Phase II study of combined chemotherapy with docetaxel, CDDP and 5-FU for highly advanced esophageal cancer.

Advanced esophageal cancer with widespread metastasis to lymph nodes or other organs is difficult to treat and has an extremely poor prognosis. A new combined chemotherapy of docetaxel with cisplatin (CDDP) and 5-fluorouracil (5-FU) (DPF therapy) was performed and its efficacy and safety were examined. Among those hospitalized between May 2003 and October 2009, 30 patients with stage III or stage IV unresectable, untreated advanced esophageal squamous cell carcinoma which had invaded other organs were enrolled in this study. The regimen of DPF therapy was as follows: a set of intravenous drips of 60 mg/m(2) of docetaxel (day 1), 60 mg/m(2) of CDDP (day 1) and 800 mg/m(2) of 5-FU (days 1-5) was administered twice at an interval of 3 to 4 weeks. Antitumor effects, adverse reactions and treatment outcomes were then examined. The patients included 26 men and 4 women aged 40 to 73 years (average age, 58.1 years), and the performance status (PS) was 1 in 18 cases and 2 in 12 cases. The main location of the esophageal cancer was the upper/middle/lower thoracic esophagus in 7/14/9 cases, respectively. Clinical stage was III in 5 cases and IV in 25. The effective rate of DPF therapy was 83.3% for the primary lesion (complete response, CR: 4 cases, partial response, PR: 21 cases), 72.4% for lymph node metastasis (CR: 3 cases, PR: 18 cases) and 72.0% for distant organ metastasis (CR: 3 cases, PR: 15 cases). The observed adverse reactions of grade 2 or higher of National Cancer Institute-Common Toxicity Criteria (NCI-CTC) included anemia (16.7%), leukopenia (73.3%), liver dysfunction (20.0%), anorexia (16.7%), stomatitis (33.3%), esophagitis (16.7%), alopecia (16.7%) and diarrhea (26.7%). The therapy completion rate was 96.7% and the therapy-related death rate was 3.3%. Treatments given after the completion of the DPF therapy were surgery in 6 cases, chemotherapy such as additional DPF in 12, chemoradiation in 4, esophageal stent placement in 1, and no treatment in 7. The patients' median survival time was 271 days, the 1-year survival rate was 41.9% and the 5-year survival rate was 13.3%. DPF therapy can be used as a standard chemotherapy for advanced esophageal cancer in view of its strong antitumor effect and relatively safe outcome.

Regulator of calcineurin 1 modulates cancer cell migration in vitro.

Metastasis suppressors and other regulators of cell motility play an important role in tumor invasion and metastases. We previously identified that activation of the G protein coupled receptor 54 (GPR54) by the metastasis suppressor metastin inhibits cell migration in association with overexpression of Regulator of calcineurin 1 (RCAN1), an endogenous regulator of calcineurin. Calcineurin inhibitors also blocked cell migration in vitro and RCAN1 protein levels were reduced in nodal metastases in thyroid cancer. The purpose of the current study was to determine directly if RCAN1 functions as a motility suppressor in vitro. Several cancer cell lines derived from different cancer types with different motility rates were evaluated for RCAN1 expression levels. Using these systems we determined that reduction of endogenous RCAN1 using siRNA resulted in an increase in cancer cell motility while expression of exogenous RCAN1 reduced cell motility. In one cell line with a high migratory rate, the stability of exogenously expressed RCAN1 protein was reduced and was rescued by treatment with a proteasome inhibitor. Finally, overexpression of RCAN1 was associated with an increase in cell adhesion to collagen IV and reduced calcineurin activity. In summary, we have demonstrated that the expression of exogenous RCAN1 reduces migration and alters adhesion; and that the loss of endogenous RCAN1 leads to an increase in migration in the examined cancer cell lines. These results are consistent with a regulatory role for RCAN1 in cancer cell motility in vitro.

[A case of stenosis of the reconstructed jejunum due to recurrent cancer after total gastrectomy in which stent-in-stent placement was effective].

OBJECTIVES: We report one case of stenosis of the reconstructed jejunum due to recurrent cancer after total gastrectomy in which stenting was effective and good QOL was achieved. CASE: The patient was a 70-year-old woman. In July 2000, the patient underwent total gastrectomy.Roux-en Y reconstruction with a diagnosis of gastric cancer. The pathological diagnosis was U-Post, Type 3, por 1, T3, N1, H0, P0, CY0, M0, and Stage IIIA. From 9 months after the operation, aphagia occurred and stenosis of the reconstructed jejunum was noted. Based on a biopsy of the stenosis, a diagnosis of post-operative recurrent gastric cancer was made. Although the patient received two cycles of low-dose FP therapy, complete response was not obtained, and the patient stayed at home under the IVH control for about 4 months. In June 2001, the patient was hospitalized for a stent placement due to the patient's request. METHOD: After a guide wire was endoscopically inserted and a good passage on the anal side of the stenosis was confirmed, a stent was placed. Self Expandable Metallic Stent (SEMS) was used. CLINICAL COURSE: Following the stent placement, the patient was able to ingest orally, but 6.5 months later, stenotic symptoms developed and another stent was deployed (stent in stent). CONCLUSION: Stenting is relatively simple and less invasive, which is useful for the improvement of QOL and in recurrent cases as well.

Usefulness of serum protein profiling for prediction of preoperative chemoradiosensitivity of esophageal cancer.

We examined whether serum protein profiling is a reliable index for prediction of therapeutic efficacy of preoperative chemoradiotherapy (PCRT) in advanced esophageal cancer compared with evaluation of the efficacy of conventional clinical examination. We entered 42 patients who received PCRT and surgery between 1998 and 2002 into this study. Serum protein profiling was performed using the preoperative serum of the patient to select the marker set that enabled the efficacy of PCRT to be evaluated accurately. The efficacy of PCRT was predicted with the marker set, and the sensitivity, specificity and accuracy of the method were calculated based on evaluation of the efficacy by pathological examination. Similarly, therapeutic efficacy was also predicted based on evaluation of the efficacy of conventional clinical examination, and the results were compared with those of prediction by serum protein profiling. The correlation between each predictive examination and outcome was evaluated. The sensitivity, specificity and accuracy of prediction of therapeutic efficacy of PCRT by serum protein profiling were 90.9, 100 and 93.3%, respectively. In clinical examination, prediction of the efficacy of PCRT by three methods was as follows: by esophagography, sensitivity 76.0%, specificity 17.6%, accuracy 52.4%; by endoscopy, sensitivity 80.0%, specificity 11.8%, accuracy 52.4%; by computed tomography, sensitivity 60.0%, specificity 47.1%, accuracy 54.8%, respectively. These results demonstrated the superiority of serum protein profiling in predicting the therapeutic efficacy of PCRT compared with conventional clinical examination. Moreover, serum protein profiling was the only significant prognostic factor as regards the correlation with outcome by multivariate analysis.

2-amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenyl} acetamide (OSU-03012), a celecoxib derivative, directly targets p21-activated kinase.

p21-Activated kinases (PAKs) are regulators of cell motility and proliferation. PAK activity is regulated in part by phosphoinositide-dependent kinase 1 (PDK1). We hypothesized that reduced PAK activity was involved in the effects of 2-amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenyl} acetamide (OSU-03012), a previously characterized PDK1 inhibitor derived from celecoxib. In three human thyroid cancer cell lines, OSU-03012 inhibited cell proliferation with reduced AKT phosphorylation by PDK1. OSU-03012 unexpectedly inhibited PAK phosphorylation at lower concentrations than PDK1-dependent AKT phosphorylation in two of the three lines. In cell-free kinase assays, OSU-03012 was shown to inhibit PAK activity and compete with ATP binding. In addition, computer modeling predicted a docking site for OSU-03012 in the ATP binding motif of PAK1. Finally, overexpression of constitutively activated PAK1 partially rescued the ability of motile NPA thyroid cancer cells to migrate during OSU-03012 treatment, suggesting that inhibition of PAK may be involved in the cellular effects of OSU-03012 in these cells. In summary, OSU-03012 is a direct inhibitor of PAK, and inhibition of PAK, either directly or indirectly, may be involved in its biological effects in vitro.

AKT in thyroid tumorigenesis and progression.

AKT (protein kinase B) is a central signaling molecule in the phosphatidyl inositol 3-kinase pathway that is frequently activated in human cancer. AKT activation regulates energy metabolism, apoptosis, proliferation, and migration in many cell systems. In thyroid cancer, AKT activation is involved in tumorigenesis, particularly in both inherited and sporadic forms of follicular thyroid cancer. Phosphatidyl inositol 3-kinase and AKT signaling also appear to play an important role in progression of both papillary and follicular cancers. In this review, the role of AKT in thyroid cancer development and progression are discussed with a focus on areas of current debate in the literature.

Concurrent preoperative chemoradiotherapy for stage III or IV esophageal squamous carcinoma.

The poor progress of advanced esophageal carcinoma cannot be expected to be improved by surgical treatment alone. We retrospectively examined the results of surgery alone (SA: 39 cases) and of concurrent preoperative chemoradiation therapy (PCRT: 51 cases) for stage III or IV esophageal squamous carcinoma. In the PCRT group, the rate of pathological complete response was 31.4% for the primary lesion and 31.1% for metastatic lymph nodes, which viable cancer cells were not recognized in either region in 25.5% of all cases. In the PCRT group, grade 2 or more toxicity was found in 39 cases of leukopenia, 10 cases of anemia, 7 cases of thrombocytopenia, 11 cases of esophagitis, 4 cases of stomatitis, 2 cases of nausea, 2 cases of diarrhea, 2 cases of liver disfunction and 2 cases of infection. In 2 cases, PCRT was terminated for about 3 weeks because of thrombocytopenia. In the remaining 49 cases, PCRT was administered as scheduled. No statistically significant differences were noted between the PCRT group and the SA group in postoperative complications. There was postoperative recurrence in 16 cases (31.4%) in the PCRT group and 26 cases (66.7%) in the SA group (p=0.008). In stage III, the 5-year survival rate was 58.6% for the PCRT group and 17.2% for the SA group (p=0.022). In stage IV, the survival rate was 0% for the SA group and 16.7% for the PCRT group, showing better results in the latter, although there was no statistically significant difference. Multivariate analysis of prognostic variables revealed that therapeutic method (presence or absence of PCRT) contributed the greatest to the prognosis. These results indicate that PCRT is an effective adjuvant therapy for squamous cell carcinoma.