Single-incision laparoscopic surgery for benign multicystic mesothelioma of the peritoneum in a young man: A case report.

Benign multicystic peritoneal mesothelioma (BMPM) is a rare condition, particularly in men, and the preoperative diagnosis poses a challenge. Here, we present a case involving single-incision laparoscopic surgery (SILS) for BMPM in a 24-year-old man with a pelvic mass and a history of ulcerative colitis. Pelvic imaging revealed multifocal cysts, prompting the performance of SILS. The tumor was successfully resected with no residual lesions, and pathology confirmed the diagnosis of BMPM. This case represents the first documented instance of SILS being employed for BMPM in a man. BMPM, characterized by pelvic multifocal cysts, is a differential diagnosis, and SILS emerges as a viable option for both diagnosis and treatment.

Laparoscopic resection of a metastatic myxoid liposarcoma in the mesentery of the small intestine: a case report.

BACKGROUND: Myxoid liposarcoma (MLS), with its risk factors, tends to spread to the lungs and extraperitoneally, with intraperitoneal metastases occurring rarely. We present an unusual case of a myxoid liposarcoma that metastasized to the abdominal organs. CASE PRESENTATION: A 60-year-old female patient was referred to our hospital for the evaluation of a right upper limb tumor that had been growing for 7 years. The patient refused surgery, and during follow-up, tumor hemorrhage resulted in hemorrhagic shock. The patient's right upper limb was immediately amputated. MLS was diagnosed histopathologically. Subsequently, the patient underwent adjuvant chemotherapy. Computed tomography (CT) revealed a right buttock mass, a pelvic mass, and left cardiophrenic angle lymph nodes 3 years after the initial surgery. Contrast-enhanced abdominal CT revealed a relatively low-density, lobulated pelvic tumor. Contrast-enhanced pelvic magnetic resonance imaging (MRI) revealed a low-intensity, lobulated mass on T1-weighted images and a high-intensity mass on T2-weighted images. The pelvic mass showed no significant fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET)-CT. On clinical examination, gynecological malignancies were ruled out as the origin of the pelvic lesions. After resection of the right buttock mass, pelvic mass, and left cardiophrenic angle lymph nodes, the patient underwent laparoscopic surgery for a preoperative diagnosis of small intestinal mesenteric metastasis of MLS. A tumor was found in the mesentery of the small intestine and removed with a margin of 5 cm on both the proximal and distal sides. The specimen measured 10 × 8 × 5 cm and contained a multifocal mass. The tumor was found in the mesentery of the small intestine, with no mucosal or submucosal invasion. The patient was diagnosed with MLS with small mesenteric intestinal metastases. On postoperative day 8, the patient was discharged after an uneventful postoperative course. Twelve months after the surgery, there was no evidence of local or distant recurrence. CONCLUSIONS: Small intestinal mesenteric metastases of MLSs are rare. Moreover, there are few reports on laparoscopic resection. In this case, the laparoscopic approach was useful in detecting the tumor location and determining the range of resection.

Characteristics, Antithrombotic Patterns, and Prognostic Outcomes in Claudication and Critical Limb-Threatening Ischemia Undergoing Endovascular Therapy.

PURPOSE: The underlying difference between intermittent claudication (IC) and critical limb-threatening ischemia (CLTI) still remains unclear. This prospective multicenter observational study aimed to clarify differences in clinical features and prognostic outcomes between IC and CLTI, and prognostic factors in patients undergoing endovascular therapy (EVT). MATERIALS AND METHODS: A total of 692 patients with 808 limbs were enrolled from 20 institutions in Japan. The primary measurements were the 3-year rates of major adverse cardiovascular event (MACE) and reintervention. RESULTS: Among patients, 79.0% had IC and 21.0% had CLTI. Patients with CLTI were more frequently women and more likely to have impaired functional status, undernutrition, comorbidities, hypercoagulation, hyperinflammation, distal artery disease, short single antiplatelet and long anticoagulation therapies, and late cilostazol than patients with IC. Aortoiliac and femoropopliteal diseases were dominant in patients with IC and infrapopliteal disease was dominant in patients with CLTI. Patients with CLTI underwent less frequently aortoiliac intervention and more frequently infrapopliteal intervention than patients with IC. Longitudinal change of ankle-brachial index (ABI) exhibited different patterns between IC and CLTI (pinteraction=0.002), but ABI improved after EVT both in IC and in CLTI (p<0.001), which was sustained over time. Dorsal and plantar skin perfusion pressure in CLTI showed a similar improvement pattern (pinteraction=0.181). Distribution of Rutherford category improved both in IC and in CLTI (each p<0.001). Three-year MACE rates were 20.4% and 42.3% and 3-year reintervention rates were 22.1% and 46.8% for patients with IC and CLTI, respectively (log-rank p<0.001). Elevated D-dimer (p=0.001), age (p=0.043), impaired functional status (p=0.018), and end-stage renal disease (p=0.019) were independently associated with MACE. After considering competing risks of death and major amputation for reintervention, elevated erythrocyte sedimentation rate (p=0.003) and infrainguinal intervention (p=0.002) were independently associated with reintervention. Patients with CLTI merely showed borderline significance for MACE (adjusted hazard ratio 1.700, 95% confidence interval 0.950-3.042, p=0.074) and reintervention (adjusted hazard ratio 1.976, 95% confidence interval 0.999-3.909, p=0.05). CONCLUSIONS: The CLTI is characterized not only by more systemic comorbidities and distal disease but also by more inflammatory coagulation disorder compared with IC. Also, CLTI has approximately twice MACE and reintervention rates than IC, and the underlying inflammatory coagulation disorder per se is associated with these outcomes. CLINICAL IMPACT: The underlying difference between intermittent claudication (IC) and critical limb-threatening ischemia (CLTI) still remains unclear. This prospective multicenter observational study, JPASSION study found that CLTI was characterized not only by more systemic comorbidities and distal disease but also by more inflammatory coagulation disorder compared to IC. Also, CLTI had approximately twice major adverse cardiovascular event (MACE) and reintervention rates than IC. Intriguingly, the underlying inflammatory coagulation disorder per se was independently associated with MACE and reintervention. Further studies to clarify the role of anticoagulation and anti-inflammatory therapies will contribute to the development of post-interventional therapeutics in the context of peripheral artery disease.

Characteristics of anal canal cancer in Japan.

Anal canal cancer (ACC) has been reported to be an uncommon cancer in Japan, as in the USA, Europe, and Australia. This retrospective multi-institutional study was conducted to clarify the characteristics of ACC in Japan. First, the histological ACC type cases treated between 1991 and 2015 were collected. A detailed analysis of the characteristics of anal canal squamous cell carcinoma (SCC) cases was then conducted. The results of the histological types revealed that of the 1781 ACC cases, 435 cases (24.4%) including seven cases of adenosquamous cell carcinomas were SCC and 1260 cases (70.7%) were adenocarcinoma. However, the most common histological type reported in the USA, Europe, and Australia is SCC. Most ACC cases are adenocarcinomas and there is a low incidence of SCC in Japan which is different from the above-mentioned countries. Moreover, we reclassified T4 into the following two groups based on tumor size: T4a (tumor diameter of 5 cm or less) and T4b (tumor diameter of more than 5 cm). The results of the TNM classification of SCC revealed that the hazard ratio (HR) to T1 of T2, T3, T4a, and T4b was 2.45, 2.28, 2.89, and 4.97, respectively. As T4b cases had a worse prognosis than T4a cases, we propose that T4 for anal canal SCC in Japan be subclassified into T4a and T4b.

Elective staged proctocolectomy and living donor liver transplantation for colon cancer with sclerosing cholangitis-related ulcerative colitis: a case report.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a well-known complication of ulcerative colitis (UC), but it is rare to encounter patients requiring both living donor liver transplantation (LDLT) and proctocolectomy. We report a case of elective two-stage surgery involving proctocolectomy performed after LDLT for a patient with early colon cancer concurrent with PSC-related UC. To our knowledge, this is the first report of concurrent cancer successfully treated with both LDLT and proctocolectomy. CASE PRESENTATION: A 32-year-old Japanese man with colon cancer associated with UC underwent restorative proctocolectomy at 3 months after living donor liver transplantation (LDLT) for PSC. He was diagnosed with PSC and UC when he was a teenager. Conservative therapy was initiated to treat both PSC and UC. He had experienced recurrent cholangitis for years; therefore, a biliary stent was placed endoscopically. However, his liver function progressively deteriorated. Colonoscopic surveillance revealed early colon cancer; hence, surgical treatment was considered. PSC progressed to cirrhosis and portal hypertension; hence, LDLT was performed before restorative proctocolectomy. Three months after LDLT, we performed restorative proctocolectomy with ileal pouch-anal anastomosis. The postoperative course was uneventful. The patient was well, with good liver and bowel functions and without tumor recurrence, more than 1 year after proctocolectomy. CONCLUSIONS: With strict patient selection and careful patient management and follow-up, elective proctocolectomy may be performed safely and effectively after LDLT for concurrent early colon cancer with PSC-related UC. There are no previous reports of the use of both LDLT and proctocolectomy for the successful treatment of PSC-related UC and concurrent cancer.

A phase I/II study of S-1 and irinotecan (IRIS) combined with cetuximab in patients with RAS wild-type metastatic colorectal cancer (KSCC1401).

PURPOSE: This study was designed to assess the tolerability, efficacy, and safety of tri-weekly irinotecan plus S-1 (IRIS) and weekly cetuximab in patients with metastatic colorectal cancer (mCRC). METHODS: The main eligibility criteria were RAS wild-type mCRC with no prior chemotherapy. S-1 was given orally at a dose of 40 mg/m2 (40-60 mg) twice for 2 weeks, followed by a 1-week rest. Irinotecan was given on day 1 of each cycle at a dose of 150 mg/m2. Cetuximab was administered on days 1 (400 mg/m2), 8 (250 mg/m2), and 15 (250 mg/m2), and then once weekly (250 mg/m2) thereafter. A standard 3 + 3 phase I dose de-escalation design was used to determine the maximum tolerated dose and the recommended dose (RD) of irinotecan. The primary end point of the Phase II study was overall response rate (ORR). RESULTS: Between December 2014 and September 2017, 4 and 54 patients were enrolled in phase I and phase II studies, respectively. No dose-limiting toxicity was observed in the phase I study, and the RD of irinotecan was 150 mg/m2. In the phase II study, the ORR was 56.9% (90% confidence interval 44.4%-68.7%). The safety profile revealed that the most common grade 3/4 adverse events were neutropenia (31.4%), appetite loss (27.5%), hypokalemia (11.8%), and diarrhea (11.8%). Grade 3/4 hand-foot skin syndrome occurred in nine patients (9.8%). CONCLUSION: This study showed that the efficacy and safety of IRIS combined with cetuximab were comparable to those for other first-line treatments. This regimen is a good candidate for first-line treatment of RAS wild-type mCRC.

New-Structure-Type Fe-Based Superconductors: CaAFe4As4 (A = K, Rb, Cs) and SrAFe4As4 (A = Rb, Cs).

Fe-based superconductors have attracted research interest because of their rich structural variety, which is due to their layered crystal structures. Here we report the new-structure-type Fe-based superconductors CaAFe4As4 (A = K, Rb, Cs) and SrAFe4As4 (A = Rb, Cs), which can be regarded as hybrid phases between AeFe2As2 (Ae = Ca, Sr) and AFe2As2. Unlike solid solutions such as (Ba(1-x)K(x))Fe2As2 and (Sr(1-x)Na(x))Fe2As2, Ae and A do not occupy crystallographically equivalent sites because of the large differences between their ionic radii. Rather, the Ae and A layers are inserted alternately between the Fe2As2 layers in the c-axis direction in AeAFe4As4 (AeA1144). The ordering of the Ae and A layers causes a change in the space group from I4/mmm to P4/mmm, which is clearly apparent in powder X-ray diffraction patterns. AeA1144 is the first known structure of this type among not only Fe-based superconductors but also other materials. AeA1144 is formed as a line compound, and therefore, each AeA1144 has its own superconducting transition temperature of approximately 31-36 K.

Large enhancement of superconducting transition temperature of SrBi3 induced by Na substitution for Sr.

The Matthias rule, which is an empirical correlation between the superconducting transition temperature (Tc) and the average number of valence electrons per atom (n) in alloys and intermetallic compounds, has been used in the past as a guiding principle to search for new superconductors with higher Tc. The intermetallic compound SrBi3 (AuCu3 structure) exhibits a Tc of 5.6 K. An ab-initio electronic band structure calculation for SrBi3 predicted that Tc increases on decreasing the Fermi energy, i.e., on decreasing n, because of a steep increase in the density of states. In this study, we demonstrated that high-pressure (~ 3 GPa) and low-temperature ( < 350 °C) synthesis conditions enables the substitution of Na for about 40 at.% of Sr. With a consequent decrease in n, the Tc of (Sr,Na)Bi3 increases to 9.0 K. A new high-Tc peak is observed in the oscillatory dependence of Tc on n in compounds with the AuCu3 structure. We have shown that the oscillatory dependence of Tc is in good agreement with the band structure calculation. Our experiments reaffirm the importance of controlling the number of electrons in intermetallic compounds.

Prognostic significance of simultaneous presence of histological and immunohistochemical metastasis to lymph nodes in patients with esophageal cancer.

PURPOSE: Presence of simultaneous pathological and immunohistochemical nodal metastasis (pNM and iNM, respectively) and/or other clinical factors may be reliable prognostic predictors of survival in esophageal cancer patients who have undergone multidisciplinary treatment. METHODS: Univariate and multivariate analysis of the data collected from 77 patients who had undergone R0 esophagectomy was performed to determine the significance of presence of iNM or pNM, presence of simultaneous pNM, and other clinical factors as prognostic indicators in patients who had (n = 40) and had not (n = 37) undergone preoperative treatment. RESULTS: Presence of pNM was found to be a significant prognostic predictor in patients who had undergone preoperative treatment, presence of iNM in patients who had not undergone preoperative treatment, and presence of simultaneous pNM and iNM in both patient groups. Multivariate analysis indicated that the sole prognostic predictor for patients who had undergone preoperative treatment was presence of simultaneous pNM and iNM while that of patients who had not undergone preoperative treatment was clinical T category. CONCLUSION: Assessment of simultaneous presence of pNM and iNM may facilitate highly accurate prediction of survival in esophageal cancer patients undergoing R0 esophagectomy, regardless of whether they have undergone preoperative treatment.

Clinical and oncological effects of triplet chemotherapy followed by radical esophagectomy for resectable esophageal cancer associated with unfavorable prognostic factors.

PURPOSES: The purpose of this study was to evaluate the hypothesis that the survival of patients undergoing R0 resection after triplet chemotherapy for resectable esophageal cancer with unfavorable prognostic factors (Category 3) would be similar to that of patients undergoing esophagectomy for esophageal cancer without such factors (Category 1). METHODS: Patients with Category 3 tumors were assigned to receive triplet chemotherapy consisting of 5-fluorouracil, doxorubicin and nedaplatin (FAN) followed by radical esophagectomy. The outcomes of the bimodality treatment for Category 3 patients (n = 25) were compared with those of Category 1 patients (n = 41) in a prospective cohort study. RESULTS: Grade 3 or higher toxicity developed during chemotherapy in 32 % of the Category 3 patients, with no treatment-related deaths. No significant difference was detected in the surgery-related mortality and morbidity rates between the two groups. The recurrence-free survival was significantly worse in Category 3 than in Category 1 patients (p = 0.002), although the overall survival was not significantly different (p = 0.085) between the two groups in cases of R0 resection (5-year survival rates: 34.4 vs. 66.5 %). CONCLUSIONS: Although FAN chemotherapy followed by radical esophagectomy can be safely performed, this treatment modality may not have sufficient power to cure Category 3 disease.

The possible separation of 12-O-tetradecanoylphorbol-13-acetate-induced skin inflammation and hyperplasia by compound A.

Activated glucocorticoid receptor (GR) acts via two different mechanisms: transcriptional regulation that requires DNA-binding, and protein-protein interaction between GR and other transcription factors, such as nuclear factor kappa B (NF-κB) or activator protein 1 (AP-1). It has been postulated that many important effects of glucocorticoids, including their anti-inflammatory properties, depend on GR's transrepressive effects on NF-κB and AP-1. In the present study, we have employed a TPA-induced model of skin inflammation and epidermal hyperplasia to determine whether partial activation of the glucocorticoid receptor by compound A (CpdA) is sufficient to reverse the effect of TPA treatment. CpdA is a nonsteroidal GR modulator with high binding affinity, is capable of partial activation of GR. Topical application of TPA twice per week for 2 wk results in inflammation and epidermal hyperplasia. TPA treatment also elevates levels of c-jun (AP-1 component), cyclooxygenase-2 (COX-2), p50 (NF-κB component), interleukin-6 (IL-6), and tumor necrosis factor (TNF) in the skin. Fluocinolone acetonide (FA) (a full GR agonist) was able to completely reverse the above effects of TPA. When applied alone, CpdA increased the epidermal thickness and keratinocyte proliferation as well as levels of c-jun, COX-2, IL-6, and IFN-γ. However, CpdA treatment resulted in a decrease in the number of p50 positive cells induced by TPA, suggesting its role in inhibition of NF-κB. The level of metallothionein-1 mRNA, regulated by GR was also significantly decreased in skin samples treated with CpdA. Our results suggest that CpdA is able to inhibit GR transactivation and activate only some transrepression properties of GR.

Effects of desipramine on the cell cycle and apoptosis in Ca3/7 mouse skin squamous carcinoma cells.

Desipramine (DMI) has been reported to induce glucocorticoid receptor-mediated signal transduction in recent studies. It has been suggested that a non-glucocorticoid receptor signaling pathway might play an important role in skin squamous carcinoma Ca3/7 cells. The aim of this study was to investigate the growth inhibitory effects of DMI on Ca3/7 cells by evaluating the mRNA expression of genes related to apoptosis and cell cycle progression. Hoechst nuclear staining and DNA fragmentation assays were used to detect apoptosis, and the cell cycle was analyzed by flow cytometry. Apoptotic bodies in the nuclei of cells and DNA fragmentation were observed when the Ca3/7 cells were treated with 20 microM DMI for 24 h. Quantitative RT-PCR (reverse transcriptional-polymerase chain reaction) showed that DMI caused a decrease in Bcl-2 and survivin but not Bcl-xL gene expression and an increase in the expression of Bax, Apaf-1, caspase-3 and caspase-7 in a dose- and time-dependent manner. DMI also caused translocation of the apoptosis-inducing factor from the cytoplasm to the nucleus as well as cell cycle arrest in the Ca3/7 cells. Quantitative RT-PCR revealed that DMI decreased the expression of the PCNA gene and caused an increase in the expression of the p21 and p27 genes in the Ca3/7 cells. Our results showed that DMI inhibited the growth of Ca3/7 cells by inducing both apoptosis and cell cycle arrest.

Reversibility of cognitive disorder after treatment of dural arteriovenous fistulae.

INTRODUCTION: Dural arteriovenous fistulae (DAVF) occasionally lead to cognitive disorders whose reversibility after DAVF treatment remains unclear. We studied changes on pre- and post-treatment magnetic resonance imaging (MRI) and single photon emission computed tomography (SPECT) scans in ten patients with cognitive disorder due to DAVF. METHODS: We studied the symptoms, pre- and post-treatment MRI scans, SPECT findings, and mini-mental state examination (MMSE) and treatment results in ten patients with cognitive disorder due to DAVF. They were divided into two groups; the post-treatment MMSE score exceeded 25 points in group 1 (n = 6) and was lower than 24 points in group 2 (n = 4). RESULTS: In the six group 1 patients, pretreatment diffusion-weighted images (DWI) showed hyperintense areas, and SPECT scans demonstrated the preservation of vasoreactivity after acetazolamide challenge. In the four group 2 patients, pretreatment SPECT demonstrated hypoperfusion areas that coincided with the hyperintense areas seen on DWI; there were areas with marked disturbance in vasoreactivity. The post-treatment MMSE score in groups 1 and 2 improved by 13.7 +/- 2.4 and 3.8 +/- 1.0 points, respectively; the difference was significant at p < 0.01. CONCLUSION: In patients with cognitive disorder due to DAVF, the preservation of vasoreactivity on SPECT after acetazolamide challenge indicates that their cognitive disorder may be reversible by DAVF treatment.

Desipramine inhibits the growth of a mouse skin squamous cell carcinoma cell line and affects glucocorticoid receptor-mediated transcription.

The purpose of this study was to examine the effect of tricyclic antidepressant desipramine (DMI) on the growth inhibition and translocation of the glucocorticoid receptor (GR) from the cytoplasm to the nucleus in cancerous and noncancerous cell lines and the effect of DMI on GR-mediated transcription. Nontumorigenic, immortalized keratinocytes cell line (3PC), papilloma (MT1/2), and squamous cell carcinoma (Ca3/7) cell lines were initially used to study the cell growth inhibition by DMI. Although, the growth of all three cell lines was suppressed by DMI, it was more effective in Ca3/7 cells. Therefore, we next examined the effect of DMI on Ca3/7 cells, resistant to growth inhibition by the synthetic glucocorticoid fluocinolone acetonide (FA). DMI inhibited cell proliferation in a time-dependent manner. The translocation of GR was induced by FA alone, DMI alone, and combination of both agents. FA induced GR-mediated transcription in Ca3/7 cells transfected with a luciferase reporter gene under the control of glucocorticoid response element (GRE), but DMI alone did not affect GR-mediated transcription. However, DMI inhibited FA-induced, GR-mediated transcription when both agents were given together. Pretreatment with DMI followed by combination of DMI and FA decreased GR-mediated transcription more than pretreatment with FA. The expression of metallothionein-1 (Mt-1) gene, which is regulated by GR, was induced significantly by the combination of DMI and FA, and enhanced significantly by pretreatment with FA but not DMI. DMI is suggested to inhibit the growth of Ca3/7 cells and to affect GR-mediated transcription.

Effect of phosphodiesterase antagonists on glucocorticoid mediated growth inhibition in murine skin cell lines.

The effects of two cyclic nucleotide phosphodiesterase type 4 (PDE4) inhibitors on proliferation of cell lines representing different stages of mouse skin tumorigenesis were studied. Skin papillomas and carcinomas become resistant to the growth inhibition by glucocorticoids. Their control of cellular functions is mediated by a well-known transcription factor, glucocorticoid receptor. The primary aim of the present study was to determine whether the PDE4 inhibitors, that raise intracellular cAMP levels, can increase the sensitivity of mouse skin papillomas and carcinomas to the glucocorticoids. We sought to establish the effect of cAMP signaling on the glucocorticoid receptor function using well-known model representing non-tumorigenic keratinocyte cell line (3PC), papilloma (MT1/2) and squamous cell carcinoma cell line (Ca3/7). These cells were treated with the glucocorticoid fluocinolone acetonide (FA) alone or in concert with PDE4 inhibitors--rolipram or YM976. Results of our study revealed that both PDE4 inhibitors may increase the sensitivity of transformed cell lines to the growth inhibitory effect of FA. In the transformed cell lines, changes in the viability of cells were accompanied by an increase in mRNA level of two negative regulators of the cell cycle--p21 and p27 proteins. Co-treatment with PDE4 inhibitors and FA caused inhibition of an endogenous glucocorticoid-responsive gene (MT-1) expression. Thus, the PDE4 inhibitors exerted a differential effect on non-transformed and transformed keratinocytes and on glucocorticoid receptor signal transduction. These findings warrant further studies to clarify the mechanism by which PDE4 inhibitors modulate glucocorticoid receptor signal transduction in transformed cells.

Differential effects of several phytochemicals and their derivatives on murine keratinocytes in vitro and in vivo: implications for skin cancer prevention.

The purpose of our study was to investigate in vitro the potential cancer preventive properties of several phytochemicals, i.e. grape seed extract (GSE), resveratrol (RES), ursolic acid (URA), ellagic acid (ELA), lycopene and N-acetyl-L-cysteine (NAC) to define the mechanisms by which these compounds may inhibit murine skin carcinogenesis. We measured quenching of peroxyl, superoxide and hydroxyl radicals by these phytochemicals. We also used adenosine triphosphate (ATP) bioluminescence, Caspase-Glo 3/7 and P450-Glo (CYP1A1 and CYP1B1) assays to study antiproliferative, proapoptotic and CYP-inhibiting effects of the phytochemicals. We next determined their effects on a 4 week inflammatory hyperplasia assay using 7,12-dimethylbenz[a]anthracene-induced murine skin carcinogenesis model to further understand their mechanism of action. Three murine keratinocyte cell lines, i.e. non-tumorigenic (3PC), papilloma-derived (MT1/2) and squamous cell carcinoma-derived (Ca3/7) cell lines, were used in in vitro assays. We have found that GSE, ELA and RES are potent scavengers of peroxyl and superoxide radicals. Statistically significant effects on activities of caspase-3 and -7 were observed only after GSE and URA treatments. All tested compounds protected cells from hydrogen peroxide-induced DNA damage. Using a short-term complete carcinogenesis assay, we have found that all selected compounds caused marked decreases of epidermal thickness and (except RES) reduced percentages of mice with mutation in codon 61 of Ha-ras oncogene. In conclusion, differential effects of tested phytochemicals on events and processes critical for the growth inhibition of keratinocytes in vitro and in vivo indicate that combinations of tested compounds may, in the future, better counteract both tumor initiation and tumor promotion/progression.

Effects of synthetic and natural in vivo inhibitors of ß-glucuronidase on azoxymethane-induced colon carcinogenesis in rats.

D-Glucaric acid is a non-toxic natural compound found in many fruits and vegetables. Our previous studies have shown that the ß-glucuronidase inhibitor D-glucaro-1,4-lactone, an active metabolite of D-glucaric acid, inhibits chemically-induced tumorigenesis in rodents. D-Glucaro-1,4-lactone has a synthetic precursor, 2,5-di-O-acetyl-D-glucaro-1,4:6,3-dilactone or aceglatone (ACE), known as a postoperative prophylactic agent, and a natural precursor, D-glucurono-γ-lactone (GL). In the present study, we first examined the effect of ACE on the initiation phase of rat colon carcinogenesis induced by 15 mg/kg azoxymethane (AOM) administered 3 times by subcutaneous (s.c.) injection at weeks 1, 2, and 3 of a 5-week short-term experiment. ACE (0.5 or 2%) was administered as a dietary supplement for 5 weeks. At 5 weeks after the initiation of treatment, the formation of aberrant crypt foci (ACF) in the rat groups treated with AOM plus a 0.5 or 2% ACE diet was significantly reduced by 48.6 and 55.3%, respectively, compared to the group administered AOM alone. In a previous study, 0.5 and 2% ACE diets dispensed during AOM treatment had a tendency to decrease AOM-induced colonic tumor incidence. In the present long-term 36-week colon tumorigenesis experiment, GL (0.5 or 2%) administered via the diet during the initiation phase (starting 1 week before the first dose of AOM and ending 1 week after the 3rd dose) did not have any significant effects on tumor incidence. On the other hand, continued post-initiation treatment with ACE (0.5 and 2%) markedly reduced colonic tumor incidence by 70 and 80%, respectively. GL was effective to a similar extent (70% inhibition), but only at a concentration of 2%. We conclude that ACE inhibits the initiation and post-initiation stages of AOM-induced colon carcinogenesis, while GL affects only the post-initiation stages.