) were enrolled in the present study. Each patient had multiple metastatic lesions of the lung. Thirteen patients completed the six‐injection vaccination schedule. One patient developed intracerebral hemorrhage after the second vaccination. Delayed‐type hypersensitivity skin tests were negative in all patients. Nine patients showed a greater than twofold increase in the frequency of CTLs in tetramer analysis. Recognized disease progression occurred in all but one of the nine patients in Protocols A1 and A2. In contrast, half the 12 patients had stable disease during the vaccination period in Protocols B1 and B2. Of note, one patient showed transient shrinkage of a metastatic lesion. The response of the patients to the B protocols is encouraging and warrants further investigation.