Adoptive Immunotherapy of Patients with Metastatic Renal Cell Cancer Using Lymphokine-Activated Killer Cells, lnterleukin-2 and Cyclophosphamide: Long-Term Results

Background Initial results of adoptive immunotherapy using lymphokine-activated killer (LAK) cells and interleukin-2 (IL-2) appeared to offer promise for treating renal cell cancer (RCC). However, lower response rates were seen in subsequent trials, and the long-term results of this treatment method have not been fully reported. In this study, we examine long-term results of adoptive immunotherapy using LAK cells, IL-2, and cyclophosphamide (LAK/IL-2/CPM therapy). Methods We administered 10 courses of therapy to 9 patients with advanced RCC. One patient had liver and para-aortic lymph node metastases; the others had only lung metastases. The clinical effects were initially evaluated 4 weeks after therapy and follow-up was continued for periods of 43 to 76 months. Results The 4-week evaluation revealed 3 complete responses (CR), 3 partial responses (PR), 1 minor response (MR), 1 patient with no change in disease status (NC), and 2 patients whose disease progressed (PD). One CR patient remained apparently free of disease for 43 months. After tumors recurred in the lung of another CR patient further disease progression was suppressed by IL-2 administration until the patient died from other causes at 46 months. The third CR patient showed tumor recurrence in the lung and was re-treated with the sameLAK/CPM/IL-2 therapy. Lung tumors decreased in size (PR), but the patient died due to brain metastasis 2 months after the second round of treatment. The 2 initial PR patients, as well as the MR and NC patients, developed regrowth or new metastatic lesions within 2 to 15 months following therapy. The 2 PD patients died 2 and 9 months after therapy. Conclusion Long-term effects ofLAK/IL-2/CPM therapy were not correlated with the maximal response observed 4 weeks after therapy. AlthoughLAK/IL-2/CPM therapy appears suitable for use as induction therapy in RCC, our data suggest that long-term suppression will require surgical removal of remnant tumors or more intensive maintenance therapy.     

Determination of diborane by adsorption sampling using modified silica gel and the chromotropic acid-HPLC method.

A method for determining atmospheric diborane in concentrations higher than 1/10 of TLV, i.e., 0.01 ppm, has been developed using the adsorption sampling method. Silica gel impregnated with potassium permanganate, synthetic resin activated carbon impregnated with or without mercury(II) chloride and activated carbon impregnated with chromate salt showed adsorption capacities larger than 18 l of 3 ppm diborane test gas when the test gas was drawn at 300 ml/min. Complete desorption of the adsorbed diborane was possible only from silica gel impregnated with potassium permanganate into a hydroxylamine hydrochloride solution. As methods for determining the desorbed boron, both the chromotropic acid-HPLC method and ICP-AES were applied. The former was more sensitive, but the latter was less influenced by coexistent substances. The most sensitive and reproducible procedure for diborane determination was as follows: diborane is collected with silica gel impregnated with potassium permanganate (0.05% (w/w)) and desorbed into hydroxylamine hydrochloride solution (400 micrograms/ml) followed by the determination of boron by the chromotropic acid-HPLC method. When diborane in 3 l of 0.1 ppm test gas was collected, the desorption efficiency was 105.3% with an RSD of 13.5%. The limit of quantitation of this method was 0.0026 ppm in 3 l air. Much lower concentrations can be determined by sampling larger amounts of air.     

Induction of uterine hemangioendothelioma and lymphoma in (C57BL/6N x C3H/2N)F1 mice by oral administration of azathioprine

The tumorigenicity of 6-(1-methyl-4-nitro-5-imidazolyl)mercaptopurine (azathioprine), an immunosuppressant, was examined in (C57BL/6N X C3H/2N)F1 mice. Animals were divided into 6 groups with 50 mice in each group, and they were given powdered diet mixed with 0, 5 or 20 ppm azathioprine starting at 6 weeks and ending at 100 weeks of age. Female mice, given 20 ppm azathioprine, developed lymphomas and uterine hemangioendotheliomas at incidences of 12.5 and 14.6%, respectively, which were significantly higher than the incidences in control mice (P less than 0.05). Lymphoma and uterine hemangioendothelioma developed independently in different mice. On the other hand, the male mice given 20 ppm azathioprine had a significantly (P less than 0.05) lower incidence of hepatic tumor (0.5%) compared to the control mice (16%).     

Corticocortical neurons projecting to the medial and lateral banks of the middle suprasylvian sulcus in the cat: An experimental study with the horseradish peroxidase method

Corticocortical afferents to both cortical walls of the cat middle suprasylvian sulcus (MSs area) were investigated by means of retrograde axonal transport of horseradish peroxidase (HRP). The visual cortex (V-I and V–II) projects to the medial wall of the MSs, the projection from V–II being heavier. The auditory cortex (A-I, A-II, and Ep), including cortical walls of the dorsal part of the anterior and posterior ectosylvian sulci, sends fibers to the lateral wall of the MSs. Connections from the first auditory area (A-I) are heavier than from the second (A-II). In the rostral part of the MSs, both the medial and lateral walls receive fibers from the somatosensory (S-I and S-II) cortex. A larger number of association fibers appear to arise from S-II than S-I. Although the MSs as a whole apparently receives various kinds of sensory inputs, there seems to be a parcellation of the MSs area such that the areas receiving cortical association fibers from the visual, auditory, or somatosensory cortical areas also receive thalamic projections from those parts of the thalamus receiving sensory connections of the same modality. The cells of origin of the association fibers were mostly pyramidal, the majority located in layer III (e.g., 80% in the visual cortex and 74% in the auditory cortex), some in layer V, and a few in other layers. Most (76–79%) of the labeled cell bodies were of 15–20 μm diameter. Smaller (8–15 μm) and larger (20–26 μm) cells constituted less than 15% in each case. The mean diameters were 17.0 ± 2.8 μm (SD) in the visual cortex and 17.7 ± 3.2 μm (SD) in the auditory cortex.     

Pharmacokinetic and pharmacological studies on cetraxate, an anti-ulcer agent

Cetraxate hydrochloride was administered either orally or intravenously to rabbits, and its concentration in body fluids was determined by using the HPLC method. Cetraxate was easily hydrolyzed in the gastrointestinal tract and blood, and it was metabolized to p-hydroxyphenylpropionic acid (PHPA) and a new metabolite, p-hydroxybenzoic acid (PHBA). After oral administration of cetraxate hydrochloride, a large amount of unchanged drug was distributed to the gastric wall. PHPA was distributed in all the organs examined, excluding the brain. To determine whether or not the anti-ulcer action of cetraxate hydrochloride was due to the unchanged drug, PHPA, or tranexamic acid, studies with aspirin and water-immersion -induced gastric ulcers in rats were performed. As a result, it was found that tranexamic acid had an anti-ulcer action similar to that of cetraxate hydrochloride.