Phase I/II study of humanized anti-CD33 antibody conjugated with calicheamicin, gemtuzumab ozogamicin, in relapsed or refractory acute myeloid leukemia: final results of Japanese multicenter cooperative study

The primary objective of this study was to investigate the tolerability, efficacy and pharmacokinetic profile of gemtuzumab ozogamicin (GO) in patients with relapsed and/or refractory CD33-positive acute myeloid leukemia (AML). Patients received 2-h infusions of GO twice with an interval of approximately 14 days. Tolerability was assessed using the National Cancer Institute Common Toxicity Criteria Version 2.0. Samples for pharmacokinetics were taken on day 1 and day 8 of the first treatment cycle. The dose was increased stepwise and, in each cohort, patients were treated at the same dose. Forty patients, median age 58 years (range 28–68) were treated; 20 and 20 patients were enrolled to the phase I and II parts, respectively. In the phase I part, dose-limiting toxicities (DLTs) were hepatotoxicities, and the recommended dose was established as 9 mg/m² given as two intravenous infusions separated by approximately 14 days. The pharmacokinetic study revealed that C _max and AUC were equivalent to those of non-Japanese patients. In the phase II part, complete remission was observed in 5 patients, and one patient had complete remission without platelet recovery. Four of these 6 in remission and one in the phase I are long-term survivors (alive for at least 44 months). GO is safe and effective as a single agent among Japanese CD33-positive AML patients. Remission lasted longer in a subset of patients than in non-Japanese patients in earlier studies. Further studies of this agent are warranted to establish standard therapy. S. Furusawa: deceased.     

Distant failure after treatment of postoperative locoregional recurrence of non-small cell lung cancer

BACKGROUND: The standard treatment for patients with locoregional recurrence of non-small cell lung cancer (NSCLC) after complete resection has not been established. The aim of this study was to evaluate clinicopathologic characteristics, type of locoregional recurrence, pattern of subsequent failure, and survival after the recurrence. METHODS: Of 743 patients undergoing pulmonary resection for NSCLC in the National Cancer Center Hospital between 1990 and 1995, we retrospectively reviewed the medical charts of the 43 patients (5.8 %) found to have locoregional recurrence without distant metastasis or pleural or pericardial involvement. RESULTS: The median time to locoregional recurrence was 13.6 months (range: 1.6 - 85.8 months). The most frequent site of recurrence was the mediastinal nodes in 21 of 43 patients (49 %). 33 patients (77 %) received further treatment for the recurrence: thoracic irradiation in 26, surgery in two, systemic chemotherapy in two, and a combination of the above in 3 patients. Subsequent distant failure was detected in 26 (68 %) of the 38 patients assessable for the analysis of failure pattern: lung in 11, brain in 6, bone in 5, and others in 13. The median interval from the recurrence to distant failure was 8.4 months (range: 1.7-56.4 months). The median survival time after diagnosis of the locoregional recurrence was 10.5 months (range: 0-74.0 months). A multivariate analysis showed that local therapy for the locoregional recurrence had no significant impact on postrecurrent survival or distant failure-free survival. CONCLUSIONS: Many patients with postoperative locoregional recurrence developed distant metastases early after the first recurrence. Systemic chemotherapy in addition to local therapy may be of benefit in this population.     

Changes in cyclic nucleotide phosphodiesterase activity and calmodulin concentration in heart muscle of cardiomyopathic hamsters

Cyclic nucleotides (cAMP and cGMP) phosphodiesterase (PDE) activities and expression are altered in the cardiac muscle of cardiomyopathic heart failure, and PDE inhibitors improve the abnormal muscle condition through changing the cyclic nucleotide concentration. These observations prompted us to investigate the role of calmodulin (CaM) in the regulation of cyclic nucleotide PDE activities, and moreover to study the modulation of the PDE isozymes in heart failure, using cardiac muscles of cardiomyopathic hamster. The CaM concentrations in the heart muscle of the normal control and cardiomyopathic hamsters (each of three to four hamsters) varied with cell fraction and with the age of the animal. The CaM concentrations in the soluble fraction obtained from cardiomyopathic hamster tissue were significantly increased at 25 and 32 weeks of age (2.02 +/- 0.62 microg/mg protein (mean +/- S.E.), and 3.21 +/- 0.95) compared with that obtained from the control (0.60 +/- 0.04) or cardiomyopathic (0.95 +/- 0.12) hamsters at 8 weeks of age. The solubilized PDE isolated from the hamster heart muscle (three or four hamsters in each age) by column chromatography on diethylaminoethyl (DEAE)-cellulose revealed three peaks of activity, which may correspond to the isozymes of PDE classified recently, namely PDE I, II, and III. These three peaks of activity, particularly peak III, seen in the soluble fraction of cardiomyopathic hamster heart declined in proportion to the age of the animal compared with that of the control hamster heart. In the cGMP-PDE assay system, the concentration of CaM inhibitor W-7 required for 50% inhibition (IC(50)) of PDE I, II, and III peak activities was 140, 29, and 46 microM, respectively, suggesting that PDE II is more sensitive to W-7. These results suggest that alteration in these isozyme activities accompanied with changes of CaM concentration may influence the cardiac muscle contractility in cardiomyopathic hamster via changes of cyclic nucleotide concentration.     

Myxoid liposarcoma metastatic to the thoracic epidural space without bone involvement: report of two cases.

Myxoid liposarcoma can frequently metastasize to extrapulmonary sites. We present two cases of myxoid liposarcoma metastatic to the epidural space. Both patients complained of back pain, but plain radiography revealed no abnormality. MR imaging clearly demonstrated metastatic tumors in the epidural space, but no involvement of vertebra. When patients with myxoid liposarcoma complain of back pain, metastasis in the epidural space should be considered even in patients without bone involvement.     

ITCH is a putative target for a novel 20q11.22 amplification detected in anaplastic thyroid carcinoma cells by array‐based comparative genomic hybridization

Anaplastic thyroid carcinoma (ATC) is one of the most virulent of all human malignancies, with a mean survival time among patients of less than 1 year after diagnosis. To date, however, cytogenetic information on this disease has been very limited. During the course of a program to screen a panel of ATC cell lines for genomic copy‐number aberrations using array‐based comparative genomic hybridization, we identified a high‐level amplification of the ITCH gene, which is mapped to 20q11.22 and belongs to the homologous to the E6‐associated protein carboxylterminus ubiquitin ligase family. The expression of ITCH was increased in 4 of 14 ATC cell lines (28.6%), including 8305C in which there was a copy‐number amplification of this gene, and six of seven primary cases (85.7%). Among the primary thyroid tumors, a considerable number of ITCH high expressers was found in ATC (40/45, 88.9%), papillary thyroid carcinoma (25/25, 100%), and papillary microcarcinoma (25/25, 100%). Furthermore, knockdown of ITCH by specific small interfering RNA significantly inhibited the growth of ITCH‐overexpressing cells, whereas ectopic overexpression of ITCH promoted growth of ATC cell lines with relatively weak expression. These observations indicate ITCH to be the most likely target for 20q11.22 amplification and to play a crucial role in the progression of thyroid carcinoma. (Cancer Sci 2008; 99: 1940–1949)     

Proton Beam Therapy for Patients with Esophageal Carcinoma

Fifteen patients with esophageal carcinoma (superficial, sixcases; advanced, nine cases) were treated with 250 MeV protonbeam irradiation with or without external x-ray irradiation(12 MV linear accelerator) from October, 1985, to May, 1991.Eleven patients were initially treated with x-ray at doses of16.2-50.4 (mean 42.5) Gy, followed by proton beam at doses of30.0-52.9 (mean 37.6) Gy. The other four patients were treatedwith proton beam alone at total doses of 75.0-88.5 (mean 81.4)Gy. The mean total dose for the 15 patients was 80.4 Gy. Asa result, the primary tumor lesions of all 15 patients disappearedand complete responses were obtained. Approximately four tofive months later, nine of the 15 patients developed esophagealulcer formations at the circumferences of their primary lesions.The ulcerations were healed, however, by conservative management.There was no evidence of local recurrence throughout the observationson six cases of superficial carcinoma. Among nine advanced carcinomapatients, three relapsed into esophageal carcinoma. Recurrenceswere observed eight, 16 and 44 months, respectively, after thetreatment. Ten of the 15 patients died, but eight died of otherdiseases. Three of four cases at autopsy did not show any cancercells in irradiated primary lesions. Four of the 15 patientslived for over five years. The results suggest that a high doseof irradiation delivered by a well-defined proton field couldresult in improved local control and long-term survival in esophagealcarcinoma without undue risk of injury to primary and adjacentorgans.     

Tilting operating table with self-control foot switch: a new neurosurgical tool

BACKGROUND: Observation of the surgical field from all directions is essential in microneurosurgery. A tilting operating table operated by the surgeon can satisfy this need. METHODS: A tilting operating table operated by the surgeon using a foot switch was developed by modifying the Sugita table incorporating the X-Y shifter. RESULTS AND CONCLUSIONS: The modified operating table allows the surgeon to move the patient in the head up or down directions, as well as the left side down or right side down directions, so the surgical field can be inspected from all aspects without changing the vertical axis of the operating microscope.     

Snare technique of vascular transposition for microvascular decompression--technical note

Recurrence of trigeminal neuralgia (TN) or hemifacial spasm (HFS) after microvascular decompression (MVD) is not rare. The prosthesis material eventually adheres to the neurovascular structures and again transmits arterial pulsation to the nerve. A snare ligature technique using a Gore-Tex tape can be used for the transposition of the offending artery. No prosthesis is necessary once the transposition is complete. This technique requires introduction of either Gore-Tex tape or thread around the artery and suture over the petrous dura, so an adequate working space as if operating in a shallow basin is essential. Therefore, the osteoplastic craniotomy is a little larger than usual with the scalp flap entirely reflected using a semicircular skin incision. The Gore-Tex tape can be directly snared around the artery and sutured over the petrous dura. If this procedure is difficult, a thread can be attached to both ends of the Gore-Tex tape to pass the tape around the vessel. Seven patients with TN and 13 patients with HFS have undergone this surgery. Although the follow-up period is not yet long enough, there has been no case of recurrence. The present technique for MVD can provide complete and permanent transposition of the offending artery.     

Differential development of cation-chloride cotransporters and Cl- homeostasis contributes to differential GABAergic actions between developing rat visual cortex and dorsal lateral geniculate nucleus

A recent study suggested that gamma-aminobutyric acid (GABA) plays differential roles in activity-dependent plasticity between the visual cortex (VC) and the dorsal lateral geniculate nucleus (dLGN). In the present study, to investigate differential GABAergic functions in postnatal visual system development, the development of [Cl(-)](i), cation-Cl(-) cotransporter expression, and the [Ca(2+)](i) responses evoked by GABA were compared between VC and dLGN during the early stages of development. Using rat brain slices from postnatal days (P) 0-17, GABA-evoked [Ca(2+)](i) responses and resting [Cl(-)](i) were measured by means of optical imaging of Ca(2+) and Cl(-), respectively. Changes in the expression of cation-Cl(-) cotransporters (viz. the outwardly-directed K(+)-Cl(-) cotransporter, KCC2, and the inwardly-directed Na(+),K(+)-2Cl(-) cotransporter, NKCC1) were examined in VC and dLGN by in situ hybridization. At birth, the excitatory actions of GABA were powerful in VC, but missing in dLGN (as indicated by neuronal [Ca(2+)](i) transients), and the resting [Cl(-)](i) was significantly higher in VC than in dLGN. Signals for KCC2 mRNA expression were significantly higher in dLGN than in VC at P0. This suggests that extrusion of Cl(-) from neurons is stronger in dLGN than in VC at P0, so that a GABAergic excitatory effect was not observed in dLGN because of more negative equilibrium potential for Cl(-). The present study indicates clear differences in the molecular and physiological bases of Cl(-) homeostasis and GABA actions between the developing VC and dLGN. Such differential GABAergic actions may underlie the distinct mechanisms involved in VC and dLGN development within the visual system.