Efficacy and toxicity of sorafenib in patients with adenoid cystic carcinoma of the head and neck: a case series of five patients.

INTRODUCTION: Adenoid cystic carcinoma (ACC) of the head and neck is a rare malignancy of the salivary glands that accounts for approximately 10% of salivary gland carcinoma. Despite aggressive local therapy, local recurrence and distant metastases occur frequently. Response rates (RR) to potential curative and palliative chemotherapy are limited, so new strategies are needed. CASE REPORTS: We describe five case reports of patients with unresectable locally advanced or metastatic ACC of the head and neck who have been treated with sorafenib, a multi-tyrosine kinase inhibitor (mTKI). RESULTS: In this case series, we found that three out of five patients treated with sorafenib survived, respectively, 16, 35 and 35 months. Two patients showed a partial response (PR) and one patient had a prolonged stable disease (SD) for almost three years. Grade 3 adverse events (AE) occur under sorafenib so adequate toxicity management is essential. This retrospective case series hints towards the possibility of clinical benefit for treating ACC patients with sorafenib. Efficacy of sorafenib should be studied in a prospective-randomized clinical trial which is a challenging task due to the rarity of the disease.

A multiplex preclinical model for adenoid cystic carcinoma of the salivary gland identifies regorafenib as a potential therapeutic drug.

Adenoid cystic carcinomas (ACC) are rare salivary gland cancers with a high incidence of metastases. In order to study this tumor type, a reliable model system exhibiting the molecular features of this tumor is critical, but none exists, thereby inhibiting in-vitro studies and the analysis of metastatic behavior. To address this deficiency, we have coupled an efficient method to establish tumor cell cultures, conditional reprogramming (CR), with a rapid, reproducible and robust in-vivo zebrafish model. We have established cell cultures from two individual ACC PDX tumors that maintain the characteristic MYB translocation. Additional mutations found in one ACC culture also seen in the PDX tumor. Finally, the CR/zebrafish model mirrors the PDX mouse model and identifies regorafenib as a potential therapeutic drug to treat this cancer type that mimic the drug sensitivity profile in PDX model, further confirming the unique advantages of multiplex system.

Epigallocatechin gallate inhibits the growth of salivary adenoid cystic carcinoma cells via the EGFR/Erk signal transduction pathway and the mitochondria apoptosis pathway.

ACC is one of the most malignant tumors in salivary gland, and of poor prognosis. A critical role in ACC development and progression is played by EGFR family members including EGFR. EGCG, a low molecular weight polyphenol contained in green tea, has broad anticancer properties, but whether EGCG regulates activity of ACC is unknown. In the present study, the effects of EGCG were investigated in vitro with particular attention to the pathway of EGFR/Erk and mitochondria apoptosis in SACC-83 cell lines. The results of MTS assay and flow cytometry demonstrated that EGCG (20-80 µM) could inhibit proliferation and promote apoptosis of SACC-83 cells. Furthermore, by Western blotting with antibodies specific for EGFR, Erk 1/2 (p-Erk 1/2), Mek (p-Mek), Bcl-2, and Bax, it was demonstrated that EGCG could reduce the expression of EGFR, inhibit phosphorylation of Erk 1/2 and Mek, downregulate Bcl-2, and upregulate Bax. In addition, it was also shown that EGCG could inhibit mRNA expression of P90 RSK by RT-PCR. In conclusion, the results suggest that EGCG might be a potential therapeutic or adjuvant strategy for the treatment of patients with ACC, by inhibiting proliferation and inducing the apoptosis of the tumor cells.

A phase II study of sorafenib in recurrent and/or metastatic salivary gland carcinomas: Translational analyses and clinical impact.

BACKGROUND: Pre-clinical and clinical evidence suggests a rationale for the use of anti-angiogenic agents, including sorafenib, in recurrent and/or metastatic salivary gland carcinomas (RMSGCs). This study evaluates the activity of sorafenib in patients with RMSGCs and also investigates whether the activity of sorafenib could be related to its main tailored targets (i.e. BRAF, vascular endothelial growth factor receptor 2 [VEGFR2], platelet-derived growth factor receptor α [PDGFRα] and ß, RET, KIT). PATIENTS AND METHODS: Patients received sorafenib at 400 mg BID. The primary end-point was response rate (RR) including complete response or partial response (PR); secondary end-points included RR according to Choi criteria, disease control rate (DCR), overall survival (OS), and progression-free survival (PFS). RESULTS: Thirty-seven patients (19 adenoid cystic cancers, ACC) were enrolled. Six PRs were recorded. RR was 16% (95% confidence interval [CI]: 6-32; 11% in ACC and 22% in non-ACC). Choi criteria could be applied in 30 out of 37 cases with a RR of 50% (95% CI: 31-69%); DCR was 76% (95% CI: 59-88%). Incidence of ≥G3 adverse events was 29.7%. Median PFS and OS for the entire population were 5.9 months and 23.4 months, respectively. Median PFS and OS were 8.9 and 26.4 months for ACC versus 4.2 and 12.3 months for non-ACC patients. All the cases showed expression of PDGFRß in the stroma and VEGFR2 in endothelial cells; PDGFRα positivity was found in the stroma of four (27%) cases. All except for two cases showed no PDGFRß, VEGFR2 and PDGFRα expression in the tumour cells. KIT expression was restricted to ACC and a weak RET expression was limited to one adenocarcinoma, not otherwise specified (NOS). No BRAF mutation was found. No correlation was observed between the sorafenib activity and the expression of its markers although all six responders (two ACC, one adenocarcinoma, NOS, one salivary duct cancer [SDC], one high-grade mucoepidermoid [HG-MEC] and one poorly-differentiated cancer) are enriched in the stromal component showing a PDGFRß immunodecoration. In ACCs, immunohistochemistry revealed MYB protein expression in 15/16 cases (94%) and the MYB-NFIB fusion oncogene was observed in 9/14 (64%). CONCLUSIONS: Sorafenib is the first anti-angiogenic agent to demonstrate activity in RMSGC patients, particularly in some histotypes such as HG-MEC, SDC and adenocarcinoma, NOS. The PDGFRß-positive rich stromal component characterising these histotypes and the lack of correlation between the activity of sorafenib and its targets suggests anti-angiogenic effect as the prevalent mechanism of action of sorafenib in SGCs.

Successful treatment of c-kit-positive metastatic Adenoid Cystic Carcinoma (ACC) with a combination of curcumin plus imatinib: A case report.

Adenoid cystic carcinoma (ACC) is an aggressive malignant neoplasm of the secretory glands. Conventional chemotherapy has poor effectiveness against metastatic ACC. Thus, a novel effective therapy is needed against metastatic ACC. A majority of ACCs (up to 94%) express c-kit. Imatinib is monoclonal antibody with specific activity against c-kit but has not been found to be effective in treating patients with ACC in which c-kit is overexpressed and activated. The NF-κB and mTOR pathways have been shown that ubiquitously and concurrently activated, indicating that the inhibition of these pathways may represent a novel treatment approach for patients with ACC. Curcumin has been shown to inhibit NF-κB and NF-κB-related pathways. 43-year-old patient was diagnosed ACC from submandibular salivary gland. After complete resection of tumor adjuvant radiotherapy was initiated. Seven years later multiple lung metastases were detected and ACC was confirmed by re-biopsy. First-line chemotherapy failed. NF-κB and c-kit were overexpressed in the metastatic specimens. Therefore, we treated the patient with metastatic chemoresistant ACC with imatinib 400mg/day and intravenous curcumin 225mg/m(2) twice a week plus oral bioavailable curcumin Arantal(®) 2×84mg/day. At 24 months, we observed near complete anatomic and complete metabolic response. To our knowledge, this is the first report of a patient with a c-kit-positive ACC that is successfully treated with the combination of imatinib and curcumin in an integrative approach.

Phase II trial of sorafenib in advanced salivary adenoid cystic carcinoma of the head and neck.

BACKGROUND: There is a need to improve the systemic treatment of advanced adenoid cystic carcinoma (ACC). Response rates to chemotherapy are poor and preliminary investigations of molecularly targeted agents have been disappointing. In this study, we evaluate sorafenib, an oral multikinase inhibitor, which has an attractive targeting profile for this disease. METHODS: In a single-arm phase II trial, patients with unresectable locally recurrent and/or metastatic ACC were treated with sorafenib 400 mg bid. RESULTS: Twenty-three patients, median age 51 years, were recruited from 2009 to 2011. Median progression-free survival (PFS) and overall survival (OS) were 11.3 and 19.6 months, respectively. PFS at 6 and 12 months were 69.3% and 46.2%, respectively. Sorafenib was only reasonably well tolerated, and 13 patients (57%) experienced grade 3 toxicity. CONCLUSION: Sorafenib showed modest activity in ACC with a 12-month PFS of 46.2%. Sorafenib 400 mg bid was associated with significant toxicity and, taken together with limited effectiveness, cannot be enthusiastically recommended for further evaluation.

Tumour response following high-dose intratumoural application of Viscum album on a patient with adenoid cystic carcinoma.

Adenoid cystic carcinoma (ACC) is a rare type of cancer that typically originates in the salivary glands. Surgical removal can lead to functional loss and psychological distress. Viscum album extract (VAE) is a herbal remedy with dose-dependent cytotoxic, apoptogenic and immunological effects. In some case reports, tumour regression has been observed following high-dose local applications of VAE. An active 88-year-old man with fast-growing ACC of the hard palate refused surgical removal and received high-dose intratumoural injections of VAE (alone) over a 10-month period. The tumour decreased in size, softened and loosened from its surroundings. A biopsy during the course showed inflammation. The patient remained well and without functional limitations during the therapy and follow-up period (5 months). VAE produced no reported side effects. This aged patient exemplifies a satisfying course of ACC under VAE resulting in good quality of life and partial tumour regression.

[Adenoid cystic carcinoma of the breast:report of 25 cases].

OBJECTIVE: To explore the clinical features, management approach and treatment outcomes for adenoid cystic carcinoma (ACC) of the breast. METHODS: The clinicopathological data of 25 patients with breasts ACC treated in our hospital from years 1990 to 2012 were retrospectively reviewed and their prognosis was analyzed. RESULTS: The median age of these 25 patients was 53 years (ranged from 31 to 81 years). With the exception of one male case, all patients were female including 17 cases of postmenopausal women. The most frequent presenting symptom is breast lumps, most (48.0%) were in the upper outer quadrant and areola area of the breast. Core needle biopsy was performed in five patients. The specimen finding were adenoids in three and invasive carcinoma in two cases. Axillary lymph node dissection was performed in 23 patients. Only two patients had histologically positive lymph nodes (3 of 14 and 2 of 20). Expression of ER and PR in 14 cases was detected by immunohistochemistry, showing one PR-positive and three ER-positive cases. The median follow-up of the 25 cases was 118 months (ranged from 12 to 244 months). Two patients died of lung metastases at 3 and 10 years after the surgery, respectively. CONCLUSIONS: Due to the complexity of the histology of ACC, adequate sampling of specimens is essential for accurate diagnosis. ACC of the breast is a rare disease with a relatively good prognosis. The low incidence of axillary lymph node metastasis suggests that axillary node dissection is not recommended as a routine procedure. Breast ACC are often with negative ER and PR expression, and the value of adjuvant therapy needs to be further investigated.

Inhibition of autophagy augments chemotherapy in human salivary adenoid cystic carcinoma.

Although cisplatin (DDP)-based adjuvant chemotherapy is widely used in the treatment of salivary adenoid cystic carcinoma (SACC), SACCs have developed resistance to cisplatin, resulting in chemotherapy failure. Autophagy serves as a critical adaptive response, which was increased in tumor cells in chemotherapy. However, the function of autophagy is not clear in SACC. In this study, apoptosis induced by DDP in SACC high metastatic cell line (ACC-M) was revealed using MTT assay, flow cytometry, and caspase-3 immunoblotting. The autophagy activation induced by DDP treatment was measured by transmission electron microscopy, green fluorescent protein-light chain 3 plasmid transfection LC3 immunoblotting and p62 immunoblotting. 3-methyladenine (3-MA) or small interference RNA targeting beclin 1 (beclin 1 siRNA) inhibited autophagy and significantly enhanced DDP-induced apoptosis. ACC-M xenografts in nude mice further verified the synergistic effect of DDP and 3-MA. In conclusion, autophagy activation was caused to protect cancer cells from DDP-induced apoptosis and autophagy inhibition could be a promising strategy for adjuvant chemotherapy in SACC.

[Influence of Ginkgo biloba extract on proliferation of ACC-2 cell, Survivin and TIP30 gene expression in adenoid cystic carcinoma of lacrimal gland].

Exploring the influence of extract of Ginkgo biloba (EGB) on the proliferation, apoptosis of ACC-2 cell in lacrimal adenoid cystic carcinoma and analyzing the influence of EGB on the gene expression of Survivin and TIP30 based on the levels of the gene and protein. ACC-2 cell in human with ACC of lacrimal gland disposed by EGB of different concentration was in vitro cultured. MTT method was used for cell proliferation detection. Annexin V/PI double-staining flow cytometer was used to detect cell apoptosis and cell cycle. Survivin and TIP30 gene expression together with protein expression were analyzed by RT-PCR and Western blotting. And it is indicated that EGB has inhibitory effect on the proliferation of ACC-2 cell in vitro. Furthermore, the dose-effect relationship was significant. Compared with the control group, it had statistical difference (P <0.01). The inhibitory concentration 50% (ICso) is 88 mg . L-1. By flow cytometer examination, it was indicated that EGB can gradually increase ACC-2 cell in G0-G1 stage and decrease it in G2-M and S stage. With the increase of dose, the apoptosis rate of ACC-2 cell obviously increased (P <0.05 or P <0.01). Both of the expression results of RT-PCR and Western hybrid proteins have showed that the concentration of EGB increased, it could be seen a significant decrease in Survivin gene expression (P <0.01). Meanwhile, the TIP30 gene expression got a significant increase. Therefore, EGB can effectively inhibit ACC-2 cell Survivin gene expression in human with adenoid cysistic carcinoma of larcrimal gland as well as promoting TIP30 gene expression, inducing the ACC-2 cell apoptosis and inhibiting tumor cell proliferation, which provided a certain theoretical and experimental basis for the application of Chinese herbal medicinal ingredient in the treatment of tumors.

Mechanisms of apple polyphenols-induced proliferation inhibiting and apoptosis in a metastatic oral adenoid cystic carcinoma cell line.

Adenoid cystic carcinoma (ACC) is characterized by intensive local invasion and high incidence of distant metastases. Conventional chemotherapy for ACC produces a poor result. We aimed to evaluate the effect of apple polyphenols (APs), a novel nutraceutical agent, on the proliferation and apoptosis levels in a metastatic oral ACC cell line. A metastatic ACC (ACC-M) cell line and control cells (MRC-5 cells derived from normal lung tissue) were treated with APs at different concentrations. MTT assay was used to determine the in vitro cytotoxicity. The cell cycle distribution and apoptosis levels were measured by flow cytometry. To evaluate the mechanism of APs, vascular endothelial growth factor receptor-2 (VEGFR-2) and caspase-3 messenger ribonucleic acid (mRNA) and protein levels were evaluated by reverse transcription-polymerase chain reaction and Western blots, respectively. After cells were cultured for 24 hours or 48 hours, the critical concentration of cytotoxicity of APs in MRC-5 cells was found to be 250 µg/mL. In contrast, in the concentration range of 100-250 µg/mL, the cytotoxicity of APs in ACC-M cells was time- and dose-dependent: ACC-M cell proliferation declined at 100 µg/mL when cultured for 48 hours, whereas growth was not inhibited at the concentrations of APs below 200 µg/mL when cultured for 24 hours. In selected time and dose patterns (ACC-M cells cultured at the concentrations of 150 and 250 µg/mL for 48 hours), the flow cytometry performance showed that apoptosis and necrosis occurred in APs-treated ACC-M cells. Also, in these patterns, VEGFR-2 mRNA and protein levels decreased whereas the levels of caspase-3 increased. In summary, APs could inhibit proliferation and induce apoptosis in ACC-M cells in vitro. These effects may be related to the downregulation of VEGFR-2 expression and the activation of caspase-3 expression.

Mammalian target of rapamycin pathway promotes tumor-induced angiogenesis in adenoid cystic carcinoma: its suppression by isoliquiritigenin through dual activation of c-Jun NH2-terminal kinase and inhibition of extracellular signal-regulated kinase.

Tumor-induced angiogenesis is essential for invasive growth and hematogenous metastasis of adenoid cystic carcinoma (ACC), a highly aggressive neoplasm mostly occurring in salivary glands. Previous studies have indicated that strategies directed against angiogenesis will help develop new therapeutic agents for ACC. The Chinese folk medicine licorice has been used for years as a natural remedy for angiogenesis-related diseases. In this study, we examined the effects of isoliquiritigenin (ISL), a flavonoid isolated from licorice, on the growth and viability of ACC cells and observed a concentration-dependent (0-20 microM) inhibition of cell growth without cell death at 24 h. In a further mimic coculture study, ISL effectively suppressed the ability of ACC cells to induce in vitro proliferation, migration, and tube formation of human endothelial hybridoma (EAhy926) cells as well as ex vivo and in vivo angiogenesis, whereas it exerted no effect on EAhy926 cells when added directly or in the presence of vascular endothelial growth factor (VEGF). The data also showed that the specific suppression of tumor angiogenesis by ISL was caused by down-regulation of mammalian target of rapamycin (mTOR) pathway-dependent VEGF production by ACC cells, correlating with concurrent activation of c-Jun NH(2)-terminal kinase (JNK) and inhibition of extracellular signal-regulated kinase (ERK). Most importantly, ISL also significantly decreased microvessel density within xenograft tumors, associating with the reduction of VEGF production and suppression of the mTOR pathway coregulated by JNK and ERK, as revealed by immunohistochemical studies and clustering analysis. Taken together, our results highlight the fact that ISL is a novel inhibitor of tumor angiogenesis and possesses great therapeutic potential for ACC.

Epirubicin, cisplatin and protracted venous infusion 5-Fluorouracil chemotherapy for advanced salivary adenoid cystic carcinoma.

AIMS: Adenoid cystic carcinoma (ACC) is a rare tumour that usually arises in the salivary glands. Initial management is surgery often combined with adjuvant radiotherapy. Chemotherapy is reserved for treatment of symptomatic recurrence. We evaluated the combination of epirubicin, cisplatin and protracted venous infusion 5-fluorouracil (ECF) in the management of ACC. MATERIALS AND METHODS: Patients referred for treatment of advanced, symptomatic ACC were considered. The drugs given were epirubicin 50 mg/m(2) 3-weekly, cisplatin 60 mg/m(2) 3-weekly and protracted venous infusion 5-fluorouracil 200 mg/m(2)/day. RESULTS: Eight patients (median age 46 years) received a median of five cycles of chemotherapy. All patients had had previous surgery, seven had had previous radiotherapy and one had had previous chemotherapy. One patient showed a partial response (duration 34 months) and five showed stable disease (median duration 13.6 months [6.8-15.9+ months]). Median survival was 27 months (3.5-62.3 months). CONCLUSIONS: The activity of ECF in ACC of the head and neck seems to be similar to the combination of cisplatin and 5-fluorouracil and single-agent epirubicin.

Synergistic inhibitory effect of sulforaphane and 5-fluorouracil in high and low metastasis cell lines of salivary gland adenoid cystic carcinoma.

The present study aimed to evaluate the growth-inhibitory effect of sulforaphane (SFN) and a traditional chemotherapy agent, 5-fluorouracil (5-Fu), against the proliferation of salivary gland adenoid cystic carcinoma high metastatic cell line (ACC-M) and low metastasis cell line (ACC-2). Furthermore, the expression of nuclear factor kappa B (NF-kappaB) which induces resistance to anticancer chemotherapeutic agents was also detected. The combination effect of SFN and 5-Fu was quantitatively determined using the method of median effect principle and the combination index. The nuclear NF-kappaB p65 expression after treatment with the SFN-5-Fu combination was also evaluated by western blot analysis. The ACC-M and ACC-2 cells exhibited relative resistant to 5-Fu. Treatment ACCs cells with SFN and 5-Fu in combination, led to synergistic inhibition on cell growth and a decreased expression in nuclear NF-kappaB p65 protein. This synergistic inhibitory effect was more significant in ACC-M cells, which is associated with the greatly decreased expression of NF-kappaB p65 (almost 5-fold) after the combination treatment. Our results demonstrate synergism between SFN and 5-Fu at higher doses against the ACC-M and ACC-2 cells, which was associated with the decreased expression of nuclear NF-kappaB p65 protein.

Vandetanib inhibits growth of adenoid cystic carcinoma in an orthotopic nude mouse model.

PURPOSE: Adenoid cystic carcinoma (ACC) can often be controlled with surgery and postoperative adjuvant radiotherapy but is also characterized by late local recurrence and distant metastasis. No effective systemic therapeutic agents have been found to alter the natural history of ACC. Therefore, new therapeutic approaches are needed. In this study, we evaluated whether vandetanib (Zactima), a potent inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR) tyrosine kinases, had antitumor efficacy in vitro and in an orthotopic nude mouse model of human ACC. EXPERIMENTAL DESIGN: The in vitro effects of vandetanib were assessed in three ACC cell lines on cell growth, apoptosis, and VEGFR-2 and EGFR phosphorylation levels. The in vivo antitumor activity of vandetanib was examined in nude mice bearing parotid gland ACC tumors. The mice were treated for 4 weeks with vandetanib (50 mg/kg/d) or placebo (control). Tumors were resected at necropsy, and immunohistochemical and immunofluorescence staining were done. RESULTS: In vitro, vandetanib caused dose-dependent inhibition of VEGFR-2 and EGFR phosphorylation in ACC cells. Vandetanib also inhibited the cell proliferation and induced their dose-dependent apoptosis. In vivo, mice in the vandetanib group had tumor volumes significantly lower than those in the control group (P < 0.01). In addition, immunohistochemical staining showed a decrease in microvessel density and an increase in apoptosis of both tumor cells and endothelial cells within the tumor xenografts. CONCLUSION: These results suggest that vandetanib inhibits the growth of ACC in vitro and in vivo, making it a promising novel agent for the treatment of ACC.

[The outcome of treatments for carcinoma of the external auditory canal]. / Résultats des traitements des tumeurs malignes du conduit auditif externe.

OBJECTIVE: A retrospective analysis of management and survival of patients treated for temporal bone carcinoma. PATIENTS AND METHODS: Thirty patients underwent treatment for carcinoma of the temporal bone. Twenty-five squamous cell carcinomas, 1 melanoma, 2 basocellular carcinomas and 2 adenoid cystic carcinomas were treated. Thirteen patients were treated before for the same disease. RESULTS: Staging revealed 12 T1 and T2, 6 T3 and 12 T4 tumours. The mean follow up was 5 years (2-276 months). The Kaplan Meier survival curves showed survival rates at 2 years of 82%, 67% and 32%, and at 5 years of 82%, 67% and 17%, respectively for the stages T1 or T2, T3 and T4. At the end of follow up at 9 years the survival rates were 66%, 66% and 17% for the stages T1 or T2, T3 and T4 respectively. Overall stages a complete remission was found in 65% and 23%, and deceased was 35% and 77%, respectively for the primary treatment group and the salvage surgery group. CONCLUSION: Long-term prognosis of the carcinoma of the external auditory canal mainly depends on the stage and primary treatment. Surgery (lateral temporal bone or subtotal temporal bone resection, both in combination with a neck dissection and a parotidectomy) and adjuvant radiotherapy is the treatment of choice for part of stage T1 and all T2 and T3 tumours. The improved survival (65%) of patients treated de novo compared with those treated with salvage surgery (23%) suggests that early referral and aggressive primary surgical treatment with postoperative radiotherapy offer the greatest chance of cure.

[Combining of TNP-470 and 5-Fu in inhibition of adenoid cystic carcinoma in nude mice model].

OBJECTIVE: To study the effect of angiogenesis inhibitor and its combine with chemical drug in suppressing the growth of adenoid cystic carcinoma (ACC). METHODS: Acc-M cells were inoculated subcutaneous into BABL/C nu/nu mice. The mice were divided into control, different dose of TNP-470 treatment groups, 5-Fu treatment group and TNP-470 plus 5-Fu treatment group. Treatments were given 48 hours after inoculation. The mice were sacrificed on the 22nd day and excised tumors were weighted. Tumors were also investigated by immunohistochemistry and ultrastructural observations. RESULTS: TNP-470 100 mg/kg/qod efficiently inhibited the growth of Acc-M tumors. TNP-470 30 mg/kg/qod combined with 50 mg/kg/week 5-Fu also resulted in significant growth inhibit of the tumors. TNP-470 suppressed tumor growth by inhibiting neovascularization, therefore inducing apoptosis of Acc-M cells. All experimental groups had different degrees of VEGF and bFGF express. CONCLUSION: Since ACC is a slow developing tumor, blood supply is not so sufficient as sarcomas. Angiogensis inhibitor may inhibit its growth in high dosage. Combining medium dosage of angiogensis inhibitor with chemical drug may have synergistic result in inhibiting ACC growth.

Expression of p53 and p21 is useful for the prediction of preoperative chemotherapeutic effects in esophageal carcinoma.

The p53 and p21 genes are associated with G1 arrest during the cell cycle and with apoptosis, both of which have a close relationship with the effect of chemotherapy. In this study, we investigated the correlation between p53 and p21 expression in biopsy specimens and the histological effect of chemotherapy in esophageal carcinoma. A total of 30 patients with esophageal squamous cell carcinoma received preoperative chemotherapy, then underwent esophagectomy with lymph node dissection. The response rate of primary lesion and metastatic nodes was 20.0% and 25.9%, respectively. The positive rate of p53 and p21 expression was 56.7% and 36.7%, respectively. Preoperative chemotherapy against primary lesions was ineffective in all the patients who expressed p53, but not p21. In contrast, chemotherapy was effective against metastatic lymph nodes which were p53 negative but p21 positive. These findings suggest that p21 positive expression in the absence of p53 is associated with favorable effects of preoperative chemotherapy in patients with esophageal carcinoma. Therefore, the expression of these genes should be examined in biopsy specimens to predict the chemotherapeutic outcomes in patients with esophageal carcinoma.

5-Fluorouracil, cyclophosphamide, and vincristine for adenoid cystic carcinoma of the head and neck.

Twenty-one patients with adenoid cystic carcinoma of the head and neck were treated with intravenous boluses of cyclophosphamide and vincristine and 5-day continuous intravenous infusions of 5-fluorouracil (CVF) every 4 weeks. Eight patients received CVF as palliation for recurrent or metastatic disease. A sustained complete response (107+ months) was observed in one patient; one partial response and one mixed response each also were observed. In four patients disease stabilized, and in one disease progressed. Thirteen patients received six courses of CVF in the adjuvant setting after surgery and radiation for either primary or locoregional recurrent disease. Recurrences developed in two of seven patients with primary disease and three of six patients with recurrent disease with a median follow-up 45 months (range, 20-108+). Recurrence rate and time interval to recurrence were comparable to those of well-matched historical controls. Distant metastases have not developed in patients treated with CVF in the adjuvant setting, whereas distant metastases had developed in historical controls within comparable periods of follow-up. Serious toxicities were not encountered in any patient. The authors conclude that CVF is a well-tolerated combination chemotherapy program with activity in adenoid cystic carcinoma of the head and neck. This regimen, however, has not had a major impact in the adjuvant setting in preventing recurrent disease.

Combination chemotherapy with CDDP and 5-FU in head and neck cancer.

Combination chemotherapy with CDDP and 5-FU was performed in 19 patients with evaluable head and neck cancer and 2 CR patients and 7 PR patients were obtained; thus the response rate was 47.4%. Histologically, the present therapy is considered to be especially effective against well differentiated squamous cell carcinoma (83.3%). The present therapy is considered to be useful as a neo-adjuvant chemotherapy (75.0%), but it is desirable to perform at least 2 courses of treatment. The side effects observed were nausea, vomiting, anemia, leukocytopenia and alopecia, etc., and most of them were reversible. However, there were 2 patients in which the continuation of chemotherapy was impossible due to renal disorders.