Potential role of CMPK1, SLC29A1, and TLE4 polymorphisms in gemcitabine-based chemotherapy in HER2-negative metastatic breast cancer patients: pharmacogenetic study results from the prospective randomized phase II study of eribulin plus gemcitabine versus paclitaxel plus gemcitabine (KCSG-BR-13-11).

BACKGROUND: In this study, we evaluated the association between genetic polymorphisms of 23 genes associated with gemcitabine metabolism and the clinical efficacy of gemcitabine in breast cancer patients. PATIENTS AND METHODS: This prospective, pharmacogenetic study was conducted in cooperation with a phase II clinical trial. A total of 103 genetic polymorphisms of the 23 genes involved in gemcitabine transport and metabolism were selected for genotyping. The associations of genetic polymorphisms with overall survival, progression-free survival (PFS), and 6-month PFS were analyzed. RESULTS: A total of 91 breast cancer patients were enrolled in this study. In terms of 6-month PFS, rs1044457 in CMPK1 was the most significant genetic polymorphism [55.9% for CT and TT and 78.9% for CC, P < 0.001, hazard ratio (HR): 4.444, 95% confidence interval (CI): 1.905-10.363]. For the rs693955 in SLC29A1, the median duration of PFS was 5.4 months for AA and 10.5 months for CA and CC (P = 0.002, HR: 3.704, 95% CI: 1.615-8.497). For the rs2807312 in TLE4, the median duration of PFS was 5.7 months for TT and 10.4 months for CT and CC (P = 0.005, HR: 4.948, 95% CI: 1.612-15.190). In survival analysis with a multi-gene model, the TT genotype of rs2807312 had the worst PFS regardless of other genetic polymorphisms, whereas the CA genotype of rs693955 or the CT genotype of rs2807312 without the AA genotype of rs693955 had the best PFS compared with those of other genetic groups (P < 0.001). CONCLUSIONS: Genetic polymorphisms of rs1044457 in CMPK1, rs693955 in SLC29A1, and rs2807312 in TLE4 were significantly associated with the 6-month PFS rate and/or the duration of PFS. Further studies with a larger sample size and expression study would be helpful to validate the association of genetic polymorphisms and clinical efficacy of gemcitabine.

Survival of oral mucosal melanoma according to treatment, tumour resection margin, and metastases.

Because of the poor prognosis and of oral mucosal melanoma, and patients' short survival, large, randomised, clinical studies are difficult. We have investigated its demographic characteristics and analysed the effect of treatment, resection margins, and metastases on survival. We recorded age, sex, site of primary tumour, and types of treatment, survival, and metastases in 74 patients treated at the Department of Oral and Maxillofacial Surgery, Seoul National University Dental Hospital. Survival was analysed based on bony invasion, depth of invasion, and resection margins, and we found that it varied depending on the primary site (p=0.002), and declined with liver (p=0.001) or brain (p=0.033) metastases. The two-year survival according to the primary site was as follows: palate 85% (n=32), anterior maxillary gingiva 53% (n=13), mandible 58% (n=13), and posterior maxillary gingival 74% (n=10) and buccal mucosa 50% (n=4). The two-year survival was 34% (n=8) in patients with liver metastases and 23% (n=7) in patients with brain metastases. In cases of bony invasion (p=0.005), depth of invasion (p=0.042), unclear resection margin (p=0.023), or higher T stages (p=0.009), the survival declined considerably. Neck dissection did not affect survival (p=0.343). Survival of the patients given chemotherapy was significantly lower (p=0.013) and the two-year survival was 54.0%. The patients given radiotherapy showed no significant difference in survival compared with those not given radiotherapy (p=0.107). In conclusion, primary site, bony invasion, resection margins, depth of invasion and systemic metastases were critical to predict prognosis and selection of treatment of oral mucosal melanoma.

Forkhead box M1 (FOXM1) transcription factor is a key oncogenic driver of aggressive human meningioma progression.

AIMS: Aggressive meningioma remains incurable with neither chemo- nor targeted therapies proven effective, largely due to unidentified genetic alterations and/or aberrant oncogenic pathways driving the disease progression. In this study, we examined the expression and function of Forkhead box M1 (FOXM1) transcription factor during meningioma progression. METHODS: Human meningioma samples (n = 101) were collected, followed by Western blotting, quantitative PCR, immunohistochemical and progression-free survival (PFS) analyses. For in vitro assays, FOXM1 was overexpressed or knocked-down in benign (SF4433 and SF4068) or malignant (SF3061 and IOMM-Lee) human meningioma cell lines respectively. For in vivo studies, siomycin A (a FOXM1 inhibitor)-pretreated or control IOMM-Lee cells were implanted subcutaneously in nude mice. RESULTS: FOXM1 expression was increased in higher grades of meningioma and correlated with the mitotic index in the tumour tissue. Moreover, FOXM1 was increased in recurrent meningioma compared with the matched primary lesions. The patients who had higher FOXM1 expression had shorter PFS. In the subsequent in vitro assays, knockdown of FOXM1 in malignant meningioma cell lines resulted in decreased tumour cell proliferation, angiogenesis and invasion, potentially via regulation of ß-catenin, cyclin D1, p21, interleukin-8, vascular endothelial growth factor-A, PLAU, and epithelial-to-mesenchymal transition-related genes, whereas overexpression of FOXM1 in benign meningioma cell lines had the opposite effects. Last, suppression of FOXM1 using a pharmacological inhibitor, siomycin A, decreased tumour growth in an in vivo mouse model. CONCLUSIONS: Our data demonstrate that FOXM1 is a key transcription factor regulating oncogenic signalling pathways in meningioma progression, and a promising therapeutic target for aggressive meningioma.

Therapeutic advantage of genetically engineered Salmonella typhimurium carrying short hairpin RNA against inhibin alpha subunit in cancer treatment.

Background: In contrast to its well-known endocrine function, the role of inhibin in cancer development and therapeutic response is unclear. Salmonella, particularly less toxic attenuated Salmonella strains, are used to treat cancer in two ways. First, Salmonella accumulate around tumors, penetrate the cell barrier, and replicate inside the tumors. Second, Salmonella can act as a vehicle for delivering anticancer agents or proapoptotic genes to attack tumors. In this study, we aimed to develop a suitable cancer therapeutic strategy by genetically modifying attenuated Salmonella typhimurium to harbor short hairpin RNA (shRNA) expression plasmids targeting alpha subunit of inhibin (sh-INHA). Methods: We analyzed the expression of human INHA in normal and cancer cells and tissues. We developed genetically engineered attenuated S. typhimurium harboring sh-INHA (S. typhimurium/sh-INHA) and assessed its cancer therapeutic effects by using cell culture models and syngeneic mouse tumor models. Results: INHA expression levels were markedly higher in colon cancer and melanoma cells and tissues than in their normal counterparts. Suppression of INHA expression mildly reduced cancer cell survival and induced caspase activation and downregulation of anti-apoptotic Bcl-2 and Bcl-xL expressions. Although the genetically engineered S. typhimurium mildly interfered with the invasion of S. typhimurium into host colon cancer and melanoma cells, S. typhimurium/sh-INHA caused remarkable cytotoxicity in cancer compared with unmodified S. typhimurium or S. typhimurium expressing a control scrambled shRNA (S. typhimurium/sh-Cont). Salmonella typhimurium/sh-INHA-treated mice also showed a significantly inhibited growth of colon cancers and melanomas, with a survival advantage. Conclusion: Our results suggest that tumor-targeted therapy using S. typhimurium/sh-INHA may provide a novel cancer treatment option.

Observation of room temperature negative differential resistance in multi-layer heterostructures of quantum dots and conducting polymers.

Multi-layer heterostructure negative differential resistance devices based on poly-[2-methoxy-5-(2'-ethyl-hexyloxy)-1,4-phenylenevinylene] (MEH-PPV) conducting polymer and CdSe quantum dots is reported. The conducting polymer MEH-PPV acts as a barrier while CdSe quantum dots form the well layer. The devices exhibit negative differential resistance (NDR) at low voltages. For these devices, strong negative differential resistance is observed at room temperature. A maximum value of 51 for the peak-to-valley ratio of current is reported. Tunneling of electrons through the discrete quantum confined states in the CdSe quantum dots is believed to be responsible for the multiple peaks observed in the I-V measurement. Depending on the observed NDR signature, operating mechanisms are explored based on resonant tunneling and Coulomb blockade effects.

Early onset of acute GVHD indicates worse outcome in terms of severity of chronic GVHD compared with late onset.

Acute GVHD (aGVHD) is an important risk factor for predicting the incidence or severity of chronic GVHD (cGVHD). Transplant outcome can be influenced by the onset time of aGVHD in patients who have received allogeneic PBSC transplants (PBSCTs). The medical records of 134 patients who survived more than 3 months after myeloablative allogeneic PBSCT were retrospectively reviewed. In all, 38 patients (28.4%) developed grade II-IV aGVHD before day +28 (early aGVHD) and 25 patients (18.7%) after day +28 (late aGVHD). The 5-year cumulative incidence of cGVHD was 78.9% in the early-aGVHD group and 56.6% in the late-aGVHD group (P=0.034). The 5-year OS was 51.0% for the early-aGVHD and 80.8% for the late-aGVHD group (P=0.406). Infection was the primary cause of death for the early-aGVHD group (51.4 vs 16.7%, P=0.017), whereas relapse of the primary disease was higher among the patients with late aGVHD, although this was statistically insignificant (58.3 vs 25.7%, P=0.309). In a multivariate analysis, early aGVHD was identified as a risk factor for developing cGVHD (hazard ratio (HR) 2.278, P=0.004). The development of aGVHD early after allogeneic PBSCT increased the risk of cGVHD and infection-related death rate when compared with the late onset of aGVHD.

IVS10+12A>G polymorphism in hMSH2 gene associated with prognosis for patients with colorectal cancer.

BACKGROUND: The polymorphisms in DNA repair genes may contribute to a variation in the DNA repair capacity, thereby affecting the risk of carcinogenesis and prognosis of colorectal cancer. Accordingly, the present study analyzed 14 polymorphisms in DNA repair genes and their impact on the prognosis for patients with colorectal cancer. MATERIALS AND METHODS: Three hundred and ninety-seven consecutive patients with curatively resected colorectal adenocarcinoma were enrolled in the present study. The genomic DNA was extracted from fresh colorectal tissue and 14 polymorphisms of DNA repair genes determined using a real-time PCR genotyping assay. RESULTS: The median age of the patients was 63 years, and 218 (54.9%) patients had colon cancer, while 179 (45.1%) patients had rectal cancer. A multivariate survival analysis, including age, differentiation, carcinoembryonic antigen level, and stage, revealed a better survival for the patients with the combined IVS10+12AG and GG genotype than for the patients with the IVS10+12AA genotype [disease-free survival: hazard ratio (HR) 0.47, 95% confidence interval (CI) 0.30-0.75, P = 0.002; overall survival: HR 0.50, 95% CI 0.26-0.98, P = 0.042]. None of the other polymorphisms was associated with survival. CONCLUSION: The IVS10+12A>G polymorphism in the hMSH2 gene was found to be an independent prognostic marker for patients with colorectal cancer.

Pilot study on the use of zoledronic acid to prevent bone loss in allo-SCT recipients.

Bone loss is recognized as worsening the quality of life in long-term survivors of Allo-SCT. This study evaluated the risk factors associated with bone loss and the role of zoledronic acid in preventing bone loss in allogeneic recipients. Fifty-three patients who underwent HLA-matched Allo-SCT were evaluated for their bone mineral density (BMD) in the lumbar spine and femoral neck at regular intervals. Zoledronic acid (4 mg) was given i.v. to 18 patients (ZA patients) at 2 months after SCT and then every 3 months until 2 years. Grade 2-4 acute GVHD was associated with bone loss (odds ratio (OR)=4.90, 95% confidence interval (CI)=1.41-16.99; P=0.012) at 1 year after SCT, whereas extensive chronic GVHD and steroid use were both unfavorable prognostic factors (OR=9.00 and 7.22, 95% CI=1.52-53.40 and 1.44-36.22; P=0.016, respectively) in terms of osteopenia/osteoporosis at 2 years after transplantation. The use of zoledronic acid significantly prevented bone loss in the femoral neck as well as the spine (OR=0.18, 95% CI=0.05-0.69, P=0.012). Therefore, BMD measurements and the use of zoledronic acid are recommended in cases of GVHD or long-term steroid use after Allo-SCT to prevent bone loss and threatening skeletal events.

Multicenter phase II study of docetaxel plus oxaliplatin combination chemotherapy in patients with advanced gastric cancer: Daegu Gyeongbuk Oncology Group.

The present study was conducted to evaluate the efficacy and safety of a combination regimen of docetaxel plus oxaliplatin in patients with advanced gastric cancer. Patients with previously untreated metastatic or recurrent, measurable gastric cancer received intravenous docetaxel 65 mg m(-2) plus oxaliplatin 120 mg m(-2) on day 1 based on a 3-week cycle. Forty-two patients were enrolled in the current study, among whom 39 were assessable for efficacy and all assessable for toxicity. One complete response and 18 partial responses were confirmed, giving an overall response rate of 45.2% (95% confidence interval (CI); 31.7-59.7%). At a median follow-up of 7.7 months, the median time to progression and median overall survival was 5.7 (95% CI; 4.3-7.2) months and 9.9 (95% CI; 7.8-12.0) months, respectively. Grade 3/4 neutropenia occurred in 11 patients (26.1%) and febrile neutropenia was observed in four patients (9.5%). The common non-haematologic toxicity was fatigue (grade 1/2, 61.9%) and nausea (grade 1/2, 47.7%). The combination of docetaxel and oxaliplatin was found to be well tolerated and effective in patients with advanced gastric cancer.

Multicenter study of intravenous busulfan, cyclophosphamide, and etoposide (i.v. Bu/Cy/E) as conditioning regimen for autologous stem cell transplantation in patients with non-Hodgkin's lymphoma.

The current study aimed to evaluate the efficacy and toxicity of a combination of intravenous busulfan, cyclophosphamide and etoposide (i.v. Bu/Cy/E) as a conditioning regimen prior to autologous hematopoietic stem cell transplantation in patients with non-Hodgkin's lymphoma (NHL). Sixty-four patients with relapsed/refractory (n=36) or high-risk (n=28) lymphoma were enrolled. The high-dose chemotherapy consisted of i.v. Bu (0.8 mg kg(-1) i.v. q 6 h from day -7 to day -5), Cy (50 mg kg(-1) i.v. on day -3 and day -2) and E (400 mg m(-2) i.v. on day -5 and day -4). The median age was 43 (range 18-65) years, and 39 patients were male. Diffuse large B-cell lymphoma (40.6%) was the most common histological subtype. All evaluable patients achieved an engraftment of neutrophils (median, day 12) and platelets (median, day 13). Hepatic veno-occlusive disease was observed in four patients (three mild, one moderate grade), and two patients (3.1%) died from treatment-related complications. At a median follow-up of 16.4 months, 15 patients (23.4%) exhibited a relapse or progression, while 13 patients (20.3%) had died of disease. The estimated 3-year overall and progression-free survival for all patients was 72.1 and 70.1%, respectively. In conclusion, the conditioning regimen of i.v. Bu/Cy/E was well tolerated and seemed to be effective in patients with aggressive NHL.

New myeloablative conditioning regimen with fludarabine and busulfan for allogeneic stem cell transplantation: comparison with BuCy2.

A regimen of busulfan and cyclophosphamide (BuCy2) is regarded as the standard myeloablative regimen for SCT. This study evaluated the hypothesis that fludarabine can replace cyclophosphamide for myeloablative allogeneic SCT. Ninety-five patients underwent allogeneic SCT from HLA-identical donors, following BuCy2 (n=55) or busulfan+fludarabine (BF, n=40). The efficacy of fludarabine compared to cyclophosphamide was retrospectively evaluated. The BF group exhibited a shorter duration until engraftment (P=0.001), lower incidence of acute and chronic GVHD (P<0.001 and P=0.003, respectively), and non-relapse mortality (NRM) (P=0.039). Furthermore, the event-free survival and overall survival were significantly higher for the BF group compared to the BuCy2 group (P=0.004 and 0.002, respectively). After adjusting for age, the risk status of disease, GVHD prophylaxis and donor type, the BF regimen was found to be an independent favorable risk factor for event-free survival (hazard ratio (HR), 0.181; 95% confidence interval, 0.045-0.720; P=0.016) and overall survival (HR, 0.168; 0.035-0.807; P=0.026). The replacement of cyclophosphamide with fludarabine for myeloablative conditioning seems to be more effective in terms of short-term NRM, and GVHD compared to BuCy2 regimen in allogeneic transplantation.

Vascular endothelial growth factor gene polymorphisms associated with prognosis for patients with gastric cancer.

BACKGROUND: The present study analyzed vascular endothelial growth factor (VEGF) gene polymorphisms and their impact on the prognosis for patients with gastric cancer. PATIENTS AND METHODS: Five hundred and three consecutive patients with surgically resected gastric adenocarcinoma were enrolled in the present study. The genomic DNA was extracted from paraffin-embedded tissue and four VEGF (-460T > C, -116G > A, +405G > C, and +936C > T) gene polymorphisms were determined using a polymerase chain reaction-restriction fragment length polymorphism assay. RESULTS: The survival analysis showed no association of three VEGF gene polymorphisms with the prognosis. For the +936C > T polymorphism, the T/T genotype, however, had a worse overall survival (OS) compared with the C/C genotype (P = 0.037). The -460 T/C or C/C genotype was a poor prognostic factor in patients with stage 0 or I gastric cancer (OS: hazard ratio (HR) = 3.96, disease-free survival (DFS): HR = 4.87). In the haplotype analysis, the CACC haplotype was associated with a significantly worse survival when compared with the TGGC haplotype (OS: HR = 1.72, DFS: HR = 1.73). CONCLUSIONS: VEGF gene polymorphisms were found to be an independent prognostic marker for patients with gastric cancer. Consequently, the analysis of VEGF gene polymorphisms can help identify patient subgroups at high risk of a poor disease outcome.

Phase II study of capecitabine and irinotecan combination chemotherapy in patients with advanced gastric cancer.

The present study was conducted to evaluate the efficacy and safety of a combination regimen of capecitabine plus irinotecan in patients with advanced gastric cancer. Patients with previously untreated metastatic or recurrent, measurable gastric cancer received oral capecitabine 1000 mg m(-2) twice daily from day 1 to 14 and intravenous irinotecan 100 mg m(-2) on days 1 and 8, based on a 3-week cycle. Forty-one patients were enrolled in the current study, among whom 38 were assessable for efficacy and 40 assessable for toxicity. Three complete responses and 16 partial responses were confirmed, giving an overall response rate of 46.3%. At a median follow-up of 269 days, the median time to progression and overall survival were 5.1 and 8.6 months, respectively. Grade 3/4 neutropenia occurred in four patients and grade 3 febrile neutropenia was observed in two patients. Grade 3 diarrhoea and grade 2 hand-foot syndrome occurred in six patients and eight patients, respectively. The combination of capecitabine and irinotecan was found to be well tolerated and effective in patients with advanced gastric cancer. Accordingly, this regimen can be regarded as one of first-line treatment options for advanced gastric cancer.

Phase II study of concurrent chemoradiotherapy with capecitabine and cisplatin in patients with locally advanced squamous cell carcinoma of the head and neck.

We aimed to evaluate the efficacy and safety of concurrent chemoradiotherapy with capecitabine and cisplatin in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). In total, 37 patients with stage III or IV SCCHN were enrolled on the study. The chemotherapy consisted of two cycles of intravenous cisplatin of 80 mg m(-2) on day 1 and oral capecitabine 825 mg m(-2) twice daily from day 1 to day 14 at 3-week intervals. The radiotherapy (1.8-2.0 Gy 1 fraction day(-1) to a total dose of 70-70.2 Gy) was delivered to the primary tumour site and neck. The primary tumour sites were as follows: oral cavity (n=6), oropharynx (n=11), hypopharynx (n=8), larynx (n=3), nasopharynx (n=6), and paranasal sinus (n=3). After the chemoradiotherapy, 29 complete responses (78.4%) and 6 partial responses (16.2%) were confirmed. Grade 3 or 4 neutropenia occurred only in two patients, plus grade 3 febrile neutropenia was observed only in one patient. At a median follow-up duration of 19.8 months, the estimated overall survival and progression-free survival rate at 2-year was 76.8 and 57.9%, respectively. Concurrent chemoradiotherapy with capecitabine and cisplatin was found to be well tolerated and effective in patients with locally advanced SCCHN.

Effectiveness of transdermal fentanyl patch for treatment of acute pain due to oral mucositis in patients receiving stem cell transplantation.

The current study was performed to evaluate the effectiveness and safety of transdermal therapeutic system (TTS) fentanyl in the management of acute pain due to oral mucositis in patients receiving stem cell transplantation. A cohort of consecutive patients with painful oral mucositis were enrolled. Initially, 25 microg/h of TTS fentanyl was administered for the treatment of oral mucositis pain. The pain score, based on a visual analogue scale, and mood and quality of sleep as determined by EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire, Cancer 30), were all recorded before the treatment, then 2, 6, and 10 days later. Twenty-two patients with hematologic malignancies were enrolled. Three patients were excluded from the response assessment, as their TTS fentanyl treatment was stopped owing to related complaints, including severe dizziness, severe vomiting, and an extensive body rash. The total duration of the treatment was 8 days (range, 6-15 days) and the total amount of TTS fentanyl administered per patient was 2.21 at 25 microg/h and 0.63 at 50 microg/h. Six (31.6%) of the remaining 19 patients required an escalated dose of TTS fentanyl at 50 mug/h. The mean pain scores before treatment and 2, 6, and 10 days later were 6.68, 5.17, 3.42, and 2.13, respectively (P < .001). Eight (42.1%) and seven (36.8%) patients experienced improved sleep and mood after treatment, respectively. The TTS fentanyl was effective in both relieving oral mucositis pain with an excellent tolerability and improving the quality of life for hematological patients receiving high-dose chemotherapy with stem cell transplantation.

GM-CSF-based mobilization effect in normal healthy donors for allogeneic peripheral blood stem cell transplantation.

It is important to optimize methods to mobilize hematopoietic stem cells into peripheral blood (PB) for successful allogeneic peripheral blood stem cell (PBSC) transplantation. Our primary intent was to investigate the role of GM-CSF for mobilization in normal healthy donors and to compare its efficacy in mobilizing stem cells alone, in concurrent combination and in sequential combination with G-CSF in this study. We analyzed the results of the PBSC harvest through large volume leukapheresis from 48 normal healthy donors mobilized by three different regimens including GM-CSF. Donors were assigned sequentially to one of the following regimens for mobilization: GM-CSF 10 microg/kg/day alone (group 1, n = 9); concurrent combination (group 2, n = 20) of G-CSF 5 microg/kg/day and GM-CSF 5 microg/kg/day; sequential combination (group 3, n = 19) of GM-CSF alone 10 microg/kg/day for 3 days followed by G-CSF alone 10 microg/kg/day for 2-3 days. The harvested CD34(+) cell count (P < 0.05) was statistically higher in group 3 than in group 1 or 2. Pre-collection WBC count in donors (P < 0.05), harvested MNC (P < 0.05) and CD3(+) cell count (P < 0.05) of group 2 or 3 were significantly higher than those of group 1. Recipients who received stem cells mobilized with combination regimens showed an earlier recovery of WBC and platelets count than those with GM-CSF alone. The incidence of acute graft-versus-host disease was not statistically different among three recipient groups. GM-CSF-based mobilization was well tolerated in normal healthy donors. The sequential combination regimen appears to be an excellent mobilization strategy and might be preferred as the optimal method in some clinical situations that need a higher number of stem cells.

Superficial nerve damage of thumb of laparoscopic surgeon.

We report a case of digital nerve (superficial branch of the radial nerve) compression injury in the thumb caused by repeated compression at the proximal phalanx level by a finger grip of a laparoscopic instrument during laparoscopic surgery.

Low expression of p27(Kip1) in advanced mucoepidermoid carcinomas of head and neck.

BACKGROUND: p27(Kip1), a cyclin-dependent kinase inhibitor, negatively regulates the G1 phase progression of the cell cycle by binding to the cyclin E/cyclin-dependent kinase 2 complex. This study was done to investigate the expression of p27(Kip1) in mucoepidermoid carcinomas and its usefulness as an indicator in tumor progression, aggressiveness, and prognosis. METHODS: Thirty-one patients with mucoepidermoid carcinomas who had surgical resection were studied retrospectively. Clinicopathologic features, including histologic types, T stage, nodal status, perineural invasion, overall AJCC stage, and survival data, were obtained from medical records. Immunohistochemical staining with monoclonal antibodies against p27(Kip1) was performed on the formalin-fixed, paraffin-embedded specimens from each patient. The percentage of tumor cells expressing p27(Kip1) (labeling index) was evaluated by counting 1000 cells per slide in at least four different areas and comparing with the patients' clinicopathologic features and survival rates. RESULTS: Significant correlation was found between low p27(Kip1) expression and tumors with high-grade, advanced T stages, positive nodal status, and advanced clinical stages (p =.001 for all) except perineural invasion. Multivariate analysis indicated that p27(Kip1) expression (p =.030) was the most significant, and gender (p =.048) was the next significant predictor of overall survival among the variables. Also patients with low p27(Kip1) expression showed poor prognosis (p =.002). CONCLUSIONS: We suggest that p27(Kip1) is a reliable independent marker of tumor progression, invasiveness, and prognosis in the mucoepidermoid carcinomas.