Salvage pharyngolaryngectomy with total esophagectomy following definitive chemoradiotherapy.

Historically, total pharyngolaryngectomy with total esophagectomy has been the standard radical surgical treatment for synchronous cancer of the thoracoabdominal esophagus and pharyngolaryngeal region, and for cancer of the cervical esophagus that has invaded as far as the thoracic esophagus. Although definitive chemoradiotherapy that enables preservation of the larynx has often been the first choice of treatment for cancers involving the cervical esophagus, total pharyngolaryngectomy with total esophagectomy is required as a salvage therapy for cases involving failure of complete remission or locoregional recurrence after chemoradiotherapy. However, salvage esophageal surgery after definitive high-dose chemoradiotherapy is generally associated with high morbidity and mortality. The aim of this study was to examine the short-term outcome of salvage total pharyngolaryngectomy with total esophagectomy. From 2001 to 2014, nine patients underwent salvage total pharyngolaryngectomy with total esophagectomy at the Department of Gastroenterological Surgery, Nagoya University. The mortality and morbidity rates were high at 22% and 89%, respectively. Four patients (44%) developed tracheal necrosis, which in two patients eventually led to lethal hemorrhage. Salvage total pharyngolaryngectomy with total esophagectomy is an uncommon and highly demanding surgical procedure that should be carefully planned and conducted in selected centers of excellence. Measures must be taken to preserve the tracheal blood supply, thus avoiding fatal complications.

Involvement of nitric oxide released from microglia-macrophages in pathological changes of cathepsin D-deficient mice.

Cathepsin D (CD) deficiency has been shown to induce ceroid-lipofuscin storage in lysosomes of mouse CNS neuron (Koike et al., 2000). To understand the behavior of microglial cells corresponding to these neuronal changes, CD-deficient (CD-/-) mice, which die at approximately postnatal day (P) 25 by intestinal necrosis, were examined using morphological as well as biochemical approaches. Light and electron microscopic observations revealed that microglia showing large round cell bodies with few processes appeared in the cerebral cortex and thalamus after P16. At P24, microglia often encircled neurons that were occupied with autolysosomes, indicating increased phagocytic activity. These morphologically transformed microglia markedly expressed inducible nitric oxide synthase (iNOS), which was also detected in the intestine of the mice. To assess the role of microglial nitric oxide (NO) in neuropathological changes in CD-/- mice, l-N(G)-nitro-arginine methylester (l-NAME), a competitive NOS inhibitor, or S-methylisothiourea hemisulfate (SMT), an iNOS inhibitor, was administered intraperitoneally for 13 consecutive days. The total number of terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling-positive cells counted in the thalamus was found to be significantly decreased by chronic treatment of l-NAME or SMT, whereas neither the neuronal accumulation of ceroid-lipofuscin nor the microglial phagocytic activity was affected by these treatments. Moreover, the chronic treatment of l-NAME or SMT completely suppressed hemorrhage-necrotic changes in the small intestine of CD-/- mice, resulting in normal growth of the body weight of the mice. These results suggest that NO production via iNOS activity in microglia and peripheral macrophages contributes to secondary tissue damages such as neuronal apoptosis and intestinal necrosis, respectively.

Combination therapy of a vitamin D3 analog and all-trans-retinoic acid: effect on human breast cancer in nude mice.

BACKGROUND: Vitamin D3 analogs and all-trans-retinoic acid (ATRA) are able to inhibit the growth of a variety of malignant cells. MATERIAL AND METHODS: We examined the ability of three vitamin D3 analogs to inhibit the growth of a human mammary cancer cell line (MCF-7) in Beige Nude xid (BNX) mice either alone or with ATRA. Vitamin D3 analogs 1,25 dihydroxyvitamin D3 (code name, compound C), 1,25 (OH)2-16-ene-23-yne-19-nor-26,27-F6-D3 (compound LH) and 24a,26a,27a,-trihomo-22,24-diene-1,25(OH)2D3 (EB1089) were used. RESULTS: The antitumor effect of ATRA alone was greater than that of either of the vitamin D3 analogs alone, and an additive effect was observed when a vitamin D3 analog and ATRA were administered together. EB1089 was the most potent vitamin D3 analog; and EB1089 plus ATRA was the most potent combination decreasing the tumor mass nearly 3-fold compared to tumors of diluent control mice. None of the animals became hypercalcemic. Their complete blood counts, serum electrolyte analysis as well as their liver and renal functions were all fairly similar and within the normal range. CONCLUSION: This combination of a vitamin D3 analog and ATRA has the potential to be an adjuvant therapy for breast cancer.

19-nor-26,27-bishomo-vitamin D3 analogs: a unique class of potent inhibitors of proliferation of prostate, breast, and hematopoietic cancer cells.

Vitamin D3 [1,25-dihydroxyvitamin-D3 (1,25(OH)2D3)] modulates the proliferation and differentiation of many cell types. Analogs of 1,25(OH)2D3 that have greater potency may become adjuvant therapy for breast and prostate cancers, myelodysplastic syndrome, acute myelogenous leukemia in remission and other cell types, especially in the setting of low disease burden. A new class of analogs of 1,25(OH)2D3 has been synthesized that has a novel 19-nor motif, as well as incorporating many structural elements previously shown to increase potency. These analogs were examined for their effects on prostate cancer cell lines (PC-3, LNCaP, and DU 145), a human breast cell line (MCF-7), and an acute myeloid leukemia cell line (HL-60). Dose-response clonogenic studies showed that each of these analogs had more potent antiproliferative activities against the cancer cells than 1,25(OH)2D3, and 1,25-(OH)2-16,23Z-diene-26,27-bishomo-19-nor-D3 (Ro 27-2014) was the most potent analog [10-fold increased activity compared to 1,25(OH)2D3]. Further studies were performed using Ro 27-2014. Pulse-exposure studies showed that a 5-day pulse-exposure to Ro 27-2014 (10(-7) M) in liquid culture was adequate to achieve a 50% inhibition of MCF-7 clonal growth in soft agar in the absence of the analog, suggesting that the growth inhibition mediated by the analog was irreversible. Cell cycle analyses using MCF-7 cells showed that Ro 27-2014 (10(-7) M for 4 days) induced a significant increase in the number of cells in G0-G1 (72.8+/-8.9% versus 49.9+/-3.5% in control cells), with a concomitant decrease in the percent of cells in S phase (13.1+/-6.2% versus 35.8+/-3.5% in control cells). The chief toxicity of vitamin D3 compounds is hypercalcemia, and therefore, we examined calcemic activity of Ro 27-2014 in mice and found it not to induce hypercalcemia at doses of 0.05 microg i.p. three times per week. In contrast, the same dose of a 19-nor vitamin D3 compound with 6 fluorines on the side chain (1,25-(OH)2-16-ene-23-yne-26,27-F6-19-nor-D3), although also having potent anticancer activity, caused severe hypercalcemia (18 mg/dl). In summary, 19-nor vitamin D3 compounds with desaturation and lengthening of their side chains result in a series of compounds with a good therapeutic index, having potent anticancer activity and low toxicity.

Biotin deficiency in an infant fed with amino acid formula and hypoallergenic rice.

An amino acid formula produced in Japan is not supplemented with biotin since biotin is not permitted as a food additive. Biotin deficiency developed in an 11-month-old Japanese infant who had been diagnosed as a neonate with cow milk and soy bean allergy and fed with an amino acid formula and hypoallergenic rice processed by protease. Serum levels of zinc, essential fatty acids and biotinidase were within the normal range while that of biotin was below the normal range. Urinary 3-hydroxy-isovalerate and slightly elevated levels of plasma branched-chain amino acids disappeared 1 week after oral supplementation with 1 mg day-1 of biotin as did the symptoms of orificial skin lesions, lethargy, hypotonia and alopecia later. In summary, to prevent biotin deficiency, biotin should be added to the Japanese amino acid formula.

Synergistic effect of methionine-depleting total parenteral nutrition with 5-fluorouracil on human gastric cancer: a randomized, prospective clinical trial.

Methionine-depleting total parenteral nutrition (Met-depleting TPN), infusing AO-90 amino acid solution (lacking both L-methionine and L-cysteine) as a sole nitrogen source, showed synergistic effects with 5-fluorouracil (5-FU) in tumor-bearing rats and in clinical trials with gastrointestinal tract cancers. In this study, the effect of Met-depleting TPN with 5-FU upon thymidylate synthase (TS) activity was examined, and the histological effect of this treatment on human gastric cancer was evaluated. Fourteen preoperative advanced gastric cancer patients were divided randomly into two groups. Seven cases were given Met-depleting TPN for 7 days before surgery with continuous intravenous administration of 5-FU (500 mg/body per day; total 4.0 g/body) (AO-90 group). The other 7 received conventional L-methionine-containing TPN with 5-FU (control group). All patients underwent gastrectomy without complications due to these treatments. Resected materials were examined for TS kinetics, and the anti-cancer effect was also assessed histopathologically. The specimens in the AO-90 group showed marked degeneration of cancer, while almost no effect was seen in the control group. The free TS activity of carcinoma tissue in the AO-90 group was decreased and the TS inhibition rate was increased in comparison with the control group (P = 0.0165 and P = 0.0243, respectively). Met-depleting TPN appears to play a role as a biomodulator of 5-FU in human gastric cancer.

Laterality of mental imagery generation and operation: tests with brain-damaged patients and normal adults.

The relationships between hemispheric function and components of the imagery process were examined in patients with unilateral right and left brain damage and in intact adult subjects. In the image generation condition, subjects were required to mentally generate Katakana letters corresponding to Hiragana letters displayed on a CRT. The results for the intact adults suggested a left hemisphere superiority, but the unilaterally brain-damaged subjects showed no hemispheric difference in this task. In the imagery operation task (transformation or lateral translation), subjects were asked to find a genuine Kanji among distractors (pseudo-Kanji) that were constructed from two Kanji radicals (themselves real Kanji) that were either displayed in reverse order or shifted apart. The results for both intact adults and patients with unilateral brain damage suggest the superiority of the right hemisphere.

Combination therapy with transfer factor and high dose stronger neo-minophagen C in chronic hepatitis B in children (HBe Ag positive).

This study mainly describes the efficacy of the combination therapy with Transfer Factor (TF) and high dose Stronger Neo-Minophagen C (SNMC) for HBV carrier children with HBe Ag positive chronic hepatitis. There were 12 patients, 10 males and 2 females aged from 7 months to 14 years 8 months. Liver biopsy was done in 11 patients, and the histopathological findings of the liver were chronic active hepatitis (8 cases) and chronic inactive hepatitis (3 cases). In 6 of 8 patients, HBe-Ag became negative (75%) within 18 weeks (mean 8 weeks) after the initiation of the combination therapy with TF and SNMC (HBe-seronegative), and 4 of these 8 patients (50%) became anti-HBe positive within 29 weeks (mean 15 weeks) (HBe-seroconversion). These results suggest that combination therapy with TF and high dose SNMC may be beneficial in the treatment of chronic hepatitis B in children.

Effect of intraoperative radiotherapy on pancreatic carcinoma: histopathological findings from autopsy cases.

Histopathological examinations of 18 necropsy patients with pancreatic carcinoma who died after receiving intraoperative radiotherapy (IOR) revealed the following: 1) Cancer cells were suspected of remaining in the periphery of the irradiated areas. 2) Thickening of intima of small arteries, some of which were obstructed, was found in the tumor tissues. 3) Highly degenerated nerve fibers were observed within the necrotic or viable tumor tissues. These findings provide evidence of the effects of IOR, while they also demonstrate the problems encountered in improving this treatment and the necessity of a complementary therapy for complete local control of pancreatic cancer by IOR.

[The subrenal capsule assay modified with three-dimensional measurement (volume method) and its higher predictivity].

Subrenal Capsule Assay (SRCA) developed by Bogden et al. is a new in vivo sensitivity test for anticancer agents. However, the presence of host reaction on about day 6 is largest problem for this method, and now many researchers are scrutinizing or introducing several modifications for this assay chiefly by immunosuppressing procedures. As one of the means to measure the actual change of the tumor volume and minimize the misreading of host reactions, we introduced three dimensional measurements of the grafts (volume method) instead of original mean diameter measurement. Using this method, prospective quantitative study was made. The results of 16 assays with 15 cases of miscellaneous malignancies showed 94% evaluability and in 22 treatments predictive accuracy was 77%. Assay/clinical correlation coefficient was 0.38 and coincidence of ranking order of the effectiveness was 6/6, with good contrast to those of 78%, 56%, 0.00 and 1/3, by original method respectively. Clinical responses more than PR were obtained in 9 of 15 cases. Two cases are still in CR for two years by assay directed single agent treatments. Many other minor modifications were also adopted and evaluated by quantitative observation of assay/clinical correlations. SRCA with our modifications seemed to have utilities than original.

[Clinical correlation and modification of the subrenal capsule assay].

A prospective study using 10 cases with miscellaneous tumors was performed. Discoid (columnar) tumors were measured three-dimensionally (volume method). Modified criteria for evaluability and for both absolute and relative quantitative sensitivities were employed. The evaluability was 9/10 (90%) and by the volume method true positives (more than PR) were 2/2, true negatives (less than PR) were 9/10 and overall predictive accuracy was 11/12 (92%), and accordance in relative sensitivity ranking (e.g. A drug is better than B drug) was seen in 4/4. However using the original method (mean diameter method) the corresponding figures were 0/0, 9/12, 9/12, (75%) and 2/4, respectively. The utility of this assay in the field of clinical chemotherapy therefore seems very promising.

[Clinical application of local hyperthermia combined with antineoplastic agents].

At present hyperthermia shows great promise when combined with other modalities. Local thermo-chemotherapy may also be a very attractive research field, but the combination of hyperthermia and anti-cancer drugs is still poorly understood. In this review, the background and the clinical reports on heat and chemotherapy which have been reported during the last year were analyzed. Finally, our clinical experiences with local hyperthermia combined with anti-cancer drugs for gastrointestinal cancer were also reported.

Application of reconstruction computed tomography in a case of tuber cinereum hamartoma.

A case of a 2-year-old girl with tuber cinereum hamartoma is evaluated by computed tomography (CT). Special reference is made to the application of CT image reconstruction, which has not yet been reported in the literature. The location, extent, shape and size of the mass lesion and also the anatomical relationship to adjacent structures are clearly demonstrated in sagittal and coronal CT images reconstructed from serial thin-section CT images in conjunction with target imaging and a review program.

Effect of polymyxin on the bacteriophage receptors of the cell walls of gram-negative bacteria.

Treatment of gram-negative bacteria with lethal doses of polymyxin B and colistin resulted in the formation of projections of the outer layer of the cell wall. Phages T3, T4, and T7, which use wall lipopolysaccharide as receptors, were specifically prevented from adsorbing to Escherichia coli B cells treated with polymyxin, whereas phages T1, T2, T5, and T6 were not. In the systems of phage P22C-Salmonella typhimurium LT2 and phage C21-S. typhimurium variant SL1069, the phage were prevented from adsorbing to the host cell treated with the antibiotics. Electron microscopic observations show that phage T2 adsorbed irreversibly to the normal smooth surface between the projections on the outer layer caused by the drug treatment. These results indicate that lipopolysaccharide is affected by polymyxin functionally and morphologically, but lipoprotein is not. The purified lipopolysaccharide showed a ribbon-like structure when viewed face on and showed trilamellar structure when viewed edge on. The lipopolysaccharide from E. coli B was irreversibly adsorbed by phages T3, T4, and T7, but not phage T2. Often, phage T4 adsorbed to both sides of the lipopolysaccharide strand at comparable distances. Phage P22C adsorbed through the spikes of the tail-plates to the lipopolysaccharide from S. typhimurium LT2. Lipopolysaccharide which was treated with low doses of the drug (2.5 to 6.25 mug of polymyxin B per ml to 100 mug of lipopolysaccharide per ml) turned into the coiled form and was partially broken down into short segments with coiled form. The loosely coiled lipopolysaccharide retains both its function as the receptor and its trilamellar structure. Treatment with high doses of the drug (12.5 to 25 mug of polymyxin B per ml to 100 mug of lipopolysaccharide per ml) caused the collapse of the trilamellar structure of the strand. These collapsed lipopolysaccharides became flat and fused with each other, making an amorphous mass, and finally they were broken into small collapsed fragments.