Efficacy of intracerebral microinfusion of trastuzumab in an athymic rat model of intracerebral metastatic breast cancer.

PURPOSE: The monoclonal antibody (MAb) trastuzumab (Herceptin) effectively treats HER2-overexpressing extracerebral breast neoplasms. Delivery of such macromolecule therapeutic agents to intracerebral metastases, however, is limited by the tight junctions characteristic of the cerebral vasculature. Direct intracerebral microinfusion (ICM) is a technique that bypasses this blood-brain barrier and allows for a greater delivery of drugs directly into intracerebral tumors. EXPERIMENTAL DESIGN: A human breast cancer cell line transfected to overexpress HER2, MCF-7/HER2-18, was transplanted into the cerebrum of athymic rats. Saline, trastuzumab, or an isotype-matched control MAb was delivered systemically or by ICM to assess toxicity and efficacy. RESULTS: No clinical or histological toxicity related to trastuzumab was evident under any of the conditions studied. Delivery of trastuzumab (2 mg/kg) i.p. led to a median survival of 26.5 days, whereas treatment with trastuzumab (2 mg/kg) by ICM increased the median survival by 96% to 52 days, with two of nine rats surviving >120 days (P = 0.009). Treatment with an isotype-matched control MAb (16 mg/kg) resulted in a median survival of 21 days, which did not differ significantly from the survival of rats treated by ICM with saline (16 days; P = 0.42). Treatment by ICM with trastuzumab (16 mg/kg) led to a median survival of 45 days, with 2 of 10 rats surviving >120 days. These results represent 181% and 114% increases in median survival over the saline and MAb controls, respectively (P < 0.001). CONCLUSION: ICM of trastuzumab is safe and superior to systemic delivery as therapy for HER2-overexpressing intracerebral neoplasms in an athymic rat model.     

Superiority of a new UICC-TNM staging system for gastric carcinoma

BACKGROUND: The definition of the degree of lymph node metastasis (n-classification) for gastric cancer differs greatly in the new Union Internationale Contre le Cancer--TNM classification (5th edition) and the Japanese gastric cancer classification (JGC). The feasibility of the new TNM classification is evaluated in comparison with the JGC. METHODS: At Chiba University, 940 patients who underwent a gastrectomy were retrospectively classified into appropriate stages with both the TNM and JGC systems, and the survival curves of the respective stages were also compared. RESULTS: Patients with 1 to 6 metastatic nodes (TNM-pN1) showed similar survival rates whether the metastases were limited to the perigastric area (JGC-n1) or reached distant areas (JGC-n2). The patients with node metastasis that was limited to the perigastric area (JGC-n1) had significantly different survival rates, depending on the number of metastatic nodes (TNM-pN1 or pN2, P = .022). A similar phenomenon was also observed in patients with TNM-N2 and JGC-n2. A multivariate analysis indicated the TNM N-classification, rather than the JGC n-classification, as an independent prognostic factor. CONCLUSIONS: The new TNM classification appears to be a better prognostic indicator than the JGC system for patients with gastric carcinoma.     

Macroscopic features at the deepest site of tumor penetration predicting liver metastases of colorectal cancer

Liver metastasis is the gravest prognostic factor in colorectal cancer. To identify a reliable indicator for liver metastasis, we evaluated macroscopic features and seven established histopathological findings at the cut section containing the deepest penetration using univariate and multivariate analyses in 417 colorectal cancers. Macroscopic features were divided into two types, streak type and non-streak type, according to the presence or absence of white streak(s) at the advancing margin of tumor invasion. Streak type was observed in 109 patients (26%). The frequency of liver metastasis in streak type tumors (56%) was significantly higher than that in non-streak type tumors (13%) (p < 0.001). The white streak corresponded histologically with cancer cells showing focal dedifferentiation with marked stromal and perivascular fibrosis extending towards the serosa or adventitia. In 343 curatively treated patients, univariate analysis showed that recurrent liver metastasis was significantly associated with macroscopic features, venous invasion, focal dedifferentiation and lymph node metastasis. Multivariate analysis disclosed that macroscopic features and lymph node metastasis were independent indicators of liver metastasis. These macroscopic features, corresponding histologically to stromal behavior against invading cancer cells, are a simple and useful indicator of liver metastasis of colorectal cancer.      

Survey on visual and musculoskeletal symptoms in VDT workers]

With the spread of visual display terminals (VDT) in offices, the numbers of workers using VDT and the working hours at such equipment have increased rapidly in recent years. Also, preventive measures for fatigue have been proposed and the office-working environment has been improved. To examine the effects of the rapid changes in working conditions and environment on the health of VDT workers, we conducted a questionnaire survey in 2002. A self-reported questionnaire was distributed to 3,927 office workers; 2,374 (60.5%) responded. Subjects whose questionnaires had missing data were excluded from analysis. As a result, 1,406 (male: 1,069, female: 337) workers aged 20 to 59 were subjected to analysis. By a logistic regression model, we examined the association between VDT use and visual and musculoskeletal symptoms. Prevalence of eye strain and/or pain (72.1%) was the highest, followed by neck stiffness and/or pain (59.3%), low back stiffness and/or pain (30.0%) and hand or arm strain and/or pain (13.9%). Women consistently reported more discomfort than men. As a result of the logistic regression model, eye strain and/or pain was associated with dissatisfaction with airflow, but not with factors affecting visual symptoms as reported in previous studies, for example, reflection of light and blurred characters on the screen. It was thought that airflow appeared as a risk factor because the lighting environment had been improved in offices to prevent reflection of light on the screen. Neck stiffness and/or pain was associated with raising the shoulders during VDT work, the unsuitable shape of the computer mouse for a hand, and the inconvenient arrangement of the mouse in relation to the body. Hand or arm strain and/or pain were associated with the arrangement of the mouse and inappropriate height of the desk. Low back stiffness and/or pain were associated with dissatisfaction with the chair and using the keyboard without a wrist rest. Although measures to prevent fatigue had been implemented for VDT workers, risk factors for musculoskeletal symptoms would be the same as in previous studies.     

Gastric and non-gastric signals in electrogastrography

Electrogastrography (EGG) is the cutaneous recording of gastric myoelectrical activity, and the dominant frequency reflects the rhythm of the gastric slow wave. Ambulatory EGG is contaminated with a large amount of motion artifacts, and it is unclear how much of the signals comprising the dominant frequency originates from non-gastric sources. The aim of the present study was to evaluate the pattern of gastric and non-gastric signals in the dominant frequency histogram (DFH) obtained from long-term ambulatory EGG recordings. Ten normal controls and five post-gastrectomy patients participated in the present study. Twenty-four hour ambulatory EGG was recorded under normal daily conditions. The DFH of normal controls showed two distinctive peaks, and that of the post-gastrectomy patients, a single peak. The common peak at approximately 1.5 cpm was seen in both DFHs, and the peak at 3 cpm was seen only in the DFH of normal controls. Thus, the common peak was thought to be a product of non-gastric origin. In conclusion, the dominant frequency consists of gastric and non-gastric components which have a specific distribution pattern in the DFH. These findings quantified the contribution of gastric and non-gastric signals to the dominant frequencies in long-term ambulatory EGG.     

Electrodiagnosis in entrapment neuropathy by the arcade of Struthers

Two cases of high ulnar nerve neuropathy are reported. Lesions were localized at the midarm level by electrophysiologic studies. In the first case, the lesion was found mainly to be a prolonged neurapraxia, and neurolysis was effective. The ulnar nerve was swollen 1 cm in length under the arcade of Struthers. After neurolysis, the palsy recovered rapidly. In the other case, the lesion seemed to be a mild injury to the myelin sheath. Delayed segmental conduction velocity and partial conduction block were found at the midarm level. The paresis improved slightly during the 11-month followup without any treatment, but the electrophysiologic studies were unchanged. In both cases, physical examination did not distinguish the lesions from cubital tunnel syndrome. Electrophysiologic examination proved to be effective as a diagnostic procedure. In the presence of ulnar neuropathy, the upper arm segment should be included in a routine nerve conduction study to screen for the rare but important entrapment neuropathy caused by the arcade of Struthers.     

Laterality of vestibular evoked myogenic potentials

To clarify the laterality of acoustically evoked vestibulocollic reflexes with a short latency (vestibular evoked myogenic potentials, VEMPs), responses on the bilateral sternocleidomastoid muscles (SCMs) to unilateral acoustic stimulation were studied. Twenty-one healthy volunteers were enrolled. Surface electrodes were placed on the upper half of each SCM (active) and on the lateral end of the upper sternum (reference). Clicks and 500-Hz tone-bursts (95 dB nHL) were used. All subjects showed positive-negative biphasic responses on the ipsilateral SCM by clicks and tone-bursts. Click-stimulation of 41 of the 42 ears did not evoke any response on the contralateral SCM. However, in one ear, positive-negative biphasic responses were evoked on the contralateral SCM. Recordings on the contralateral SCM by tonebursts showed no response in 32 ears, small positive-nega-tive biphasic responses in four ears, and small negative-positive biphasic responses in six ears. These findings show that VEMPs are ipsilateral-dominant, basically consistent with the hypothesis that they are of saccular origin.