Immunohistochemical detection of P-glycoprotein and carcinoembryonic antigen in small cell lung cancer: with reference to predictability of response to chemotherapy.

In an attempt to elucidate the tumor properties relating to responsiveness to chemotherapy, we examined immunohistochemically the expression of P-glycoprotein (P-gp) and carcinoembryonic antigen (CEA) in small cell lung cancer (SCLC) tumors. Tumor specimens from 33 patients were obtained at the time of diagnosis and relapse. Four patients expressed P-gp in their initial tumors, and 7 others did in recurrent tumors. The overall response rate to chemotherapy of the initial tumors was 75% for P-gp-positive initial tumors and 86% for P-gp-negative tumors, whereas the disease-free and overall survival times were significantly shorter in the former than the latter. Three patients showed CEA in their initial tumors, and 5 others did in recurrent tumors. The patients with CEA-positive initial tumors tended to relapse earlier than those with CEA-negative tumors. In addition, recurrent tumors expressing CEA were resistant to salvage chemotherapy. A clear correlation between CEA expression by tumors and the CEA level in the serum was observed at diagnosis as well as at relapse. These findings indicate that P-gp and/or CEA expression by a tumor and elevated CEA level in the serum may predict refractoriness of the tumor to chemotherapy.

[Phase II study of ifosfamide and vindesine combination of non-small cell lung cancer in elderly patients and patients with reduced renal function].

A pilot phase II study of a ifosfamide and vindesine combination of non-small cell lung cancer was conducted in the elderly patients and patients with reduced renal function. The combination consisted of ifosfamide, 2.3 g/m2, on day 1 through 3, and vindesine, 3 mg/m2, on day 1 and 8. Cycles were repeated at 4-week intervals. The dose of ifosfamide and vindesine was reduced in the elderly. Of 24 evaluable patients, one had a complete response and 8 had partial response, with an overall response rate of 37.5%. The projected median response duration was 6.8 months and the median survival for all patients was 15.1 months. The toxicity was tolerable with moderate myelosuppression. These results indicate that this combination chemotherapy is safe and effective for non-small cell lung cancer in the elderly patients and patients with reduced renal function and warrants further clinical trials.

[A case of chronic hypersensitivity pneumonitis induced by shiitake mushroom spores].

A 73-year-old woman was admitted to our hospital with a low-grade fever, dry cough and dyspnea on exertion as the chief complaints. She had been a professional shiitake mushroom grower for 50 years. Three years before visiting our hospital, she had been suspected of having hypersensitivity pneumonitis as a result of chest X-ray examination, bronchoalveolar lavage and transbronchial lung biopsy performed at another clinic. No antigens were identified at that time, but prednisolone was administered. On admission to our hospital, chest radiography and chest computed tomography revealed an interstitial shadow with subpleural honey-combing in both lower lung fields. After steroid pulse therapy, dyspnea on exertion and hypoxia improved moderately. Because of recurrence of the dyspnea, however, she was admitted on four separate occasions. On the second admission, an increase in lymphocytes was found by bronchoalveolar lavage, and septal lymphocytic infiltration accompanying fibrosis was demonstrated by transbronchial lung biopsy. On the fourth admission, a detailed immunological examination and an environmental survey were performed. The environmental provocation test yielded clinical symptoms similar to those experienced at the mushroom farm. Furthermore, tests of precipitation and lymphocyte proliferation in response to shiitake mushroom extracts were positive. Finally a diagnosis of chronic hypersensitivity pneumonitis induced by shiitake mushrooms was confirmed.

[Assessment of antitumor activity rhizoxin for human lung cancer cell lines: a potent new drug for drug-resistant lung cancer].

Rhizoxin is a new macrocyclic lactone isolated from the fungus Rhizopus chinensis. In an attempt to predict the effectiveness of rhizoxin in the treatment of lung cancer, we compared the antitumor activity of rhizoxin with those of cisplatin and etoposide using four small cell lung cancer (SCLC) cell lines, SBC-2, -3, -4, and -7, and two non-small cell lung cancer (NSCLC) cell lines, ABC-1 and EBC-1. The concentrations producing 50% inhibition of the growth of these cell lines (IC50) for each drug were obtained by MTT assay. The IC50 of rhizoxin for these cell lines ranged 0.408 nM to 1.56 nM, which were significant lower than those of cisplatin (660 nM to 16,300 nM) and etoposide (275 nM to 31,300 nM). The ratio of IC50 for the most sensitive cell line, SBC-3, to that for the most resistant cell line was less than 4-fold in rhizoxin, in contrast to more than 20-fold in cisplatin and 100-fold in etoposide. Cross-resistance of rhizoxin to cisplatin and etoposide was investigated using a cisplatin-resistant SCLC subline, SBC-3/CDDP, and an etoposide-resistant SCLC subline, SBC-3/ETP. Of interest, the parent cell line, and the resistant sublines were equally sensitive to rhizoxin, indicating rhizoxin being non-cross-resistant to cisplatin and etoposide. In conclusion, rhizoxin may be beneficial in the salvage chemotherapy of drug-resistant SCLC and non-SCLC.

[Successful treatment of two patients with advanced gastric cancer by neoadjuvant chemotherapy with EAP regimen].

Two patients with unresectable gastric cancer accompanied with multiple liver metastases were treated with a 3-drug combination consisting of etoposide, adriamycin, and cisplatin (EAP) as neoadjuvant chemotherapy. After confirmation of maximal response to EAP, both patients received surgical resection of the primary tumor and infusion of cisplatin and 5-FU into hepatic artery, and they survived 15.0 and 15.8 months, respectively. These results indicate that neoadjuvant chemotherapy with EAP regimen is useful in the treatment of advanced gastric cancer.

P15 in tibial nerve SEPs as an example of the junctional potential.

Tibial nerve stimulation at the ankle elicited a stationary, dipolar potential P15/N15 over the buttock with a reference electrode at the contralateral greater trochanter (GTc). P15 was distributed in the rostral and contralateral region and N15 in the caudal and ipsilateral region. The derivation from the contralateral iliac crest to the ipsilateral greater trochanter (ICc-GTi) registered a large P15 (= P15-N15) potential which was well free from artifacts. The Cz'-contralateral knee lead, which had been employed in previous studies, registered a smaller P15 of poor quality. Sequential bipolar recording along the course of the sciatic nerve indicated that P15 was generated around the greater sciatic foramen. Comparison with a simulation study suggested that P15 is a junctional potential which is generated when the sciatic nerve enters the bone at the greater sciatic foramen. P15 is expected to be a useful tool to evaluate the proximal segment of the tibial nerve.

Stimulation of corticospinal pathways at the level of the pyramidal decussation in neurological disorders.

A newly developed technique of brainstem stimulation was applied in 14 normal subjects and 23 patients with various neurological disorders. The electromyographic (EMG) responses of limb muscles following cortical, brainstem and cervical stimulation were recorded. The cortical-brainstem conduction time and brainstem-cervical conduction time were then calculated from the difference in latency between the two sites of stimulation. From the regression lines of the relationship between the normal conduction times in the first dorsal interosseous muscle and the length of the descending tracts, the site of activation by brainstem stimulation was estimated to lie near the cervical-medullary junction. The most distal lesion causing prolongation of cortical-brainstem conduction time was a small cerebral infarction in the lower pons. Herniation of the third cervical spinal disc was the most rostral lesion resulting in delayed brainstem-cervical conduction time and normal cortical-brainstem conduction time. These observations suggest that activation occurs at the level of the cervical-medullary junction where the pyramidal decussation lies. The conduction velocities of the activated tracts estimated from the regression lines for normal individuals were 57-92 m/s. In patients with supratentorial lesions, the threshold for brainstem stimulation was abnormally high. The abnormal findings in this test were correlated significantly with the clinical pyramidal signs. This suggests that the EMG responses elicited by brainstem stimulation are mediated mainly by the corticospinal tract. We conclude that the brainstem stimulation technique would be clinically useful for localization of lesions in the corticospinal tract; the primary lesion can be localized whether above or below the pyramidal decussation.

Somatosensory evoked potential recovery (SEP-R) in myoclonic patients.

Recovery of somatosensory evoked potentials (SEPs) was studied by paired stimulation of the median nerve in patients with various kinds of myoclonus. This technique revealed the hyperexcitability of the central nervous system (CNS) which could not be detected by the conventional SEP technique using a single stimulus. This technique would be useful for studying the excitability of the CNS.

Onset and offset of electromyographic (EMG) silence in asterixis.

The onset and offset of electromyographic (EMG) silence were studied physiologically by silent period locked averaging method (SPLA) combined with a computer-assisted method for detecting EMG changes in 11 patients with asterixis of various aetiologies. The onset followed the EMG discharge which was closely associated with a sharp wave probably generated by the motor cortex in three patients. No EEG activity could be shown to be related to the offset of EMG silence in every patient. Jerky movement of asterixis was temporally related to the offset of EMG silence rather than the onset.

Physiologic analysis of central motor pathways--simultaneous recording from multiple relaxed muscles.

The central motor pathways were studied with the technique of percutaneous electrical stimulation of the central nervous system in 40 normal volunteers. There were no significant differences between the right and left sides, or between males and females. A linear correlation between the cortical latency (Lcor) or the spinal latency (Lsp) and body height was observed, however, there was no correlation between the central conduction time (CCT) (Lcor-Lsp) and body height. Consequently, the CCT appears to provide a reliable estimate of the function of central motor pathways. We have established normal values for eight muscles at rest that would be required for localizing a very small intraspinal lesion.

SEPs in two patients with localized lesions of the postcentral gyrus.

Scalp distributions of median nerve SEPs were studied in normal controls and 2 patients with localized lesions of the postcentral gyrus. In controls, parieto-occipital electrodes registered N20-P27 while frontal electrodes registered P20-N27. Other small components, parieto-occipital P22 and frontal N22, were recognized in about half of the control records. The wave forms at a frontal and a parieto-occipital electrode, both distant from the central region, formed exact mirror images of each other concerning N20-(P22)-P27 and P20-(N22)-N27. Electrodes near the central region contralateral to the stimulation registered cP22-cN30 (central P22 and central N30). When the postcentral gyrus was damaged, N20/P20-P27/N27 and cP22-cN30 were eliminated and the only remaining components were a frontal negative wave (frN) and a contralateral parieto-occipital positive wave (poP). Digital nerve stimulation also evoked poP and frN in both cases. In case 2, poP coincided with P22 of the non-affected side. The following generators were proposed; N20/P20-P27/N27: area 3b, cP22-cN30: areas 1 and 2, poP/early frN (= P22/N22): area 4 at the anterior wall of the central sulcus (due to direct thalamic inputs to motor cortex), late frN: uncertain (SMA?, SII?).

The interval between the positive peak of premyoclonus spike and the onset of myoclonus is shorter than the cortical latency in cortical myoclonus.

In 6 patients with cortical myoclonus, the intervals between the positive peak of the premyoclonus cortical spike and the onset of the myoclonic jerk [interval (Sp-Mcl)] were precisely measured by the computer-assisted jerk-locked averaging method. The intervals (Sp-Mcl) were 13.0-15.8 ms for the abductor pollicis brevis, 8.0-10.4 ms for the extensor digitorum communis and 5.5 ms for the biceps brachii, respectively. These were apparently shorter than the normal latencies of the responses elicited by transcranial cortical stimulation. The difference between the interval (Sp-Mcl) and the spinal latency was -0.8 to 3.5 ms, which was not long enough for the time required for the descending volleys going down from the cortex to the spinal cord. We have concluded that the motor cortex is activated before the positive peak of the premyoclonus spike in cortical myoclonus.

Origin of the widespread N18 in median nerve SEP.

The widespread N18 potential in median nerve SEP was studied in normal subjects and in patients with high cervical, brain-stem and thalamic lesions who had profound disturbances of deep sensation. N18 was well identified in the HSi-CV2 derivation in every normal subject as a broad elevation from the baseline lasting about 20 msec. The cortical N20 was absent in all patients. N18 was absent in a patient with a dorsal column lesion at C1-2 level. The amplitude and configuration of N18 were normal in all other patients with brain-stem and thalamic lesions, including a patient with a lesion at the ponto-medullary junction. The sagittal distribution of N18 was studied in a patient with a thalamic lesion and an oblique distribution with the maximum region between Cz and nasion was demonstrated. The present results indicate that at least the greater part of N18 is generated at the caudal most brain-stem or through branches from this level. Taking previous animal and intraoperative studies into consideration, we think it most probable that the main part of N18 corresponds to the ventro-rostral negative pole of the dipolar potential generated at the cuneate nucleus by the primary afferent depolarization of presynaptic terminals of dorsal column fibers.

Widespread N18 in median nerve SEP is preserved in a pontine lesion.

Widespread N18 potential to median nerve stimulation was preserved in a patient who had profound unilateral disturbance of deep sensation and a lesion of the pontine medial lemniscus confirmed by MRI. It was concluded from this result that at least a significant part of the N18 potential was generated caudal to the pontine level or at higher levels via extralemniscal pathways. Careful review of studies in man with intraoperative recordings seemed to support that the N18 potential already exists at the medullary level. We suggested that the potential generated at the cuneate nucleus which was described in cats may correspond to part of the N18 potential.

Posterior cervical N13 in median nerve SEP has two components.

Somatosensory evoked potentials (SEPs) to median nerve stimulation were investigated in normal controls and patients with cervical lesions. Attention was paid primarily to the N13 and P13 components in the posterior and anterior cervical records with non-cephalic references. In normal subjects the CV2 and CV6 electrodes registered N13 with almost the same amplitude. Dissociation between N13 at the CV2 electrode (ucN13) and N13 at the CV6 electrode (lcN13) was observed in the patients. In 4 patients with cervical dorsal column lesions, lcN13 was preserved but ucN13 was almost completely absent. Anterior cervical P13 (acP13) was preserved. In a patient with syringomyelia, lcN13 and acP13 were greatly attenuated while ucN13 was relatively well preserved. These results suggested that the origins of ucN13 and lcN13 are different. The generator of lcN13-acP13 was assumed to be the postsynaptic potential of the dorsal horn interneurons. Upon comparison with previous animal studies and intraoperative studies, it was concluded that the generator of ucN13 is the postsynaptic potential of the cuneate nucleus.

Results of endoscopic management of carpal tunnel syndrome.

This paper is a retrospective study of 27 women with carpal tunnel syndrome (39 hands) who underwent a new endoscopic operative procedure utilizing the Universal Subcutaneous Endoscope system developed by the lead author. Operations on 199 hands were performed under local anesthesia on an outpatient basis. The etiology was considered idiopathic in all cases. Complete preoperative and postoperative clinical and electrophysiologic data were analyzed in 39 hands. The follow-up period ranged from 12 to 45.8 months (mean, 18.3 months). Symptoms of sensory disturbances disappeared in an average of 20 weeks in all patients. Electrophysiologic studies showed definite improvement when compared with preoperative studies. No complications were recorded. Clinical and electrophysiologic results showed that the less-invasive management of carpal tunnel syndrome by endoscopy is safe and effective.

[Meningeal carcinomatosis in patients with small cell lung cancer].

Six patients (2.7%) developed meningeal carcinomatosis among 207 patients with small cell lung cancer (SCLC) receiving intensive combination chemotherapy. The cumulative probability of developing meningeal carcinomatosis was 2.7% at 3 years and 7.8% at 5 years after diagnosis of SCLC. Pain in legs, gait disturbance, headache, nausea and vomiting were the characteristic symptoms at the onset of meningeal carcinomatosis. Although cytological examination of cerebro-spinal fluid (CSF) was essential for the diagnosis of meningeal carcinomatosis, elevated protein, LDH, CEA and/or NSE concentration and decreased glucose concentration in CSF were also helpful for the diagnosis. For treatment of meningeal carcinomatosis, all patients received intrathecal administration of methotrexate, cytosine arabinoside and/or prednisolone. Additionally, 3 patients received spinal irradiation, and one received cerebro-spinal irradiation. However, only 2 patients responded, and survival was brief ranging from 2 to 38 weeks. Development of meningeal carcinomatosis seems to be a rare event; however, it may be an obstacle to the prolongation of patient survival in the treatment of SCLC.

[A case of gastric carcinoid tumor with coexisting adenocarcinoma in the same tumor].

A case of a gastric carcinoid tumor with a coexisting adenocarcinoma in the same tumor is reported. The patient was a 71-year-old man who complained of epigastralgia. His physical examination and routine laboratory data were unremarkable. An upper GI x-ray series and the gastroendoscopic findings, however, demonstrated a Borrmann 2-like tumor of the antrum. An endoscopic biopsy specimen from the tumor revealed that it was a gastric adenocarcinoma. Therefore, a subtotal gastrectomy with a lymph node dissection was performed. The resected specimen showed a Borrmann 2-like tumor, but also that infiltration was limited to within the submucosal layer. The pathological findings revealed that the tumor contained two differential component structures (a carcinoid and an adenocarcinoma). The carcinoid and adenocarcinoma structures coexisted with transitional changes that connected both structures. Pathohistologically, it was thought that these two differential components developed from a common origin.