A Prospective Multicenter Study Evaluating Secondary Adrenal Suppression After Antiemetic Dexamethasone Therapy in Cancer Patients Receiving Chemotherapy: A Korean South West Oncology Group Study

Background.

In a previous pilot study, adrenal suppression was found to be common after antiemetic dexamethasone therapy in cancer patients. The objective of this large prospective multicenter study was to confirm the incidence and factors associated with secondary adrenal suppression related to antiemetic dexamethasone therapy in cancer patients receiving chemotherapy.

Methods.

Chemotherapy-naïve patients who were scheduled to receive at least three cycles of highly or moderately emetogenic chemotherapy with dexamethasone as an antiemetic were enrolled. Patients with a suppressed adrenal response before chemotherapy or those administered corticosteroids within 6 months of enrollment in the study were excluded.

Results.

Between October 2010 and August 2014, 481 patients receiving chemotherapy underwent the rapid adrenocorticotropic hormone (ACTH) stimulation test to assess eligibility; 350 of these patients were included in the final analysis. Fifty-six patients (16.0%) showed a suppressed adrenal response in the rapid ACTH stimulation test at 3 or 6 months after the start of the first chemotherapy. The incidence of adrenal suppression was affected by age, performance status, stage, and use of megestrol acetate in univariate analysis. Multivariate analysis revealed that secondary adrenal suppression associated with antiemetic dexamethasone therapy was significantly associated with megestrol acetate treatment (odds ratio: 3.06; 95% confidence interval: 1.60 to 5.86; p < .001).

Conclusion.

This large prospective study indicates that approximately 15% of cancer patients receiving chemotherapy with a normal adrenal response show suppressed adrenal responses after antiemetic dexamethasone therapy. This result was particularly significant for patients cotreated with megestrol acetate.

Implications for Practice:

This large prospective multicenter study indicates that approximately 15% of cancer patients receiving chemotherapy with a normal adrenal response show secondary adrenal suppression after antiemetic dexamethasone therapy. Adrenal suppression was particularly significant for patients cotreated with megestrol acetate. Clinicians need increased awareness of the potential for adrenal insufficiency secondary to antiemetic dexamethasone therapy in cancer patients receiving chemotherapy. These findings should help encourage prospective studies designed to determine the adequate doses and durations of antiemetic dexamethasone therapy required to reduce dexamethasone-related adverse effects while controlling chemotherapy-induced nausea and vomiting.     

A combination of chemoimmunotherapies can efficiently break self-tolerance and induce antitumor immunity in a tolerogenic murine tumor model

Her-2/neu is a well-characterized tumor-associated antigen overexpressed in human carcinomas such as breast cancer. Because Her-2/neu is a self-antigen with poor immunogenicity due to immunologic tolerance, active immunotherapy targeting Her-2/neu should incorporate methods to overcome immunologic tolerance to self-proteins. In this study, we developed a tolerogenic tumor model in mice using mouse Her-2/neu as self-antigen and investigated whether genetic vaccination with DNA plasmid and/or adenoviral vector expressing the extracellular and transmembrane domain of syngeneic mouse Her-2/neu or xenogenic human Her-2/neu could induce mouse Her-2/neu-specific CTL responses. Interestingly, adenoviral vectors expressing xenogenic human Her-2/neu (AdhHM) proved capable of breaking immune tolerance and of thereby inducing self-reactive CTL and antibodies, but not to the degree required to induce therapeutic antitumor immunity. In attempting to generate therapeutic antitumor immunity against established tumors, we adopted several approaches. Treatment with agonistic anti-glucocorticoid-induced TNFR family-related receptor (GITR) antibody plus AdhHM immunization significantly increased self-reactive CTL responses, and alpha-galactosylceramide (alphaGalCer)-loaded dendritic cells (DC) transduced with AdhHM were shown to break self-tolerance in a tolerogenic murine tumor model. Furthermore, gemcitabine treatment together with either AdhHM plus agonistic anti-GITR antibody administration or alphaGalCer-loaded DC transduced with AdhHM showed potent therapeutic antitumor immunity and perfect protection against preexisting tumors. Gemcitabine treatment attenuated the tumor-suppressive environment by eliminating CD11b(+)/Gr-1(+) myeloid-derived suppressor cells. When combined with immunotherapies, gemcitabine offers a promising strategy for the Ag-specific treatment of human cancer.     

Tumor angiogenesis promoted by ex vivo differentiated endothelial progenitor cells is effectively inhibited by an angiogenesis inhibitor, TK1-2

Neovascularization plays a critical role in the growth and metastatic spread of tumors and involves recruitment of circulating endothelial progenitor cells (EPC) from bone marrow as well as sprouting of preexisting endothelial cells. In this study, we examined if EPCs could promote tumor angiogenesis and would be an effective cellular target for an angiogenesis inhibitor, the recombinant kringle domain of tissue-type plasminogen activator (TK1-2). When TK1-2 was applied in the ex vivo culture of EPCs isolated from human cord blood, TK1-2 inhibited adhesive differentiation of mononuclear EPCs into endothelial-like cells. In addition, it inhibited the migration of ex vivo cultivated EPCs and also inhibited their adhesion to fibronectin matrix or endothelial cell monolayer. When A549 cancer cells were coimplanted along with ex vivo cultivated EPCs s.c. in nude mice, the tumor growth was increased. However, the tumor growth and the vascular density of tumor tissues increased by coimplanted EPCs were decreased upon TK1-2 treatment. Accordingly, TK1-2 treatment reduced the remaining number of EPCs in tumor tissues and their incorporation into the host vascular channels. In addition, overall expression levels of vascular endothelial growth factor (VEGF) and von Willebrand factor in tumor tissues were decreased upon TK1-2 treatment. Interestingly, strong VEGF expression by implanted EPCs was decreased by TK1-2. Finally, we confirmed in vitro that TK1-2 inhibited VEGF secretion of EPCs. TK1-2 also inhibited endothelial cell proliferation and migration induced by the conditioned medium of EPCs. Therefore, we concluded that EPCs, as well as mature endothelial cells, could be an important target of TK1-2.     

CXC chemokine receptor-4 antagonist blocks both growth of primary tumor and metastasis of head and neck cancer in xenograft mouse models

Squamous cell carcinoma of the head and neck (SCCHN) metastasizes to the lymph nodes and lungs. We have generated previously an orthotopic mouse model for head and neck metastasis and did in vivo selection of SCCHN cells through four rounds of serial metastases. A subpopulation of 686LN cells with high metastatic potential (686LN-Ms) was isolated. When the highly metastatic cells were compared with their low metastatic parental cells (686LN-Ps), we found that CXC chemokine receptor-4 (CXCR4) mRNA levels were significantly higher in the 686LN-Ms cells than the 686LN-Ps cells. Interestingly, the metastatic subclones had lost epithelial morphology and acquired mesenchymal features, which were maintained during cell expansion in vitro. This was featured by decreased E-cadherin and involucrin and increased vimentin and integrin beta(1). These results imply that CXCR4 and epithelial-mesenchymal transition markers can be potential biomarkers to identify the subpopulation of cells with high metastatic potential. Using the orthotopic SCCHN animal model, we showed that anti-CXCR4 treatment suppressed primary tumor growth by inhibiting tumor angiogenesis and prevented lung metastasis. Because the reduction of metastasis seen in the treated group could have resulted from 2-fold reduction in primary tumor size compared with that in the control group, we examined the effects of the CXCR4 antagonist in an experimental metastatic animal model in which 686LN-Ms cells were i.v. injected. 686LN-Ms cells failed to metastasize in the CXCR4 antagonist-treated group, whereas they metastasized to the lungs in the control group. Our data indicate that CXCR4 is an important target to inhibit tumor progression in SCCHN.     

Histological diagnosis of prostate cancer in Korean men aged 70-79 years

BACKGROUND: The objective of this study was to evaluate the value of the prostate-specific antigen (PSA) in the diagnosis of prostate cancer in elderly Korean men, aged 70-79 years. METHODS: Patients with an abnormal digital rectal examination (DRE) and/or a serum PSA level greater than 2.0 ng/ml underwent a biopsy. A total of 344 men (median age 73 years) constituted the study cohort. RESULTS: Of 344 men, 163 (47.4%) were diagnosed with prostate cancer upon initial biopsy. The positive predictive value (PPV) for cancer was 48.4% for a PSA cutoff of 4 ng/ml, 65.3% for a cutoff of 10 ng/ml, and 87.0% for a cutoff of 20 ng/ml. When combined with an abnormal DRE, the predictive values for these PSA cutoffs increased to 79.3, 87.3 and 100%, respectively. When 10 ng/ml was chosen as a PSA cutoff level, about 50% of patients were found to have a Gleason score of 7 or higher. When 4 ng/ml was chosen as a PSA cutoff level, more than 50% of patients with an abnormal DRE were found to have a Gleason score of 7 or higher. CONCLUSIONS: In elderly men, more than 50% of patients are found to have cancers with a Gleason score of 7 or higher when their PSA level is greater than 10 ng/ml. This threshold may be lowered to 4 ng/ml in the presence of an abnormal DRE. Our findings provide a rationale for recommending a prostate biopsy in elderly patients with an abnormal DRE and/or an elevated serum PSA level. However, at present, it is not clear whether elderly men have better outcomes when they undergo cancer screening.     

The synergistic therapeutic effect of cisplatin with Human papillomavirus E6/E7 short interfering RNA on cervical cancer cell lines in vitro and in vivo

Human papillomavirus (HPV) types 16 and 18 are the major etiologic factors in the development of cervical epithelial neoplasia. Our study was designed to validate antiviral short interfering RNA (siRNA) targeting the E6 and E7 oncogenes as a potential chemosensitizer of cisplatin (cis-diaminedichloroplatinum II; CDDP) in cervical carcinoma. Specifically, the therapeutic efficacy of combination of CDDP and E6/E7-specific siRNA was assessed in an in vivo cervical cancer xenograft models. The combination of CDDP and E6/E7-specific siRNA had greater efficacy than the combination of CDDP and E6-specific siRNA especially in terms of inducing cellular senescence. Through in vitro and in vivo experiments, the mechanism of synergy between these two treatments was revealed, demonstrating that the combination of E6/E7-specific siRNA and CDDP therapy was significantly superior to either modality alone. In vitro, long-term exposure of HeLa cells to the combination of CDDP and E6/E7-specific siRNA induced apoptosis and cellular senescence. In vivo, E6/E7-specific siRNA potentiated the antitumor efficacy of CDDP via induction of apoptosis, senescence and antiangiogenesis. Our results suggest that E6/E7-specific siRNA may be an effective sensitizer of CDDP chemotherapy in cervical cancer.     

Clinicopathological characteristics and prognosis of signet ring cell carcinoma of the stomach

Background

Signet ring cell carcinoma (SRC) of the stomach is a histological type based on microscopic characteristics. Although the distinctive clinicopathological features of SRC have been reported, results are inconsistent and survival outcomes are uncertain.

Methods

We retrospectively studied 769 patients with gastric carcinoma who underwent gastrectomy in our institute from 1999 to 2009. Among them, 326 patients (42.4 %) had early gastric cancer (EGC) and 443 patients (57.6 %) had advanced gastric cancer (AGC). Sex, age, tumor location, macroscopic type, tumor size, microscopic invasion, and survival rate were compared between patients with SRC, differentiated-, and undifferentiated-type gastric carcinomas.

Results

Fifty-one patients (15.6 %) had SRC in EGC; there were significant differences in sex, age, location, macroscopic type, and size between SRC and the differentiated histological type. However, there was no difference between SRC and undifferentiated-type gastric carcinoma, except for the macroscopic type. Fifty-seven patients (12.9 %) had SRC in AGC. Sex, age, location, size, macroscopic type, perineural invasion, N stage, and hepatic metastasis were significantly different between SRC and the differentiated histological type. Undifferentiated-type gastric carcinoma differed in sex, macroscopic type, and hepatic metastasis. The overall survival rate differed between SRC and other cell types (P < 0.001). Among all the study patients, age [hazard ratio (HR) 1.013, P = 0.041] and tumor, node, and metastasis (TNM) stage (HR 2.350, P < 0.001) were important factors for predicting survival. Omitting patients with palliative resection or metastases, TNM stage was still an important factor for survival (HR 2.077, P < 0.001).

Conclusions

Patients with SRC showed similar clinicopathological features with undifferentiated histology. The survival of patients with SRC reflected a better prognosis in patients with undifferentiated gastric carcinoma. However, when narrowing the patients to those with EGC only, survival in EGC patients exhibited no difference between histological types. Among AGC patients, SRC patients had a worse prognosis than other cell types.     

Kinetic analysis about the bidirectional transport of 1-anilino-8-naphthalene sulfonate (ANS) by isolated rat hepatocytes

The purpose of the present study was to investigate the bidirectional transport of 1-anilino-8-naphthalene sulfonate (ANS) using isolated rat hepatocytes. The initial uptake rate of ANS by isolated hepatocytes was determined. The uptake process of ANS was saturable, with a Km of 29.1 +/- 3.2 microM and Vmax of 2.9 +/- 0.1 mmol/min/mg protein. Subsequently, the initial efflux rate of ANS from isolated hepatocytes was determined by resuspending preloaded cells to 3.0% (w/v) BSA buffer. The efflux process for total ANS revealed a little saturability. The mean value of the efflux clearance was 2.2 +/- 0.1 microL/min/mg protein. The efflux rate of ANS from hepatocytes was markedly decreased at 4 degrees C, indicating that the apparent efflux of ANS might not be attributed to the release of ANS bound to the cell surface, but to the efflux of ANS from intracellular space. The efflux clearance was furthermore corrected for the unbound intracellular ANS concentration on the basis of its binding parameters to cytosol. The relation between efflux rate and unbound ANS concentration was fitted well to the Michaelis-Menten equation with a saturable and a nonsaturable components. The Vmax and Km values were 0.54 mmol/min/mg protein, and 10.0 microM, respectively. Based on the comparison of the ratios of Vmax to Km (Vmax/Km) corresponding to the transport clearance, the influx clearance was two times higher than the efflux clearance. Together with our preliminary studies that ATP suppression in hepatocytes substantially inhibited ANS influx rate, we concluded that the hepatic uptake of ANS is actively taken up into hepatocytes via the carrier mediated transport system.     

COMPARISON OF PHARMACOKINETICS OF M1, M2, M3, AND M4 AFTER INTRAVENOUS ADMINISTRATION OF DA-125 OR ME2303 TO MICE AND RATS. NEW ADRIAMYCIN ANALOGUES CONTAINING FLUORINE

The pharmacokinetics of M1, M2, M3, and/or M4 were compared after intravenous (iv) administration of DA-125 and/or ME2303 to mice (25 mg kg⁻¹) and rats (5, 10, 20, 30, and 40 mg kg⁻¹). The mean plasma concentrations of M1 were detected up to 8 h after iv administration of both DA-125 and ME2303 to mice, and were significantly higher for DA-125 than ME2303; this resulted in a considerably greater AUC (303 against 148 μg min mL⁻¹) and a considerably slower CL of M1 (69·3 against 136 mL min⁻¹ kg⁻¹) after iv administration of DA-125. The MRT (371 against 189 min) and CL_NR of M1 (68·7 against 136 mL min⁻¹ kg⁻¹) were considerably greater and slower, respectively, after iv administration of DA-125. The mean plasma concentrations of M2 were detected up to 8 and 4 h after iv administration of DA-125 and ME2303, respectively, to mice and were significantly higher for DA-125 than ME2303, resulting in a considerably greater AUC of M2 (148 against 27·1 μg min mL⁻¹) after iv administration of DA-125. The mean plasma concentrations of M3, being the lowest among M1–M4, were detected only up to 15 min after iv administration of both DA-125 and ME2303 to mice, and were comparable after iv adminstration of DA-125 and ME2303 to mice. The mean plasma concentrations of M4 were detected up to 8 h after iv administration of both DA-125 and ME2303 to mice, and were higher after iv administration of DA-125 than ME2303, resulting in a considerably greater AUC of M4 (197 against 61·9 μg min mL⁻¹) after iv administration of DA-125. Similar results on M1 and M2 were also obtained from rats: the mean plasma concentrations of both M1 and M2 were significantly higher after iv administration of DA-125, 10 mg kg⁻¹, than after ME2303. The plasma concentrations of M1, M2, and M4, and hence their AUCs, were significantly higher after iv administration of DA-125, 5, 10, 20, 30, and 40 mg kg⁻¹, to rats than after ME2303: the mean plasma concentrations of M2, approximately 0·1–0·4 μg mL⁻¹, were maintained from 30 min to 8–10 h after iv administration of DA-125, 20, 30, and 40 mg kg⁻¹, to rats; the plasma concentrations of M3 were the lowest among M1–M4 at all DA-125 doses; and those of M1 and M4 were maintained for a long period of time. However, after iv administration of M2, 5 mg kg⁻¹, to rats, the mean plasma concentrations of M2 were detected up to 60 min with a mean terminal half-life of only 38·8 min, and the concentrations of M3 were negligible. After iv administration of M3, 5 mg kg⁻¹, to rats, the mean plasma concentrations of M3 were detected up to 15 min; the plasma concentrations of M4, reaching their peak at 5 min, decayed more slowly and were higher than those of M3. The AUC of M4 after iv administration of M3, 5 mg kg⁻¹, was comparable to that after iv administration of M4, 5 mg kg⁻¹, to rats, suggesting that M4 is formed fast and almost completely from M3. M1 was not detected in plasma after iv administration of either M2 or M3 to rats. After iv administration of M4, 5 mg kg⁻¹, to rats, the mean plasma concentrations of M4 decayed fast with a mean terminal half-life of 43·9 min and neither M2 nor M3 were detected in plasma. The following disposition mechanisms for M1, M2, M3, and M4 after iv administration of DA-125 to rats could be obtained from the above data: (i) the maintenance of plasma concentrations of M2 for a longer period of time after iv administration of DA-125 than those after iv administration of M2 could be due to the continuous formation of M2 from M1; (ii) the lowest plasma concentrations of M3 among M1–M4 after iv administration of DA-125 could be due to the fast and almost complete formation of M4 from M3 as soon as M3 is formed from M1, and not due to the fast renal excretion of unchanged M3; (iii) M4 was exclusively and continuously formed from M3 and the formation of M4 from M2 was negligible; and (iv) reversible metabolism among M1–M4 did not take place. The following results could also be obtained after iv administration of DA-125 or ME2303 to mice and rats: (i) the lower plasma concentrations of M1 after iv administration of ME2303 than of DA-125 could be due to the greater biliary excretion of unchanged ME2303 (approximately 30% of iv dose) than unchanged DA-125 and (ii) the lower plasma concentrations of M2 and M4 after iv administration of ME2303 than after DA-125 could be due to lower plasma concentrations of M1 and hence less formation of both M2 and M4 from M1. Liver showed the highest metabolic activity for M1 and a considerable amount of M1 was also metabolized in the kidney after 30 min incubation of 50 μg of DA-125 in 9000 g supernatant fraction of rat tissue homogenates. The mean amount of M1 remaining per gram of tissue, the total amount of M1 remaining in whole tissue, and the tissue to plasma ratio of M1 were significantly higher in the heart, lung, large intestine, and kidney at 15 min after iv administration of DA-125, 25 mg kg⁻¹, to mice than after ME2303. M1, the active antineoplastic moiety of DA-125, had higher affinity for the lung after iv administration of DA-125 to mice than after ME2303, indicating that lung tumours could be subjected to a greater exposure to M1 after iv administration of DA-125 than ME2303. The 24 h biliary excretion of M1 was significantly greater after the iv administration of ME2303 than after DA-125 (344 against 79·3 μg). However, reversed results were obtained for M2 (267 against 467 μg). M3 and M4 were under the detection limit in the bile sample after iv administration of either DA-125 or ME2303.