Differentiation of human induced pluripotent stem cells into hypothalamic vasopressin neurons with minimal exogenous signals and partial conversion to the naive state.

Familial neurohypophyseal diabetes insipidus (FNDI) is a degenerative disease of vasopressin (AVP) neurons. Studies in mouse in vivo models indicate that accumulation of mutant AVP prehormone is associated with FNDI pathology. However, studying human FNDI pathology in vivo is technically challenging. Therefore, an in vitro human model needs to be developed. When exogenous signals are minimized in the early phase of differentiation in vitro, mouse embryonic stem cells (ESCs)/induced pluripotent stem cells (iPSCs) differentiate into AVP neurons, whereas human ESCs/iPSCs die. Human ESCs/iPSCs are generally more similar to mouse epiblast stem cells (mEpiSCs) compared to mouse ESCs. In this study, we converted human FNDI-specific iPSCs by the naive conversion kit. Although the conversion was partial, we found improved cell survival under minimal exogenous signals and differentiation into rostral hypothalamic organoids. Overall, this method provides a simple and straightforward differentiation direction, which may improve the efficiency of hypothalamic differentiation.

Poly (ADP-ribose) polymerase inhibitors sensitize cancer cells to hypofractionated radiotherapy through altered selection of DNA double-strand break repair pathways.

PURPOSE: Poly (ADP-ribose) polymerase inhibitors (PARPi) are known to induce radiosensitization. However, the exact mechanisms of radiosensitization remain unclear. We previously reported that PARPi may have a unique radiosensitizing effect to enhance ß-components of the linear-quadratic model. The aim of this study was to evaluate PARPi in combination with high-dose-per-fraction radiotherapy and to elucidate the underlying mechanisms of its radiosensitization. MATERIALS AND METHODS: Radiosensitizing effects of PARPi PJ34, olaparib, and veliparib were measured using a colony-forming assay in the human cancer cell lines, HCT116, NCI-H460, and HT29. Six different radiation dose fractionation schedules were examined by tumor regrowth assay using three-dimensional multicellular spheroids of HCT116, NCI-H460, SW620, and HCT15. The mechanisms of radiosensitization were analyzed by measuring DNA double-strand breaks (DSB), DNA damage responses, chromosomal translocations, cellular senescence, and cell cycle analysis. RESULTS: Olaparib and PJ34 were found to show radiosensitization preferentially at higher radiation doses per fraction. Similar results were obtained using a mouse model bearing human tumor xenografts. A kinetic analysis of DNA damage responses and repairs showed that olaparib and PJ34 reduced the homologous recombination activity. However, a neutral comet assay showed that PJ34 treatment did not affect the physical rejoining of DNA-DSBs induced by ionizing radiation. Cell cycle analysis revealed that olaparib and PJ34 strikingly increased G1 tetraploid cells following irradiation, leading to premature senescence. The C-banding analysis of metaphase spreads showed that olaparib and PJ34 significantly increased ionizing radiation-induced dicentric chromosomes. The data suggests that PARPi olaparib and PJ34 altered the choice of DNA-DSB repair pathways rather than reducing the total amount of DNA-DSB repair, which resulted in increased repair errors. Increased quadratic misrepair was one of the mechanisms of PARP-mediated radiosensitization, preferentially at the higher dose range compared to the lower dose range. CONCLUSION: PARPi may be a promising candidate to combine with stereotactic hypofractionated radiotherapy, aiming at high-dose region-directed radiosensitization.

Pharmacokinetic study of Ninjin'yoeito: Absorption and brain distribution of Ninjin'yoeito ingredients in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Ninjin'yoeito (NYT), a Japanese traditional Kampo medicine, has been reported to exert various clinical benefits such as relief from fatigue, malaise, anorexia, frailty, sarcopenia, and cognitive dysfunction. Recently, some review articles described the pharmacological effects of NYT and additionally indicated the possibility that multiple ingredients in NYT contribute to these effects. However, pharmacokinetic data on the ingredients are essential in addition to data on their pharmacological activities to accurately determine the active ingredients in NYT. AIM OF THE STUDY: This study assessed the in vivo pharmacokinetics of NYT using mice. MATERIALS AND METHODS: Target liquid chromatography-mass spectrometry (LC-MS) and wide target LC-MS or LC-tandem MS of NYT ingredients in plasma and the brain after oral administration of NYT were performed. Imaging MS was performed to investigate the detailed brain distributions of NYT ingredients. RESULTS: The concentrations of 13 ingredients in plasma and schizandrin in the brain were quantified via target LC-MS, and the wide target analysis illustrated that several ingredients are absorbed into blood and transported into the brain. Imaging MS revealed that schizandrin was homogenously dispersed in the NYT-treated mouse brain. CONCLUSION: These results should be useful for clarifying the active ingredients of NYT and their mechanisms of actions.

Local hyperthermia combined with CTLA-4 blockade induces both local and abscopal effects in a murine breast cancer model.

PURPOSE: To evaluate the antitumor efficacy in local and distant tumors induced by local hyperthermia with CTLA-4 blockade. METHODS: A mouse breast cancer cell line was inoculated into both sides of the legs of mice. The mice were treated with three administrations of CTLA-4 blockade, a single application of local hyperthermia (42.5 °C for 20 min) to the tumor on one side of the leg, or the combination of the two. Tumor growth in locally heated tumors (HT tumors) and unheated distant tumors (UnHT tumors) and overall survival were evaluated. RESULTS: In the combination group, tumor volume significantly decreased for both HT and UnHT tumors compared with the tumors in the untreated and local hyperthermia monotherapy groups. Remarkable efficacy was only observed in the combination therapy group, in which 7 of 18 mice responded to HT and UnHT tumors, with significant prolonged overall survival. CONCLUSIONS: Combination therapy enhanced the antitumor response not only in HT tumors but also in UnHT tumors and prolonged overall survival.

Green Nut Oil or DHA Supplementation Restored Decreased Distribution Levels of DHA Containing Phosphatidylcholines in the Brain of a Mouse Model of Dementia.

Dementia is a major public health concern nowadays. Reduced levels of brain docosahexaenoic acid (DHA) and DHA-phosphatidylcholines (DHA-PCs) in dementia patients were reported previously. Recently, we have reported that supplementation of green nut oil (GNO) or DHA improves memory function and distribution levels of brain DHA in senescence accelerated mice P8 (SAMP8). GNO is extracted from Plukenetia volubilis seeds, and SAMP8 is a well-known model mouse of dementia. In this current study, we examined the results of GNO or DHA supplementation in the distribution levels of brain DHA-PCs in same model mouse of dementia using desorption electrospray ionization (DESI) mass spectrometry imaging (MSI). We observed significantly decreased distribution of brain DHA-PCs, PC (16:0_22:6), and PC (18:0_22:6) in SAMP8 mice compared to wild type mice, and GNO or DHA treatment restored the decreased distribution levels of PC (16:0_22:6) and PC (18:0_22:6) in the brain of SAMP8 mice. These results indicate that GNO or DHA supplementation can ameliorate the decreased distribution of brain DHA-PCs in dementia, and could be potentially used for the prevention and treatment of dementia.

Qualitative and Quantitative Evaluation of Drug and Health Food Products Containing Red Vine Leaf Extracts on the Japanese Market.

Red vine leaf extracts (RVLEs) have traditionally been used for leg wellness and are now standardized to be used as OTC drugs in Europe. In Japan, one brand of RVLE products was recently approved as a direct OTC drug, and RVLEs are still used as ingredients in health food products. Since there is no mandated criterion for the quality of health food products in Japan, the consistent quality and composition of these products are not assured. Here we analyzed OTC drug and health food products containing RVLEs with different lot numbers by LC/MS. Subsequent multivariate analyses clearly indicated that the quality of the health food products was highly variable compared to that of the drug products. Surprisingly, the component contents in the health foods were different even within a same lot in a same brand. The quantitative analyses of flavonols and stilbene derivatives in the drugs and health foods indicated that the concentration of each substance was kept constant in the drugs but not in the health foods. These results strongly indicated that the quality of RVLEs as a whole was not properly controlled in the manufacturing process of health foods. Since RVLE is an active ingredient with pharmaceutical evidences and is used for drugs, the proper regulation for ensuring the consistent quality of RVLEs from product to product would be recommended even in the health foods.

Identification of New Diterpenes as Putative Marker Compounds Distinguishing Agnus Castus Fruit (Chaste Tree) from Shrub Chaste Tree Fruit (Viticis Fructus).

Agnus Castus Fruit is defined in the European Pharmacopoeia as the dried ripe fruit of Vitex agnus-castus. In Europe it is used as a medicine targeting premenstrual syndrome and climacteric disorder. In Japan, Agnus Castus Fruit is becoming popular as a raw material for over-the-counter drugs and health food products, though its congenic species, Vitex rotundifolia and Vitex trifolia, have been used as Shrub Chaste Tree Fruit in traditional medicines. Therefore, it is important to discriminate these Vitex plants from the viewpoint of regulatory science. Here we tried to identify putative marker compounds that distinguish between Agnus Castus Fruit and Shrub Chaste Tree Fruit. We analyzed extracts of each crude drug by liquid chromatography-mass spectrometry, and performed differential analysis by comparison of each chromatogram to find one or more peaks characteristic of Agnus Castus Fruit. A peak was isolated and identified as an equilibrium mixture of new compounds named chastol (1) and epichastol (1a). The planar structures of 1 and 1a were determined spectroscopically. Their relative configurations were revealed by nuclear Overhauser effect spectroscopy and differential nuclear Overhauser effect-NMR data. Since avoiding contamination from closely related species is needed for the quality control of natural pharmaceuticals, this information will be valuable to establish a method for the quality control of both, Agnus Castus Fruit and Shrub Chaste Tree Fruit products.

Novel Monoterpene Lactones from Cinnamomum inunctum.

Four new monoterpene lactones, 5-(2,3-dihydroxy-3-methylbutyl)-4-hydroxy-4-methyldihydrofuran-2(3H)-one (1), 5-(2,3-dihydroxy-3-methylbutyl)-4-methylfuran-2(5H)-one (2), 8-hydroxy-4,7,7-trimethyl-1,6-dioxaspiro[4.4]non-3-en-2-one (3) and 8-hydroxy-4,7,7-trimethyl-1,6-dioxaspiro[4.4]non-3-en-2-one (4), were isolated from the methanolic extract of the fruit of Cinnamomum inunctum, a folk medicine in Myanmar, together with a known compound, 3-hydroxy-4,4-dimethyl-4-butyrolactone (5). Their chemical structures were determined by spectral methods. Among these, 3 and 4 possessed unique spirolactone moieties.

Comparison of acute and subacute genitourinary and gastrointestinal adverse events of radiotherapy for prostate cancer using intensity-modulated radiation therapy, three-dimensional conformal radiation therapy, permanent implant brachytherapy and high-dose-rate brachytherapy.

AIMS AND BACKGROUND: To examine acute and subacute urinary and rectal toxicity in patients with localized prostate cancer monotherapeutically treated with the following four radiotherapeutic techniques: intensity-modulated radiation therapy, three-dimensional conformal radiation therapy, low-dose-rate permanent implant brachytherapy using I-125 seeds, and high-dose-rate brachytherapy. METHODS: One hundred and fifty-six patients with localized prostate cancer were distributed as follows: 57 underwent intensity-modulated radiation therapy, 35 underwent three-dimensional conformal radiation therapy, 37 underwent I-125 implant, and 27 underwent high-dose-rate brachytherapy. The prescribed doses were 70-74 Gy/35-37 fractions, 70 Gy/35 fractions, 145 Gy, and 45.5 Gy/7 fraction/4 days for intensity-modulated radiation therapy, three-dimensional conformal radiation therapy, I-125 implant, and high-dose-rate brachytherapy, respectively. Toxicities (≤6 months) were retrospectively evaluated using the Common Terminology Criteria for Adverse Events version 4.03. RESULTS: The frequency of grade 1 or 2 urinary toxicities using three-dimensional conformal radiation therapy (33/35, 94%) was significantly higher than that with high-dose-rate brachytherapy (18/27, 67%) or intensity-modulated radiation therapy (37/57, 65%) (P <0.05). The frequency of grade 1 or 2 urinary toxicities using I-125 implant was 31/37, 84%. The frequency of grade 1 or 2 gastrointestinal toxicities using three-dimensional conformal radiation therapy (17/35, 49%) was significantly higher than that using I-125 implant (4/37, 11%) or high-dose-rate brachytherapy (0/27, 0%) (P <0.05). Using intensity-modulated radiation therapy, the frequency of grade 1 or 2 gastrointestinal toxicities was 18/57 (32%), which was significantly higher than that using high-dose-rate brachytherapy (0/27, 0%) (P <0.05). Grade 3 or greater adverse events were not observed. CONCLUSIONS: Acute and subacute genitourinary toxicities were observed more frequently after three-dimensional conformal radiation therapy than after high-dose-rate brachytherapy or intensity-modulated radiation therapy. Acute and subacute gastrointestinal toxicities were seen more often after three-dimensional conformal radiation therapy than after brachytherapy (I-125 implant or high-dose-rate brachytherapy).

Evaluation of the botanical origin of black cohosh products by genetic and chemical analyses.

Despite the increasing sales of black cohosh (the dried rhizome and root of Cimicifuga racemosa L.) in the world herbal market, these products have continuous adulteration issues. The botanical authenticity of the black cohosh products is the first important step for ensuring their quality, safety and efficacy. In this study, we genetically identified the botanical sources of 10 black cohosh products and 5 Cimicifuga Rhizome crude drugs of Japanese Pharmacopoeia grade, and analyzed the metabolic profiling of 25 black cohosh products using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Consequently, we found that C. dahurica and possibly C. foetida are misused as sources of the black cohosh products and in some cases, the extracts of black cohosh were adulterated with the plant materials of C. dahurica. We demonstrated that these three species can be distinguished by three marker compounds in a specific mass range. These results must be helpful in establishing regulations for the safe use of the black cohosh products.

Two new labdane diterpenes from fresh leaves of Leonurus japonicus and their degradation during drying.

Degradation of the components of Leonurus Herb was examined during drying. Compounds 1 and 2 were detected on TLC at lower temperature, but not at higher temperature. Their chemical structures were determined by spectral methods. They immediately decomposed even at 40°C in chloroform solution. They are believed to be transformed through a retro-aldol reaction. Compounds 1 and 2 have not been previously reported.

The use of complementary and alternative medicine by pediatric food-allergic patients in Japan.

BACKGROUND: In developed countries, increasing food allergy prevalence and concern regarding food allergies have been reported. Although the use of complementary and alternative medicine (CAM) for the treatment of allergic diseases has increased in some Western countries, the actual proportion and patterns of CAM use for pediatric food allergies in Japan are still unknown. METHODS: Fourteen allergy centers in Japan participated in the study using a questionnaire survey regarding the use of CAM by pediatric patients. A diagnosis of food allergy was made at each hospital by pediatric allergists. RESULTS: Surveys were completed by parents/guardians, and data were collected for a total of 962 pediatric food-allergic patients. Overall, 8.4% of the participants used CAM to treat a food allergy. The major CAM therapies used were herbal teas (22.2%), including several Japanese herbal teas, Chinese herbal medicine (18.5%) and lactic acid bacteria (16%). Among the participants using CAM to treat food allergy, 13.6% thought that the CAM being used was very effective, while 11.1% of participants thought that CAM caused some type of side effect. CONCLUSIONS: Our study is the first large-scale national survey regarding the use of CAM in pediatric patients with food allergies in Japan. Unlike in the USA, which has a higher rate of CAM use (17%), approximately 8.4% of food-allergic patients used CAM in Japan. Interestingly, the major types of CAM used in Japan differed from those used in the USA. Cultural differences and food customs may affect the use of CAM.

Effect of embedded metal reinforcements and their location on the fracture resistance of acrylic resin complete dentures.

PURPOSE: This study evaluated the effect of metal reinforcement and its location on the flexural load at the proportional limit (FL-PL) and the flexural deflection of maxillary acrylic resin complete dentures. MATERIALS AND METHODS: Maxillary acrylic resin complete dentures reinforced with Remanium and without reinforcement were tested. The reinforcing material was embedded in the denture base resin in the doughy state and placed (1) under the ridge lap region; (2) in the anterior region; (3) in the middle region; and (4) in the anterior and posterior regions. The FL-PL (N) and the flexural deflection (mm) at 100 N of the reinforced maxillary denture specimens were tested using a load testing machine at a 5.0 mm/min crosshead speed. The data were analyzed statistically using one-way ANOVA; Tukey's post hoc comparisons test was applied when appropriate (95% confidence level). RESULTS: The FL-PL of the dentures without reinforcement (909 ± 195 N) and the dentures reinforced at the ridge lap (1094 ± 176 N) and in the middle (977 ± 215 N) regions were not significantly different (p > 0.05). The dentures reinforced in the anterior (1348 ± 205 N) and the anterior and posterior (1190 ± 191 N) regions had a higher FL-PL than the dentures without reinforcement (p < 0.05) and were not significantly different from each other (p > 0.05). The efficiency (times) of the reinforcing material on the dentures without reinforcement was 1.08 to 1.48. The flexural deflection of the dentures without reinforcement (0.133 ± 0.014 mm), the dentures reinforced at the ridge lap (0.125 ± 0.014 mm), in the anterior (0.122 ± 0.009 mm), and in the middle (0.132 ± 0.015 mm) regions were not significantly different (p > 0.05), and the dentures reinforced in the anterior and posterior (0.117 ± 0.011 mm) regions had significantly lower deflection than the dentures without reinforcement (p < 0.05). CONCLUSION: The location of the metal reinforcement affected the fracture resistance of the maxillary acrylic resin complete dentures.

Effect of surface preparation on the bond strength of heat-polymerized denture base resin to commercially pure titanium and cobalt-chromium alloy.

The aim of this study was to investigate the bond durability of heat-polymerized denture base resin to cast CP Ti and Co-Cr alloy. The alloy specimens were divided into five groups: 1) airborne-particle abraded with 50 µm alumina (SAND), 2) Rocatec tribochemical silica coating system (RO), 3) air-abraded followed by application of Epricord Opaque Primer (EP), 4) air-abraded followed by application of Super Bond C&B liquid (SB), 5) air-abraded followed by application of Alloy Primer (AL). Heat-polymerized denture resin was applied to the bonding area and polymerized according to the manufacturer's instructions. The halves of all specimens were thermocycled up to 10,000 cycles. Before thermocycling SB and AL showed significantly higher shear bond strengths than SAND, RO, EP for both metals. The shear bond strength of AL group after thermocycling was significantly higher than that of the other groups.

Effect of surface preparation on the failure load of a highly filled composite resin bonded to a denture base resin.

PURPOSE: The purpose of this study was to evaluate the effect of the surface preparation on the maximum fracture load value of a highly filled gingival shade composite resin bonded to a denture base resin. MATERIALS AND METHODS: Block specimens were prepared from a heat-processed denture base resin and divided into five groups. The flat surfaces of the specimens were abraded with 400-grit silicon carbide paper, then prepared in one of the following ways: (1) without preparation (group 1); (2) application of silane coupling agent (group 2); (3) application of dichloromethane (group 3); (4) application of dichloromethane following the silane coupling agent (group 4); or (5) tribochemical silica coating (group 5). A highly filled gingival shade composite resin was applied (area diameter= 5 mm) and polymerized with a light polymerizing unit. Specimens made entirely of heat-processed denture base resin were also fabricated as references (group 6). The halves of the specimens of groups 4, 5, and 6 were thermocycled up to 10,000 times in water between 5 degrees C and 55 degrees C with a 1-minute dwell time at each temperature. Shear testing was performed in a universal testing machine at a crosshead speed of 1 mm/min, and the maximum fracture load values were determined (n = 10). RESULTS: The maximum fracture load values of the highly filled gingival shade composite resin bonded to the denture base resin for all preparation groups were significantly enhanced before thermocycling (p < 0.05). Group 5 exhibited the greatest fracture load value, followed by group 4, compared to the other groups (p < 0.05), however, the fracture load values significantly decreased for these groups after thermocycling (p < 0.05), whereas the fracture load value of group 6 did not decrease (p > 0.05). CONCLUSIONS: Tribochemical silica coating and the application of dichloromethane after the silane coupling agent were effective surface preparations for the bonding of a highly filled gingival shade composite resin to a denture base resin, however, the bond durability of these treatments may be insufficient.

A case of hypothalamic panhypopituitarism with empty sella syndrome: case report and review of the literature.

Empty sella syndrome is frequently accompanied with pituitary dysfunction. Most of the patients with empty sella syndrome demonstrate primary pituitary or stalk dysfunction and few cases show hypothalamic dysfunction. A 71-year-old man manifested appetite loss, nausea and vomiting with hyponatremia and adrenal insufficiency. Hormonal evaluation and cranial MRI revealed a panhypopituitarism with empty sella. Intriguingly, while the response of ACTH to CRH administration was exaggerated, the response to insulin hypoglycemia was blunted. Serum PRL levels were normal. Further, decreased level of fT4, slightly elevated basal levels of TSH, and delayed response of TSH to TRH administration were observed. These findings strongly suggest that the panhypopituitarism is caused by hypothalamic dysfunction. The presence of autoantibodies to pituitary and cerebrum in the patient's serum implies an autoimmune mechanism as a pathogenesis.

Bonding of autopolymerizing acrylic resins to magnetic stainless steel alloys using metal conditioner.

OBJECTIVES: The shear bond strengths of a barbituric acid derivative-activated autopolymerizing acrylic resin to two magnetic stainless steel alloys using a metal conditioner were investigated. METHODS: The surfaces of the two magnetic stainless steel alloys were abraded with 600-grit silicon carbide paper. The surface preparations were: Group 1 (without preparation), Group 2 (airborne particle abrasion with 50 microm alumina), and Group 3 (airborne particle abrasion followed by priming with a metal conditioner). The alloys were bonded with a barbituric acid derivative-activated autopolymerizing acrylic resin. For comparison, airborne particle abrasion and bonding with a tri-n-butylborane-initiated autopolymerizing acrylic resin (Group 4), as well as airborne particle abrasion followed by priming with a metal conditioner and bonding with the same resin (Group 5) were added. Half of the specimens were thermocycled up to 10,000 cycles. The shear bond strengths were determined. RESULTS: Group 3 had significantly improved shear bond strengths with the barbituric acid derivative-activated autopolymerizing acrylic resin to both stainless steel alloys. Although there were no significant differences in the bond strength among Groups 3-5 before thermocycling, the decrease in the bond strength of Group 3 was considerably greater than that of Groups 4 or 5 after thermocycling for both stainless steel alloys. CONCLUSIONS: Significant improvements in the bond strength of the barbituric acid derivative-activated autopolymerizing acrylic resin to two magnetic stainless steel alloys were achieved by airborne particle abrasion followed by priming with the metal conditioner. The bond durability to this resin, however, was inferior to that to a tri-n-butylborane-initiated autopolymerizing acrylic resin.

[Usefulness of hepatic arterial infusion chemotherapy using lecithin-added lipiodol emulsion in hepatocellular carcinoma].

After implanting a reservoir in the hepatic artery, we performed intra-arterial chemotherapy with a smaller particle size lipiodol emulsion and examined its therapeutic effect. Subjects were 21 patients with advanced/recurrent hepatocellular carcinoma (HCC). Arterial infusion was performed once every 2 weeks on an outpatient basis using 2 mL lipiodol emulsion with lecithin added as a surface active agent and 10 mg doxorubicin hydrochloride. As of 6 months after the start of treatment, the response rate was 38.1%. Median survival was 17.0 months. Serious adverse events were not noted in any of the subjects;during the course of treatment, catheter occlusion was observed in 2 patients. This therapy allows fewer visits and provides a relatively substantial therapeutic effect while maintaining QOL, so it may serve as an effective treatment for highly advanced/multiple HCC not suited to other treatments.

Adjuvant immunochemotherapy with protein-bound polysaccharide K for colon cancer in relation to oncogenic beta-catenin activation.

PURPOSE: Protein-bound polysaccharide K is an immunotherapeutic agent that promotes apoptosis by inhibiting nuclear factor-kappaB activation in cancer cells. We previously showed that oncogenic beta-catenin activates nuclear factor-kappaB and inhibits apoptosis by up-regulating beta-transducin repeat-containing protein. We investigated whether the activation state of beta-catenin in the primary tumor is associated with differences in survival rates of patients with colon cancer undergoing immunochemotherapy with 5-fluorouracil plus polysaccharide K vs. chemotherapy with 5-fluorouracil alone. METHODS: We assessed the activation states of beta-catenin and nuclear factor-kappaB in the primary tumors of 202 colon cancer patients, and analyzed the data in terms of the clinicopathologic characteristics and survival of patients undergoing the two forms of adjuvant therapy. RESULTS: We found two distinct patterns of nuclear accumulation of activated beta-catenin in the tumor cells: diffuse nuclear accumulation in 89 cases (44 percent) and selective nuclear accumulation at the tumor invasion front in 18 cases (9 percent). Nuclear factor-kappaB activation was found in 64 cases (32 percent). In patients with diffuse nuclear accumulation-type beta-catenin activation, immunochemotherapy significantly improved recurrence-free survival, cancer death survival, and overall survival rates compared with patients receiving chemotherapy alone. No survival benefit was found in cases with nuclear accumulation at the tumor invasion front-type beta-catenin activation or no activation. Similarly, immunochemotherapy favored the survival of patients with nuclear factor-kappaB activation. Multivariate analysis established the TNM stage and administration of polysaccharide K as independent prognostic factors in the patients with diffuse nuclear accumulation-type beta-catenin activation. CONCLUSIONS: The presence of diffuse nuclear accumulation-type beta-catenin activation identifies patients with colon cancer who respond better to immunotherapy with polysaccharide K.

Preoperative CEA and PPD values as prognostic factors for immunochemotherapy using PSK and 5-FU.

PURPOSE: Immunochemotherapy using PSK used as postoperative adjuvant chemotherapy for colorectal cancer in Japan, is a treatment that depends on the immunocompetence of the host. Therefore, we analyzed the data of Hokuriku district conducted by the CIP study group to compare the long-term survival for preoperative CEA level and PPD reaction. PATIENTS AND METHODS: Between February 1991 and March 1993, 87 patients with primary colon cancer and macroscopic lymph node metastasis (macroscopic Dukes' C) underwent macroscopic curative resection. The patients were randomly allocated to receive 5-FU/PSK therapy or 5-FU alone. The 7-year disease-free survival (DFS), 7-year overall survival (OS) and 7-year cancer death survival (CDS) were compared using the preoperative CEA levels and PPD values. RESULTS: In cases with preoperative CEA level > or =3.0 ng/mL, the 7-year DFS, 7-year OS and 7-year CDS were significantly better in the PSK group (85.7, 90.5, 90.5%) than in the control group (52.4, 52.4, 57 1%; p=0.019, 0.007, 0.014,). In cases with preoperative PPD level <19.0 mm, the 7-year DFS, 7-year OS and 7-year CDS were significantly better in the PSK group (85.7, 85.7, 89.3%) than in the control group (56.7, 60.0, 63.3%; p=0.018, 0.036, 0.028). Recurrence was significantly less in the PSK group. The DFS tended to be superior in the PSK group (87.4%) compared to the control group (69.9%) for hematogenous metastasis. CONCLUSION: The present study demonstrated that preoperative CEA and PPD, that can be measured easily in the clinical setting, may be effective indicators of postoperative adjuvant immunochemotherapy using PSK.