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The potential for an interaction between lapatinib and absorption of the P-glycoprotein (ABCB1) substrate digoxin at a therapeutic dose in breast cancer patients was characterized. Seventeen women with HER2-positive metastatic breast cancer received a single oral 0.5-mg dose of digoxin on days 1 and 9 and oral lapatinib 1500 mg once daily on days 2 through 9. Digoxin pharmacokinetic parameters were determined on day 1 (digoxin administration alone) and on day 9 (coadministration of lapatinib and digoxin), and parameters were compared to determine the effects of lapatinib on digoxin absorption. Concomitant medications that could affect ABCB1 were accounted for. Lapatinib 1500 mg/day increased digoxin absorption approximately 80%, implicating lapatinib inhibition of intestinal ABCB1-mediated efflux. In summary, coadministration of lapatinib with narrow therapeutic index drugs that are substrates of ABCB1 should be undertaken with caution and dose adjustment should be considered., (© 2015, The American College of Clinical Pharmacology.)

Background: The objective of this study was to evaluate the efficacy and safety of dovitinib in patients with adenoid cystic carcinoma (ACC)., Methods: ACC patients with documented disease progression within the past 12 months were eligible. Patients received oral dovitinib (500 mg once daily for 5 consecutive days followed by a 2-day rest every week) until disease progression or unacceptable toxicities. The primary endpoint was the probability of 4-month progression-free survival (PFS). Metabolic response was evaluated with positron emission tomography (PET)/computed tomography (CT) scans performed at the baseline and after 8 weeks of treatment., Results: Between September 2011 and April 2013, 32 patients with metastatic and/or unresectable ACC were enrolled in this prospective, multicenter trial. The 4-month PFS probability was 80.4%, and the median PFS was 6.0 months (95% confidence interval, 4.4-7.6 months). Tumor shrinkage was observed in 22 patients (68.8%), and 1 patient had a confirmed partial response. The disease control rate was 96.9%. Among 26 patients with PET/CT scans both before and after treatment (at 8 weeks), the metabolic activity of ACC was reduced in 13 patients (50.0%), and 5 patients (19.2%) achieved a metabolic partial response, which was defined as a ≥25% reduction in maximum standardized uptake values. Common grade 3 and 4 adverse events were asthenia (50.0%) and neutropenia (25.0%)., Conclusions: Dovitinib shows modest antitumor activity in the treatment of ACC., (© 2015 American Cancer Society.)

Background: The current study was conducted to evaluate the efficacy and safety of everolimus in the treatment of patients with nonfunctioning neuroendocrine tumors (NETs) or pheochromocytomas/paragangliomas., Methods: Patients with histologically confirmed nonfunctioning NETs or pheochromocytomas/paragangliomas and with documented disease progression before study enrollment were eligible for the current study. Everolimus was administered daily at a dose of 10 mg for 4 weeks. Response was assessed by Response Evaluation Criteria In Solid Tumors (RECIST; version 1.0) every 8 weeks. The primary endpoint was the 4-month progression-free survival rate (PFSR). The hypothesis of the current study was that the 4-month PFSR would increase from 50% to 65%. Safety was evaluated using the National Cancer Institute's Common Terminology Criteria for Adverse Events (version 3.0)., Results: A total of 34 patients were enrolled. Of these, 27 patients had nonfunctioning NETs, 5 had pheochromocytomas, and 2 had paragangliomas. The 4-month PFSR was 78%. Partial response (PR) was observed in 3 patients. Twenty-eight patients had stable disease (SD) and 2 patients developed progressive disease (PD). The response rate (RR) and overall disease control rate (DCR) were 9.0% (95% confidence interval [95% CI], 0%-18.6%) and 93.9% (95% CI, 85.8%-100%), respectively. The PFS was 15.3 months (95% CI, 4.6 months-26.0 months). Of the patients with nonfunctioning NETs, 3 achieved a PR and 23 had SD (RR, 11.1%; DCR, 100%); the PFS was 17.1 months (95% CI, 11.1 months-23.0 months) and the 4-month PFSR was 90.0%. Twenty-one patients (80.8%) demonstrated tumor shrinkage. In 7 patients with pheochromocytomas/paragangliomas, 5 achieved SD, and 2 developed PD. The PFS was 3.8 months (95% CI, 0.5 months-7.0 months) and the 4-month PFSR was 42.9%. Four patients demonstrated tumor shrinkage. The major grade 3/4 adverse events were thrombocytopenia (14.7%), hyperglycemia (5.9%), stomatitis (5.9%), and anemia (5.9%)., Conclusions: Everolimus was associated with high therapeutic efficacy and tolerability in patients with nonfunctioning NETs, and demonstrated modest efficacy in patients with pheochromocytomas/paragangliomas., (Copyright © 2012 American Cancer Society.)

Background: The purpose of this study was to investigate the overall survival (OS) of patients with advanced ALK-positive nonsmall cell lung cancer (NSCLC) who were managed in the pre-ALK inhibitor era and to compare their survival with that of a matched case cohort of ALK wild-type (WT) patients., Methods: Data from 1166 patients who had stage IIIB/IV NSCLC with nonsquamous histology were collected from the NSCLC database of Seoul National University Hospital between 2003 and 2009. ALK fluorescence in situ hybridization (FISH) was used to analyze 262 patients who either had the WT epidermal growth factor receptor (EGFR) or were nonresponders to previous EGFR tyrosine kinase inhibitor (TKI) therapy. Overall survival (OS) was compared between 3 groups: 1) ALK-positive patients, 2) EGFR mutation-positive patients, and 3) ALK-WT/EGFR-WT patients. Progression-free survival (PFS) after first-line chemotherapy and EGFR TKIs also was analyzed., Results: Twenty-three patients were ALK-positive according to FISH analysis and did not receive ALK inhibitors during follow-up. The median OS for ALK-positive patients, EGFR mutation-positive patients, and WT/WT patients was 12.2 months, 29.6 months, and 19.3 months, respectively (vs EGFR mutation-positive patients, P = .001; vs WT/WT, P = .127). The PFS after first-line chemotherapy for the 3 groups was not different. However, the PFS for patients who received EGFR TKIs was shorter in ALK-positive patients compared with the other 2 groups (vs EGFR mutation-positive patients, P < .001; vs WT/WT, P < .021)., Conclusions: In the pre-ALK inhibitor era, ALK-positive patients experienced the shortest survival, although it did not differ statistically from that of WT/WT patients. Although their responses to platinum-based chemotherapy were not different from comparator groups, ALK-positive patients were even more resistant to EGFR TKI treatment than WT/WT patients., (Copyright © 2011 American Cancer Society.)

S-CKD602 is a pegylated long-circulating liposomal formulation of CKD-602, a potent topoisomerase I inhibitor. A population pharmacokinetic (PK) model for encapsulated and released CKD-602 following administration of S-CKD602 was developed to assess factors that may influence S-CKD602 PK. Plasma samples from 45 patients with solid tumors were collected in a phase 1 study. S-CKD602 was administered as a 1-hour intravenous infusion with doses ranging from 0.1 to 2.5 mg/m(2) . Plasma concentrations of encapsulated and released CKD-602 were used to develop a population PK model using NONMEM. PK of encapsulated CKD-602 was described by a 1-compartment model with nonlinear clearance, and PK of released CKD-602 was described by a 2-compartment model with linear clearance for all patients. Covariate analysis revealed that tumor in the liver was a significant covariate for clearance of encapsulated CKD-602 and that age significantly influenced the release rate of CKD-602 from S-CKD602. Maximum elimination rate in patients with liver tumor is 1.5-fold higher compared with patients without liver tumor. Release rate of CKD-602 from S-CKD602 in patients less than 60 years old was 2.7-fold higher compared with patients 60 years old or older. These observations have potential implications in the optimal dosing of liposomal agents., (2012 American College of Clinical Pharmacology.)

To evaluate the effect of age at diagnosis on the treatment outcome after breast conservative therapy (BCT), retrospective analysis was done for 378 patients undergoing BCT for early breast cancer. Patients were divided into two groups according to their age: 'younger' (<40years, n=108) and 'older' (≥40years, n=270). Multivariate analysis was performed on the variables including tumor characteristics, the use of systemic therapy, and age to assess risk factors for local-regional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS), and overall survival rates (OS). The median follow-up duration was 94months. The 8-year LRRFS, DMFS, and OS for younger and older groups were 88.1% and 96.5% (p=0.0022); 85.7% and 93.7% (p=0.0310); 89.2% and 95.9% (p=0.0205), respectively. On multivariate analysis, younger age was the only significant predictor of poor LRRFS (p=0.0022). Younger age and ER negativity showed borderline significance for DMFS (p=0.0828 and 0.0618, respectively). Younger age had trend toward inferior OS (p=0.0702). In conclusion, age younger than 40years was associated with inferior LRRFS in early breast cancer patients treated with BCT. There was also a trend for inferior DMFS and OS in younger patients. Age at diagnosis should be considered for individualized patient management., (© 2010 Wiley Periodicals, Inc.)

Background: The aim of this study was to evaluate the clinical treatment outcomes of recurrent breast cancer with a limited number of isolated lung metastases, and to evaluate the role of pulmonary metastasectomy., Methods: The authors consecutively enrolled 140 recurrent breast cancer patients with isolated lung metastasis from 1997 to 2007 in Seoul National University Hospital and retrospectively analyzed 45 patients who had <4 metastatic lesions., Results: Fifteen patients had pulmonary metastasectomy followed by systemic treatment (pulmonary metastasectomy group), and 30 received systemic treatment alone (nonpulmonary metastasectomy group). The 3-year progression-free survival (PFS) and 4-year overall survival (OS) was significantly longer in the pulmonary metastasectomy group than in the nonpulmonary metastasectomy group (3-year PFS, 55.0% vs 4.5%, P < .001; 4-year OS, 82.1% vs 31.6%, P = .001). In multivariate analysis, a disease-free interval (DFI) of <24 months (hazard ratio [HR], 4.53; 95% CI, 1.72-11.90), no pulmonary metastasectomy (HR, 9.52; 95% CI, 3.34-27.18) and biologic subtypes such as human epithelial growth factor receptor-2 positive (HR, 3.00; 95% CI, 1.04-8.64) and triple negative (HR, 3.92; 95% CI, 1.32-11.59) were independent prognostic factors for shorter PFS., Conclusions: The authors' results demonstrated that DFI and biologic subtypes of tumor are firm, independent, prognostic factors for survival, and pulmonary metastasectomy can be a reasonable treatment option in this population. Further prospective studies are warranted to evaluate the role of pulmonary metastasectomy.

The purpose of this study is to document infection and to better understand current practice relating to antibiotic use and its effect in terminal cancer patients. We retrospectively reviewed patients with terminal stage cancer who were admitted to Seoul National University Boramae Hospital for symptom control only, and who finally died between March 2003 and April 2004. A total of 141 patients were enrolled. Mean duration from admission to death was 31.2 days. A total of 104 patients (75.2%) experienced a febrile episode, and physicians considered 113 patients (80.1%) developed a clinical infection. Total 119 patients (84.4%) received antibiotics. For 90 patients (63.8%), antibiotics were used until the day of death. After using antibiotics, 48% of fevers were controlled, and 31% of organism-proven cases were resolved. Symptomatic improvement of infection was achieved in 18 patients (15.1%), but 66 patients (55.4%) showed no improvement. Improved leucocytosis was achieved by 17% and C Reactive Protein elevation by 29%. In conclusion, our study reveals a high rate of infection and a high rate of antibiotic prescription during the last month of life in cancer patients. But symptomatic improvement was not achieved in more than half of the patients. Further study should be undertaken to clarify the benefit of antibiotics in terminal stage cancer patients.

Background: Adjuvant chemotherapy for patients with lymph node-negative breast carcinoma is being recommended currently based on the St. Gallen classification. The prognostic importance of HER-2 status in patients with lymph node-negative breast carcinoma has been investigated extensively, with contradictory results. The authors investigated the clinical relevance of HER-2 overexpression when combined with the St. Gallen classification in lymph node-negative breast carcinoma., Methods: The medical records of patients with breast carcinoma negative for lymph node involvement who underwent surgery between January 1995 and December 2000 at the Seoul National University College of Medicine (Seoul, Korea) were reviewed retrospectively. Risk groups based on the St. Gallen classification were categorized as average or minimal risk. The prognostic values of HER-2 in combination with the St. Gallen classification were analyzed with respect to disease-free survival (DFS) rates., Results: A total of 906 patients were eligible for analysis. The overall 7-year DFS rate was 87.5%. The 7-year DFS rates for patients with HER-2-positive and HER-2-negative tumors were, respectively, 77.9% and 91.2% (P = 0.002). The 7-year DFS rates for patients with average and minimal risk group were 85.0% and 97.9%, respectively. The authors found that HER-2 overexpression significantly predicted the risk of disease recurrence (odds ratio = 3.03 [95% confidence interval, 1.63-5.63]). Furthermore, when HER-2 status was combined with the St. Gallen classification, the DFS rate of the HER-2-positive average risk group was 73.3% compared with 88.4% for the HER-2-negative average risk group (P = 0.007)., Conclusions: The combination of HER-2 overexpression and the St. Gallen classification was more useful than either alone to predict the risk of disease recurrence in patients with lymph node-negative breast carcinoma., ((c) 2004 American Cancer Society)

Background: The optimal chemotherapy regimen for the treatment of olfactory neuroblastoma has not been clearly defined. The purpose of the current study was to evaluate the efficacy of neoadjuvant chemotherapy with the combination of etoposide, ifosfamide, and cisplatin (VIP) for patients with olfactory neuroblastoma., Methods: Eleven consecutive patients with newly diagnosed olfactory neuroblastoma were treated with etoposide (75 mg/m2), ifosfamide (1000 mg/m2), and cisplatin (20 mg/m2) all administered intravenously on Days 1-5. Cycles were repeated every 21 days. Patients were excluded from analysis if they had previously received surgery or radiotherapy., Results: Nine patients achieved objective responses (objective response rate, 82%; 95% confidence interval, 52-95%), which included 2 complete responses and 7 partial responses. The major side effect was hematologic toxicity, with Grade 3/4 neutropenia observed after the receipt of 37% of all cycles and febrile neutropenia observed after the receipt of 2 cycles. All toxic events were reversible, and no chemotherapy-related deaths were documented. The median survival period was 18 months (range, 3-45 months)., Conclusions: Neoadjuvant VIP chemotherapy was active in the treatment of olfactory neuroblastoma., ((c) 2004 American Cancer Society)

Background: The role of the physician in end-of-life decision-making is complicated. To analyze the controversies that surround therapeutic decision-making and the withholding of life-sustaining treatments, the authors compared values regarding therapeutic intervention that were held by physicians and family members of patients with terminal malignancies., Methods: One hundred fourteen patients with either advanced-stage or terminal disease were enrolled in the current study. Questionnaires were administered to the duty physician and to patients' family members. The questions covered issues such as the use of new anticancer agents with only partial efficacy (15%) and the use of opioid analgesics, intravenous nutrition, feeding tubes, antibiotics, and hemodialysis. In addition, participants were asked about the administration of cardiopulmonary resuscitation (CPR) and the use of ventilators, and when the patient's family consented, the same questionnaire was administered to the patient as well., Results: Seventeen of 114 families refused to answer the questionnaire. Of the 97 available families, only 14 permitted access to the patient. Of those 14 patients, 5 refused to complete the questionnaire. Overall, 100% of families and 87% of patients had some knowledge regarding malignant disease, but only 69% of families and 37% of patients clearly understood the stage of the patient's disease. The use of a new agent with only partial efficacy (approximately 15%) was accepted by 41% of physicians and by 60% of families. The concordance rate between patients' physicians and family members regarding the same patient was 42%. The rankings of the acceptance of treatment by physicians were as follows: opioid analgesics, 100%; antibiotics, 91%; feeding tube, 87%; and intravenous nutrition, 78%. The rankings of the same items by family members were as follows: opioid analgesics, 92%; antibiotics, 89%; intravenous nutrition, 86%; and feeding tube, 75%. The concordance rates between patients' physicians and families were lowest for ventilator application (39%) and CPR (47%)., Conclusions: Values held on issues such as therapeutic decision-making and the withholding of life-sustaining treatment for patients with terminal malignancies were discordant between physicians and family members. To resolve controversies regarding the role of the physician in end-of-life decision-making, the values of physicians, patients, and family members should be considered in the final decision-making process., (Copyright 2004 American Cancer Society.)

Background: Although many studies of elderly patients with non-Hodgkin lymphoma have focused on the dose intensity of chemotherapy, few studies have restricted the histologic inclusion criteria such that only patients with diffuse large B-cell lymphoma (DLCL) are considered. In the current study, treatment outcomes for elderly patients (age > or = 60 years) were analyzed, with emphasis on the dose intensity of doxorubicin., Methods: Between 1994 and 2000, 195 patients with DLCL were treated initially with doxorubicin-based chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone; or cyclophosphamide, vincristine, bleomycin, doxorubicin, procarbazine, and prednisone). Of these patients, 70 were aged 60 years or older., Results: Elderly patients had poorer treatment outcomes than did young patients (5-year survival, 30% vs. 57%; P < 0.001); however, elderly patients who received doxorubicin at dose intensities > or = 10 mg/m2 per week (n = 25) had outcomes (5-year survival, 52%) that were comparable to those of young patients. Among prognostic factors, only International Prognostic Index score (P = 0.022) and dose intensity of doxorubicin (P = 0.039) were found to have significant effects on the overall survival of elderly patients. When the reasons for doxorubicin dose reduction in 45 elderly patients who ultimately received doxorubicin at dose intensities < 10 mg/m2 per week were analyzed, it was found that 20 patients received reduced doses from the start of treatment because of their old age alone; these dose reductions in the 20 cases resulted in poorer treatment outcomes., Conclusions: Elderly patients with DLCL who received doxorubicin at dose intensities > or = 10 mg/m2 per week had treatment outcomes that were comparable to those of young patients; however, physician bias associated with patient age was found to be related to unnecessary dose reductions. Efforts to maintain doxorubicin dose intensities > or = 10 mg/m2 per week and more objective standards for the selection of elderly patients capable of tolerating doxorubicin-based regimens are required., (Copyright 2003 American Cancer Society.)

Background: A Phase I study of cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-1,3-dioxolane] platinum(II) (SKI 2053R), a new platinum derivative, was performed to determine the maximum tolerated dose (MTD), the dose limiting toxicities (DLTs), and the pharmacokinetic profile of SKI 2053R in patients with advanced, refractory malignancies., Methods: Twenty-one patients were entered into the study. SKI 2053R was administered with an intravenous infusion over 1 hour every 4 weeks. The SKI 2053R dose was escalated from 40 mg/m(2) up to 480 mg/m(2) using a modified Fibonacci scheme. Pharmacokinetic analysis was done in all patients to determine the total and ultrafiltrable platinum concentrations in both the plasma and the urine., Results: All patients were evaluable for toxicity and response. There was no significant toxicity with dosages up to 360 mg/m(2). At 480 mg/m(2), two of three patients developed Grade 4 hepatotoxicity, Grade 3 leukopenia and thrombocytopenia, and Grade 2 azotemia and proteinuria. Other toxicity included nausea and emesis, but it was controlled with antiemetics. SKI 2053R did not cause significant neurotoxicity or mucositis. There were 4 patients with stable disease among the 21 patients. Plasma decay of the total and free platinum concentrations was best fitted by using a two-compartment, open model. The terminal plasma half-life of the total platinum after SKI 2053R administration ranged from 63.4 hours to 114.1 hours in dosages ranging from 40 mg/m(2) to 480 mg/m(2) without significant dose dependency. However, the terminal plasma half-life of the free platinum concentration showed a significant dose dependent, incremental pattern. The renal excretion of SKI 2053R measured as platinum ranged from 49% to 75% of the administered dose., Conclusions: The MTD of SKI 2053R was 480 mg/m(2). The major DLTs were hepatotoxicity, nephrotoxicity, and myelosuppression. The recommended starting dose for a subsequent Phase II study is 360 mg/m(2) once every 4 weeks., (Copyright 2001 American Cancer Society.)

Background: This randomized controlled trial was to determine whether a combination chemotherapy regimen that contains anthracycline (doxorubicin and cyclophosphamide [AC]) is superior to the conventional cyclophosphamide, methotrexate, and 5-fluorouracil [CMF] combination in premenopausal women with axillary lymph node positive Stage II breast carcinoma., Methods: Premenopausal women with lymph node positive breast carcinoma were stratified according to age (younger than 35 or 35 years or older) and the number of positive axillary lymph nodes (1-3, 4-9, or >/= 10) and then randomly assigned to receive either doxorubicin 40 mg/m(2) and cyclophosphamide 600 mg/m(2) intravenously (i.v.) every 3 weeks or cyclophosphamide 100 mg/m(2) orally on Days 1 through 14, methotrexate 40 mg/m(2) and 5-fluorouracil 500 mg/m(2) i.v. on Days 1 and 8 every 4 weeks. Both arms were scheduled for six cycles., Results: The median follow-up was 57 months. Eighteen of the 55 AC patients developed recurrence compared with 16 of the 69 CMF patients. The corresponding 5-year recurrence free survival rates were 64% and 78%, respectively (P = 0.12). The site of the first recurrence for AC patients was locoregional in 7%, distant in 22%, and combined in 4%. The corresponding data for the CMF arm were 4%, 16%, and 3%, respectively. Six AC patients died compared with 9 CMF patients. The corresponding 5-year survival rates were 90% and 86%, respectively (P = 0.96). More leukopenia (52%, mostly Grade 1-2) occurred in the CMF arm than in the AC arm (33%, P = 0.001), but no febrile episode was accompanied with leukopenia., Conclusions: This study showed no difference between AC and CMF with respect to both disease free and overall survival rates in premenopausal women with axillary lymph node positive breast carcinoma., (Copyright 2000 American Cancer Society.)

Background: SKI-2053R (SK Chemicals, Kyungki-Do, South Korea) is a new platinum derivative with antitumor activity against various cell lines, including cisplatin-resistant tumor cell lines. Preclinical studies have suggested that it is less nephrotoxic than cisplatin. This study evaluated the efficacy and toxicity of SKI-2053R in the treatment of patients with advanced gastric adenocarcinoma., Methods: Thirty-seven patients with advanced gastric adenocarcinoma that was unresectable or metastatic were treated. No prior chemotherapy or radiotherapy was allowed. Patients received SKI-2053R 360 mg/m(2) by 1-hour infusion on Day 1. After the first cycle, subsequent doses were adjusted according to the toxicity. Courses were repeated every 28 days., Results: Thirty-five patients were evaluable for response and toxicity. Six patients achieved a major response (17%; 95% confidence interval, 8-33%); 2 were complete and 4 were partial responses. The median duration of response was 7.2 months, with a range of 1-20 months. Patients could tolerate the treatment without significant toxicity. No patients had Grade 3 or 4 toxicity. The most frequent toxicity was Grade 1 or 2 proteinuria (26% of cycles), but it was mild and transient. Leukopenia, thrombocytopenia, azotemia, nausea and vomiting, and neurotoxicity were not frequent. These low toxicity profiles indicated that the dose of SKI-2053R could be increased in future studies., Conclusions: SKI-2053R was active in the treatment of patients with gastric adenocarcinoma and had favorable toxicity profiles., (Copyright 1999 American Cancer Society.)

Background: Telomerase activation is thought to be essential for the stabilization of telomere length, through which immortalization and oncogenesis are achieved, but little is known about the regulation of telomerase in human gastric carcinoma cells., Methods: A total of 27 primary gastric tumors, 29 cases of intestinal metaplasia, and 30 cases of normal mucosa, as well as 8 gastric carcinoma cell lines, were examined for the relation between telomerase activation and gastric carcinogenesis. Telomerase activity was detected by telomeric repeat amplification protocol, and the expression of each telomerase subunit was evaluated by Northern blot analysis or reverse transcriptase--polymerase chain reaction., Results: Telomerase activity was found in all 8 gastric carcinoma cell lines and in 25 of 27 gastric carcinoma tissue samples (93%), and weakly observed in 11 of 29 gastric intestinal metaplasia samples (38%). None of 30 normal gastric tissue samples displayed telomerase activity. The mRNA expression of human telomerase catalytic subunit (hTERT) was up-regulated in 26 of 26 tumor tissue samples (100%) and in 19 of 24 intestinal metaplasia (79%) in which telomerase activity was weak or negative. Normal gastric mucosa expressed the telomerase gene, albeit at low levels. In contrast to hTERT, human telomerase RNA component and human telomerase-associated protein expression did not parallel telomerase activity, which was independent of tumor stage and histology., Conclusions: hTERT expression is up-regulated during an early stage in the carcinogenic process, and telomerase activation may be a critical step in gastric carcinogenesis., (Copyright 1999 American Cancer Society.)

Background: Ovarian metastases from gastric carcinoma usually present as large, symptomatic masses and sometimes represent the sole metastatic site. Accordingly, prophylactic oophorectomy may be useful in the overall management of gastric carcinoma. This retrospective study was undertaken to determine the risk factors for ovarian metastasis following curative resection of gastric adenocarcinoma., Methods: The clinicopathologic profiles of 690 female patients who underwent curative gastrectomy at Seoul National University Hospital between July 1987 and June 1996 were reviewed, and their first relapse sites were identified. The prognostic factors at the time of gastrectomy influencing ovarian metastasis were analyzed using the Cox proportional hazards model., Results: The overall 3-year ovarian relapse rate was estimated to be 6.7% (95% confidence interval [CI], 4.2-9.2%). Multiple regression analysis indicated that the number of lymph nodes with metastases and patient age were significant independent risk factors for ovarian metastasis after curative resection of gastric adenocarcinoma. The number of lymph nodes with metastases (>6) was associated with the highest risk of ovarian metastasis, with an adjusted relative risk (aRR) of 38.0 (95% CI, 3.0-480.6). The age of the patient (<50 years) also predicted the risk of ovarian metastasis, with an aRR of 3.1 (95% CI, 1.4-7.0). Lauren diffuse type tended to predict for ovarian metastasis with borderline significance (aRR, 5.9; 95% CI, 0.8-44.3). The 3-year ovarian relapse rate for patients younger than 50 years with more than 6 lymph nodes with metastases was estimated to be 39.5% (95% CI, 23.8-55.7%)., Conclusions: This study suggests that the risk of ovarian metastasis after curative gastrectomy is strongly associated with the number of metastatic lymph nodes (>6) and patient age (<50 years). Prospective studies are needed to evaluate further the role of prophylactic oophorectomy in young female gastric carcinoma patients who have multiple regional lymph nodes with metastases.

Background: It has been suggested that cyclin-dependent kinase inhibitors (CDKIs), including p16 and p15, are tumor suppressor genes. Alterations of CDKIs have been found in most types of cancer. However, little is known about the status of p16 and p15 genes, including methylation of the promoter region, in gastric carcinoma., Methods: Thirty-six primary gastric tumors and 9 gastric carcinoma cell lines were examined for alterations of the p16 and p15 genes. Deletion of the p16 and p15 genes was assessed by Southern blot analysis, expression by Northern blot analysis, and mutation by polymerase chain reaction-single strand conformation polymorphism followed by direct sequencing. The methylation status of the 5' CpG island of the p16 gene was evaluated using methylation-sensitive restriction enzymes, and reversal of the transcriptional block of the p16 gene was determined by Northern blot analysis after treatment with 5-aza-2'-deoxycytidine., Results: Homozygous deletions of the p16 and 15 genes from 2 of 9 gastric carcinoma cell lines were found. In contrast, no deletions were detected in 36 primary gastric tumors, and one primary tumor showed rearrangements of the p16 and p15 genes. Two gastric carcinoma cell lines showed a point mutation and an insertional mutation of the p16 gene, respectively; however, no point mutations were noted for the p16 and p15 genes in any of the primary gastric tumors. Constitutive levels of p16 mRNA expression in gastric carcinoma cell lines were quite heterogeneous; four gastric carcinoma cell lines had no detectable p16 mRNA and 6 gastric carcinoma cell lines had negligible expression of p15 mRNA. Of 10 primary gastric tumors, only 1 tumor expressed p16 mRNA. Furthermore, abnormal DNA methylation patterns of the p16 gene were found in 2 gastric carcinoma cell lines through the use of methylation-sensitive restriction enzymes. These cell lines lacked expression of p16 mRNA without deletions of the p16 gene. These transcriptional blocks were reversed by treatment with 5-aza-2'-deoxycytidine., Conclusions: Deletions or mutations of the p16 and p15 genes are uncommon in primary gastric carcinomas. However, defective mRNA transcription, sometimes by aberrant DNA methylation, might be one of the pathways of inactivation of the p16 gene that leads to the development of gastric carcinoma.