Cytoreductive surgery and sandwich therapy with chemohyperthermic peritoneal perfusion and intra-aortic chemotherapy for peritoneal dissemination in gastric cancer

Cytoreductive resection (RST), chemohyperthermic peritoneal perfusion (CHPP) and/or intra-aortic chemotherapy (IA-chemo) were performed for peritoneal dissemination in gastric cancer. Ninety-six patients with peritoneal dissemination were grouped into tubercular (TB), 40; nodular (ND), 31; diffuse (DF) type, 19; and others, 6, respectively, by the gross findings. Sixty-three patients underwent RST. Fifty-nine patients received CHPP by 10-liter heated saline. Thirty patients underwent intra-aortic catheterization for the IA-chemo. The 1-year and 2-year survival rate (1-ysr and 2-ysr) of the RST(+) group were 47% and 10% significantly greater than the 9% and 0% of the RST(-) group (p<0.001). The 1-ysr and 2-ysr of the CHPP(+) group were 37% and 11% significantly greater than the 27% and 0% of the CHPP(-) group (p=0.04). In the TB type the 1-ysr and 2-ysr of the former was 43% and 8% significantly greater than the 15% and 0% of the latter (p=0.04). But there was no significant difference in survival time between the CHPP(+) and the CHPP(-) group in the ND type (p=0.22) or in the DF type (p=0.42). The 1-ysr and 2-ysr of the IA-chemo(+) group were 49% and 19% significantly greater than the 27% and 2% of the IA-chemo(-) group (p<0.01). In the DF type the 1-ysr and 2-ysr of the former was 50% and 33% significantly greater than the 8% and 0% of the latter (p=0.02). However, there was no significant difference in survival time between the IA-chemo(+) and the IA-chemo(-) group in the TB type (p=0.06) or in the ND type (p=0.50). Moreover, the effect of the combination therapy of CHPP and IA-chemo (the sandwich therapy, SDW) were examined. The 1-ysr and 2-ysr of the SDW(+) group were 49% and 22% significantly greater than the 24% and 0% of the SDW(-) group (p=0.002). The sandwich therapy should be performed in addition to cytoreductive surgery for improvement of prognosis in the patient with intractable peritoneal dissemination.     

Kinetics of d-tubocurarine disposition and pharmacologic response in rats

After bolus intravenous dosing of d-tubocurarine (d-TC) to rats, the twitch heights of the tibialis anterior muscle indirectly stimulated were followed, and its decrease was defined as pharmacologic response of d-TC. The relation between dose and response intensity was found to be well described with Hill's equation. According to a theory proposed by Smolen, Hill's equation was also applicable to the biophase d-TC concentration-response relation; the time courses of the relative biophase d-TC concentration indicated linear kinetics with dose levels 0.15 mg/kg and the occurrence of dose-dependent disposition with 0.30 mg/kg. After bolus i.v. dosing of³H-d-TC, plasma d-TC concentration obeyed a dose-independent two compartment model with doses 0.15mg/kg, but not with 0.30 mg/kg. This finding matched the above estimated with pharmacologic data. The active metabolite was not found in plasma and urine. The extent of d-TC plasma protein binding was independent of the wide range of plasma levels and its mean (±SD) value was 30.5 (±3.8). Plasma d-TC levels and pharmacologie response intensity were well correlated by Hill's equation and a three compartment model (the general two and the biophase compartments) in the dose range 0.15 mg/kg.This work was presented at the First Japanese-American Symposium on Pharmacokinetics and Biopharmaceutics, Tokyo, July 1981, which was held in memory of Dr. Sidney Riegelman.     

Controlled trial of thyrotropin releasing hormone tartrate in ataxia of spinocerebellar degenerations

The clinical efficacy, dose-response relationship, and safety of TRH-T (thyrotropin releasing hormone tartrate) were assessed in 290 patients with spinocerebellar degeneration (SCD) in a 2-week, double-blind study using placebo as control. 254 patients satisfied the criteria for inclusion in evaluation of the drug efficacy. The patients were treated with TRH-T in an intramuscular dose of 2 mg, 0.5 mg or 0 mg (placebo) as TRH once a day for 2 weeks. Clinical responses to these treatments were evaluated 3 times: at the end of weeks 1 and 2 of treatment and a week after the end of treatment. The results of "global improvement rating" as well as those of "ataxia improvement rating" showed that both 2 mg and 0.5 mg TRH-T treatments were significantly superior to placebo treatment in patients with predominantly cerebellar form of SCD. The effect was well maintained a week after the end of the 2-week treatment in the patients who were given TRH-T in daily dose of 2 mg and showed improvement at the end of treatment. The results of "improvement rating of each symptom" revealed that 2 mg treatment was significantly more effective than placebo for disorders of standing, gait, speech and writing. In the patients who had no pyramidal involvement or disorder of deep sensation, the drug efficacy and dose-response relationship were evident. Adverse reactions to the drug such as headache, feeling febrile and nausea were observed in 50% of the patients on 2 mg treatment, in 38% of those on 0.5 mg treatment and in 21% of those on placebo patient, however, discontinued treatment because of adverse reactions.     

Proliferative activity in advanced gastric-cancer with ki-67 and propidium iodide - analysis by flow-cytometry

By setting the cut-off line at the level as used in a negative control study without primary antibody in the same sample, the Ki-67 labeling rate was calculated by the Ki67-DNA dual fluorescence analysis. The mean Ki-67 labeling rate of 28 advanced gastric cancer was 45.1% (13.9-76.3%). The Ki-67 labeling rates were significantly higher for larger size tumor (p<0.05), peritoneal metastasis and advanced stage (p<0.01). This is the first report that cycling cells are calculated by setting the cut-off line for solid tumors. Use of this flow cytometric procedure substantially facilitates the quantification of proliferating cells in gastric cancer.     

Hyperthermo-chemotherapy combined with cytoreductive surgery for the treatment of gastric cancer with peritoneal dissemination

Continuous hyperthermic peritoneal perfusion (CHPP) with anticancer agents (mitomycin C and cisplatin) in warm saline was performed in patients with peritoneal dissemination of gastric cancer following resection of the primary lesion. The effect of CHPP was examined by a second-look operation. This study includes 41 cases of gastric cancer with peritoneal dissemination but without liver metastasis treated during the past 6 years. The overall median survival was 14.6 months to 64.2 months from CHPP to death and the 3-year survival rate was 28.5%. Second look surgery revealed a remarkable diminution in the degree of peritoneal dissemination in 7 (50%) of 14 patients with disappearance of ascites after only one course of CHPP in 7 (77.8%) of 9 patients. Long-term 3 year-survival was noted in 4 (9.8%) patients on CHPP. Side effects were renal insufficiency in 2 (5%) patients, leukopenia in 2 (5%) patients, and perforation of the small intestine in 1 (2%) patient. These results suggest the effectiveness of CHPP in the treatment of gastric cancer with peritoneal dissemination.

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Resumen La perfusión hipertérmica continua (PHTC) con agentes anticancerosos (mitocina G y cisplatino) y solutión salina fue realizada en pacientes con cáncer gástrico con diseminación peritoneal después de resección de la lesión primaria, y el efecto de PHTC fue determinado mediante reexploración (operación de second look, OSL). La población de pacientes está constituída por 41 casos de cáncer gástrico con diseminación peritoneal pero sin metástasis hepáticas, tratdos en el curso de los últimos 6 años. La sobrevida media global fue de 437 dias (rango 28 a 1925 días) desde la PHTC hasta la muerte y la tasa de sobrevida a 3 años fue 28.5%. La OSL reveló una notoria disminución de la diseminación peritoneal en 7 (50%) de 14 casos y desaparición de la ascites después de sólo un ciclo de PHTC en 7 de 9 casos con ascitis. Sobrevida de 3 años ocurrió en 4 casos. Los efectos colaterales fueron insuficiencia renal en 2 casos (5%), leucopenia en 2 casos (5%) y perforación del intestino delgado en 1 caso (2%). Los anteriores resultados sugieren que la PHTC es eficaz en el tratamiento del cáncer gástrico con diseminación peritoneal.

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Résumé La perfusion péritonéale continue hyperthermique (PPCH) avec des agents anticancéreux comme le mitomycine C et la cis-platine avec sérum physiologique chauffé a été instaurée lorsqu'une carcinose d'origine gastrique a été trouvée. Les effets de la PCH ont été évalués chez 16 patients lors d'un second-look (SL). Cette étude concerne 41 patients avec carcinose péritonéale sans métastase hépatique observés au cours des 6 dernières années. La survie globale médiane était de 437 jours (extrêmes 28 à 1925 jours): le taux de survie a 3 ans était de 28.5%. Les lésions avaient diminué de façon notable chez 7 (50%) de 14 patients. L'ascite a disparu dans 7 des 9 cas. Une survie à long terme (3 ans) a été notée dans 4 cas. Les effets secondaires ont été une insuffisance rénale dans 2 cas (5%), une leucopénie dans 2 cas (5%) et une perforation de l'intestin grêle dans un cas (2%). Les résultats suggèrent que la PPCH est efficace dans le traitement du cancer gastrique avec dissémination péritonéale.

     

Comparative study on the cardio-respiratory change during prostaglandin E1-induced hypotension in the patients in the supine and prone position

Prostaglandin E₁-induced hypotension (25% reduction from the preadministration level in mean arterial pressure) was applied to thirteen patients. Eight patients among them were operated in the supine position (group I) and other five in the prone position (group II). The maintenance dose of PGE₁ was considerably lower in group II than in group I (0.067µg·kg^–1·min^–1 vs. 0.119µg·kg^–1·min^–1). In group I, there was a significant increase in CI, with a significant decrease in SVRI and PVRI during PGE₁-induced hypotension. Such a high dose of PGE₁ (0.119µg·kg^–1·min^–1) was considered to have a direct dilating action on the systemic resistance bed as well as on the pulmonary vasculature. It was considered that the suppression of hypoxic pulmonary vasoconstriction could be a mechanism to increase venous admixture during PGE₁-induced hypotension. In group II, there was no significant increase in CI, and no significant decrease in SVRI and PVRI. PGE₁-induced hypotension can be safely applied to the anesthetized patients, but we should be careful to apply it to the patients in the prone position, because lower dose of PGE₁ can induce severe hypotension, which is not accompanied by the increase in CI as occures in the patients in the supine position.(Hirose M, Yoda K, Sakai K, et al.: Comparative Study on the cardio-respiratory change during prostaglandin E₁-induced hypotention in the patients in the supine and prone position. J Anesth 5: 30–35, 1991)     

Quantitative measurement of the basilar arterial flow in the dog-electromagnetic flow-meter study of the extra-and intracranial arterial occlusion (author's transl)]

Recent advances in microneurosurgery have markedly improved the result of surgical treatment of aneurysm and arteriovenous malformation in the posterior cranial fossa. However, more precise study on hemodynamics of the vertebro-basilar system may be necessary for further progress in treatment of the vascular lesions. From this point of view, the authors studied the basilar arterial flow of the dog by means of an electromagnetic flow-meter and the flow probe which was specially devised by the authors. (1) The ratio of absolute value of the mean basilar flow to the total brain weight was calculated, and the flow rate was expressed in ml/100 g brain/min. Mean value was 7.1 ml/100 g brain/min under normocapnea. (2) The effect of occlusion of the common carotid, of the external carotid, of the intracranial internal carotid, and of the extracranial internal carotid on the basilar flow was less remarkable in this order. (3) Under normocapnea, occlusion of the unilateral common carotid artery produced 115% increase in the basilar arterial flow. Bilateral common carotid occlusion resulted in 312% increase of the flow, demonstrating a remarkable ability of compensation of the basilar artery through the circle of Willis and leptomeningeal anastomoses. Under hypercapnea, unilateral common carotid occlusion was followed by 81% increase in the basillar flow. Occlusion of both common carotids caused 230% increase in the basilar flow. Percent increase in the basilar flow after unilateral or bilateral common carotid occlusion under normocapnea was significantly larger than under hypercapnea (p less than 0.05 and p less than 0.01 respectively). It may be supposed that under normacapnea the increased basilar flow following bilateral common carotid occlusion may compensate the decrease in total cerebral blood flow due to carotid occlusion. However, the compensatory rise in the basilar flow under hypercapnea may be not enough to supply the dilated vascular bed in the carotid and basilar territories. There might be even a risk of deficiency of blood supply in the territory of the basilar artery, if the vascular resistance in the carotid area could become less than that in the basilar. The significance of CO2 inhalation therapy for ischemic cerebral lesion was discussed. (4) After the both common carotid arteries were occluded, the basilar aretry was clamped temporarily. Following release of basilar occlusion, reactive hyperemia was observed in the basilar flow. Magnitude and duration of the reactive hyperemia increased progressively depending on duration of the basilar occlusion to some extent. The phenomenon may be best explained by a progressive accumulation of vasodilating metabolities in the ischemic area. (5) Unilateral vertebral occlusion caused 37% decrease in the basilar flow. Bilateral vertebral occlusion resulted in reverse of the basilar flow, averaging 61% of the original value in flow rate. (6) Occlusion of the unilateral subclavian artery produced "subclavian steal phenomenon"...     

Th1 dominance in HAM/TSP and the optico-spinal form of multiple sclerosis versus Th2 dominance in mite antigen-specific IgE myelitis

To clarify the Th1/Th2 balance in spinal cord inflammation, we used ELISA to measure the total and allergen-specific IgE in 69 patients with clinically definite multiple sclerosis (MS), including 24 patients with the optico-spinal form of MS, 45 with HAM/TSP, 30 HTLV-I carriers without HAM/TSP, 40 patients with acute myelitis, 43 with neurodegenerative disorders, and 42 healthy subjects, and flow cytometry to study the intracellular IFNgamma-positive versus IL-4-positive cell ratio (intracellular IFNgamma/IL-4 ratio) in peripheral blood CD4(+) T cells in 40 patients with MS, including 17 patients with the optico-spinal form of MS, 23 with HAM/TSP, 22 with acute myelitis, 23 with neurodegenerative disorders, and 36 healthy subjects. Patients with HAM/TSP showed a significantly higher intracellular IFNgamma/IL-4 ratio, lower IL-4(+)/IFN-gamma(-) cell percentages, lower total IgE level, and lower frequency of cedar pollen-specific IgE than did the controls. The patients with optico-spinal MS showed a significantly higher intracellular IFNgamma/IL-4 ratio and higher IL-4(-)/IFN-gamma(+) cell percentages than the controls even at remission or in the convalescence phase. In contrast, in the patients with acute myelitis, the total serum IgE level and the frequency of mite antigen-specific IgE were significantly elevated in comparison to the controls, while those having mite antigen-specific IgE myelitis showed a significantly lower IFNgamma/IL-4 ratio in the CD4(+) T cells in comparison to the controls. These findings suggest that the Th1 cell response is predominant in HAM/TSP and optico-spinal MS, whereas the Th2 cell response is predominant in mite antigen-specific IgE myelitis.     

Characteristics of epilepsy in severely mentally retarded individuals

In order to clarify the characteristics of epilepsy in patients with severe mentally retarded (SMR) subjects, we analyzed 52 SMR subjects with epilepsy from the institute for SMR subjects at Kikuchi National Hospital, Kumamoto, Japan. A total of 61.5% patients had uncontrolled seizures which were resistant to treatment. The most common combinations of seizure types in those not responding to conventional anticonvulsants were generalized tonic-clonic seizures (GTCS) with tonic seizure and GTCS with atypical absence. Their clinical features were characterized by spastic paralysis associated with a slower background electroencephalogram and abnormal computed tomography scans of the head, suggesting the involvement of cortical damage. These findings suggest that a large proportion of epilepsy in SMR subjects does not respond to treatment and that the severity of organic brain damage may therefore affect the natural course of epilepsy in such patients.