Evaluation of polymerase chain reaction assays for the diagnosis of Trichomonas vaginalis infection in Russia.

BACKGROUND: In Russia, the microscopy- and culture-based diagnostics of trichomoniasis is mainly suboptimal. Recent years, domestically produced diagnostic PCR assays have been implemented; however, any evaluation of these PCRs has never been internationally reported. OBJECTIVE: To assess the performance characteristics of PCR assays developed and currently used in Russia to detect Trichomonas vaginalis. MATERIALS AND METHODS: Five PCR assays were assessed on 448 samples (317 vaginal and 131 male urethral) collected from symptomatic attendees of youth centres (n = 415) and patients of a dermatovenereological dispensary that were previously diagnosed with trichomoniasis (n = 33). As reference assay, a sensitive and specific real-time multiplex PCR was used. RESULTS: T. vaginalis DNA was detected in five (all females) of the 415 patients of youth centres (1.2%). All 33 patients previously diagnosed at the venereological dispensary proved to be true positive. For 445 (99.3%) of these 448 samples identical results were obtained by all PCRs, 35 positive and 410 negative. The three discordant samples were positive in all PCRs except one conventional PCR assay. The sensitivities of the PCRs were 94.3-100% and 66.7-100% for vaginal and urethral swabs, respectively. All evaluated assays were 100% specific. The detection limits of the different PCRs ranged from 0.1 to 5 genome equivalents per reaction. CONCLUSION: The PCR assays currently used in Russia for the detection of T. vaginalis have in general high sensitivities and excellent specificities for both vaginal samples and urethral samples from males.

A real-time quadriplex PCR assay for the diagnosis of rectal lymphogranuloma venereum and non-lymphogranuloma venereum Chlamydia trachomatis infections.

OBJECTIVES: To develop and evaluate a real-time quadriplex PCR for the diagnosis of lymphogranuloma venereum (LGV) and non-LGV chlamydial infections using rectal swab specimens. METHODS: The design of the real-time quadriplex PCR assay incorporates an LGV-specific, a non-LGV-specific target sequence, a Chlamydia trachomatis plasmid target, and the human RNase P gene as an internal control. The performance of the quadriplex PCR was compared with a previously reported real-time duplex PCR assay on which LGV diagnosis was based on exclusion. RESULTS: Very good agreement (85 of 89 specimens, 95.5%) was found between the two multiplex PCR assays for the detection of C trachomatis DNA (kappa value 0.93, 95% CI 0.86 to 0.99). Both assays identified 34 LGV, 35 non-LGV C trachomatis and 16 negative specimens. Of two specimens that tested positive for non-LGV by the duplex PCR, one was found to be a mixed infection and the other was positive only for plasmid and RNase P targets by the quadriplex PCR. Two additional specimens that had equivocal results for non-LGV by the duplex PCR also tested positive only for plasmid target and human DNA by the quadriplex PCR. In addition, six specimens that tested negative by the duplex PCR assay were found to be invalid when using the quadriplex PCR. CONCLUSIONS: A real-time quadriplex PCR assay has been developed that is capable of detecting LGV, non-LGV, or mixed infections simultaneously in rectal specimens. The assay also contains a supplemental amplification target for the confirmation of C trachomatis infection as well as a human DNA control for monitoring sample adequacy and PCR inhibition.

Chemotherapy as an adjunct to radiotherapy in locally advanced nasopharyngeal carcinoma.

BACKGROUND: A previous meta-analysis investigated the role of chemotherapy in head and neck locally advanced carcinoma. This work had not been performed on nasopharyngeal carcinoma. OBJECTIVES: The aim of the project was to study the effect of adding chemotherapy to radiotherapy on overall survival (OS) and event-free survival (EFS) in patients with nasopharyngeal carcinoma. SEARCH STRATEGY: We searched MEDLINE (1966 to October 2003), EMBASE (1980 to October 2003) and the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 3, 2003) and trial registers. Handsearches of meeting abstracts, references in review articles and of the Chinese medical literature were carried out. Experts and pharmaceutical companies were asked to identify trials. SELECTION CRITERIA: Randomised trials comparing chemotherapy plus radiotherapy to radiotherapy alone in locally advanced nasopharyngeal carcinoma were included. DATA COLLECTION AND ANALYSIS: The meta-analysis was based on updated individual patient data. The log rank test, stratified by trial, was used for comparisons and the hazard ratios (HR) of death and failure (loco-regional/distant failure or death) were calculated. MAIN RESULTS: Eight trials with 1753 patients were included. One trial with a 2 x 2 design was counted twice in the analysis. The analysis was performed including 11 comparisons based on 1975 patients. The median follow up was six years. The pooled hazard ratio of death was 0.82 (95% confidence interval (CI) 0.71 to 0.95; P = 0.006) corresponding to an absolute survival benefit of 6% at five years from chemotherapy (from 56% to 62%). The pooled hazard ratio of tumour failure or death was 0.76 (95% CI 0.67 to 0.86; P < 0.00001) corresponding to an absolute event-free survival benefit of 10% at five years from chemotherapy (from 42% to 52%). A significant interaction was observed between chemotherapy timings and overall survival (P = 0.005), explaining the heterogeneity observed in the treatment effect (P = 0.03) with the highest benefit from concomitant chemotherapy. AUTHORS' CONCLUSIONS: Chemotherapy led to a small but significant benefit for overall survival and event-free survival. This benefit was essentially observed when chemotherapy was administered concomitantly with radiotherapy.

Iododeoxyuridine chemosensitization of cis-diamminedichloroplatinum(II) in human bladder cancer cells.

We investigated the effect of iododeoxyuridine (IdUrd) exposure on cis-diamminedichloroplatinum (CDDP) cytotoxicity in the human bladder cancer cell line 647V. Following a 48-h incubation with 2-20 microM IdUrd, a 1-h exposure to 0-120 microM CDDP produced a dose-dependent increase in CDDP cytotoxicity as measured by clonogenic survival. IdUrd exposure of 2, 5, 10, and 20 microM prior to CDDP resulted in dose-modifying factors at 10% survival of 1.2, 1.6, 2.0, and 3.5, respectively. The increase in CDDP cytotoxicity appears to be associated with the level of DNA thymidine replacement in DNA by IdUrd over the range of 13-36%. Atomic absorption spectrophotometric analysis of DNA extracted from 647V cells showed that IdUrd substitution did not affect the total amount of platinum bound to the DNA or the persistence of the bound platinum over a 24-h period post-CDDP exposure versus control cells. IdUrd, unlike thymidine, was found to form two monofunctional adducts with CDDP both in vitro and in vivo. IdUrd was also found to form a mixed bifunctional adduct with deoxyguanosine (dGua) and CDDP in vitro. 1H NMR analysis of purified IdUrd-Pt and IdUrd-Pt-dGua adducts confirmed the identity of these adducts. High pressure liquid chromatography analysis of [3H]IdUrd-labeled 647V DNA digests exposed to CDDP showed the presence of two monofunctional adducts. Unlike the free solution production of adducts in vitro, the predominant adduct formed was not IdUrd-Pt. Results using 125IdUrd-labeled 647V DNA suggests that this adduct is 5-Pt-deoxyuridine. We were not able, however, to detect the presence of the bifunctional adducts IdUrd-Pt-dGua or dUrd-Pt-dGua. This was most likely due to the extremely low proportion of mixed bifunctional adducts produced in vivo. Nonetheless, these results suggest that IdUrd DNA incorporation may enhance CDDP cytotoxicity through the increase of available sites for Pt adduct formation. A Phase I clinical trial of this approach is planned.

Effect of granulocyte-macrophage colony-stimulating factor on oral mucositis in head and neck cancer patients after cisplatin, fluorouracil, and leucovorin chemotherapy.

PURPOSE: To evaluate prospectively the efficacy of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the reduction of chemotherapy-induced oral mucositis. PATIENTS AND METHODS: Twenty patients with stage IV squamous cell carcinoma of head and neck were studied. Two-cycles (periods) of identical doses of cisplatin, fluorouracil (5-FU), and leucovorin (PFL) chemotherapy with cisplatin 20 mg/m2/d, 5-FU 800 mg/m2/d, leucovorin 90 mg/m2/d by 96-hour continuous intravenous infusion every 3 weeks were given to each patient. After PFL chemotherapy, GM-CSF 4 micrograms/kg subcutaneously from days 5 to 14 or no therapy was given by a randomized self-controlled crossover study design. Oral mucositis was graded with modified Radiation Therapy Oncology Group criteria. RESULTS: In the first cycle of PFL chemotherapy, GM-CSF significantly reduced the incidence, mean duration, and mean area under the curve (AUC) of severe oral gross mucositis (grade > or = 3) compared with no therapy. These beneficial effects continued into the second cycle of PFL chemotherapy after crossover to no GM-CSF. The incidence of severe mucositis was reduced when GM-CSF was given in the second cycle of PFL. Analysis of variance indicated significant direct GM-CSF treatment effects on the mean AUC of gross/functional scores and duration of moderate gross mucositis (grade > or = 2) over both periods. There was a significant period effect in favor of giving GM-CSF in the first cycle of chemotherapy. CONCLUSION: GM-CSF can significantly reduce the severity and duration of chemotherapy-induced oral mucositis after PFL chemotherapy.

A novel approach for nasopharyngeal carcinoma treatment uses phenylbutyrate as a protein kinase C modulator: implications for radiosensitization and EBV-targeted therapy.

Sodium phenylbutyrate (NaPB) represent a new non-toxic class of compounds with antiproliferative activities to different tumors and has been shown to modulate many gene expressions by inhibiting histone deacetylation and DNA methylation as the major mechanism. Butyrate and other protein kinase C (PKC) activators have been reported to be able to activate virus enzymes. The present work investigates whether NaPB has an antiproliferative effect or modulatory effects on EBV-associated nasopharyngeal carcinoma (NPC) and whether EBV thymidine kinase gene can be activated to make cells susceptible to ganciclovir (GCV) therapy. NaPB treatment displayed a dose- and time-dependent antiproliferative effect on the NPC cell line CNE2. Cell cycle analysis revealed an inhibitory effect of NaPB on G1-S-phase progression. Shortly after NaPB treatment, we found that PKC activity was activated rapidly but also decreased rapidly. Down-regulation of PKC-alpha and translocation of PKC-alpha from the cytosol to membrane were seen by Western blot. The decrease in PKC activity by NaPB corresponds to an enhanced response to radiation on CEN2 cells. Moreover, NaPB up-regulated EBV thymidine kinase activity to render EBV-associated Daudi cells susceptible to killing by GCV. Based on the observations of NaPB as a PKC modulator, the combination of NaPB, GCV, and radiation may provide a potential novel approach for treatment of EBV-associated NPC.

Serum responses to the combination of Epstein-Barr virus antigens from both latent and acute phases in nasopharyngeal carcinoma: complementary test of EBNA-1 with EA-D.

Elevated serum IgA to antigens of EBV is associated with nasopharyngeal carcinoma (NPC). We have tested 620 NPC sera by ELISA for the presence of antibodies to EBV-encoded DNA binding protein, EBV-specific DNA polymerase, early antigen-diffused (EA-D), EBV nuclear antigen 1 (EBNA-1), EBV-specific thymidine kinase, and BamHI Z fragment EBV replication antigen. Sensitivity of these proteins was in the range of 51.5-79.5% for IgA and 69.4-82.8% for IgG. The complementary use of EBNA-1 with EA-D, however, could increase the sensitivity significantly to 98.1%. Western blot analysis further showed that the combination of EBNA-1 and EA-D is most useful for the detection of NPC. This is the first report of using double biomarkers including EBV gene products from both latent and active infections. The results of this study suggest that EBV in NPC may not be latent alone and that the method may be valuable for the early detection, early treatment, and better survival rate of patients with NPC. Because the application of recombinant EBV protein in ELISA is cost-effective and feasible for mass screening, the method may be of worth for further clinical investigation.

Preclinical evaluation of locoregional delivery of radiolabeled iododeoxyuridine and thymidylate synthase inhibitor in a hepatoma model.

UNLABELLED: We report improved incorporation of the radiolabeled-thymidine analog [125I/131I]5-iodo-2'-deoxyuridine ([125I/131I]IdUrd) into DNA by the addition of Thymitaq, a thymidylate synthase inhibitor, as a strategy of molecular radiotherapy for hepatoma treatment. METHODS: The synergistic effect of combination [125I]IdUrd and Thymitaq in clonogenic survival and DNA incorporation was shown on the human hepatoma cell line Hep3B. Radiobiodistribution of intrahepatic arterially injected [125I]IdUrd and Thymitaq was studied in a rat N1S1 hepatoma model. In vivo therapeutic effects of locoregional delivery of both drugs were evaluated in mouse subcutaneous hepatoma and ascitic hepatoma models. RESULTS: In a clonogenic assay, Thymitaq showed a synergistic effect with [125I]IdUrd but not cold IdUrd. Thymitaq had a dose-dependent modulation effect on DNA-[125I]IdUrd incorporation. The biodistribution study indicated a slower clearance rate of [125I]IdUdR in the hepatoma as well as an initially higher uptake of [125I]IdUrd into DNA when the [125I]IdUrd was combined with Thymitaq. In vivo studies showed a superior therapeutic effect of combination Thymitaq and [125I]IdUrd in both subcutaneous and ascites tumor models, but the combination of [131I]IdUrd and [125I]IdUrd may be more effective than Auger electron emitters alone for the treatment of subcutaneous tumor. CONCLUSION: The strategy of locoregional delivery of [125I/131I]IdUrd to a tumor site through an intrahepatic arterial, intratumoral, or intraperitoneal route in combination with Thymitaq is promising and may also have a favorable therapeutic index in vivo.

Menadione-induced DNA damage in a human tumor cell line.

The nature and extent of menadione (MD)-induced DNA damage were explored using the human breast cancer cell line MCF-7. Concentration-dependent single-strand (ss) and double-strand (ds) DNA breaks were detected in MD-treated MCF-7 cells using the alkaline- and neutral-elution techniques, respectively. The repair of ss and ds DNA breaks was extensive but not complete after a 6-hr incubation in drug-free medium. Evidence was found for the production of DNA interstrand cross-links in MCF-7 cells treated with the bifunctional alkylating agent, mitomycin C, but not for cells treated with MD. Exposure of MCF-7 cells to etoposide (VP-16), mitoxantrone and camptothecin resulted in the detection of significant amounts of protein-linked DNA breaks, whereas none were found in MD-treated cells. These results support the proposition that MD-induced DNA damage is not likely to be mediated via topoisomerases, nor do significant amounts of protein-linked DNA form in MD-treated cells. Thus, MD serves as a good model for examination of the role of the quinone moiety in DNA damage in relation to redox cycling. Future studies directed at elucidation of the biochemical determinants mediating formation of reactive oxygen species effecting the MD-induced DNA damage are necessary and underway.

The clinical features and prognostic factors of hepatocellular carcinoma patients with spinal metastasis.

OBJECTIVE: Hepatocellular carcinoma is the most common malignancy in Taiwan, and spinal metastasis is a serious complication in cancer patients. In this study, we aimed to delineate the clinical features, evaluate the radiotherapy response and analyse the prognostic features in hepatocellular carcinoma subjects with spinal metastasis. METHODS: From 1981 to 1997, 102 patients with spinal metastasis were enrolled, taken from the 5887 documented hepatocellular carcinoma patients treated at Taipei Veterans General Hospital. All the clinical and laboratory data were recorded, including: age; gender; liver biochemistry; tumour characteristics; Child-Pugh's score; performance status; number and location of vertebral metastasis; motor capacity; neurological symptoms and signs; response to radiotherapy of the spinal lesion; and survival. Prognostic factors in hepatocellular carcinoma patients with spinal metastasis were analysed using Cox's regression model. RESULTS: The most common symptoms in hepatocellular carcinoma patients with spinal metastasis were lower back pain (74.5%), thoracic numbness (52.9%) and lower limb weakness (51.0%). Of the 102 patients, 84 received palliative radiotherapy using 3000 cGy for spinal lesions. Of these 84 patients, 32.1% showed a complete response, 26.2% a partial response and 41.7% a non-response to the radiotherapy. Multivariate Cox's regression analysis revealed that responsive radiotherapy (complete response + partial response) and good performance status (score

Salvage surgery for recurrent nasopharyngeal carcinoma.

OBJECTIVE: To evaluate the efficacy of salvage surgery in the treatment of recurrent nasopharyngeal carcinoma (NPC) at the primary site. STUDY DESIGN: A retrospective investigation of the outcome of salvage surgery for 28 patients with recurrent NPC after definite radiation therapy. METHODS: The nasopharynx was approached anteroposteriorly by the transmaxillary approach (maxillary swing, maxillectomy) or inferior approach (midline mandibulotomy or median labiomandibular glossotomy), or laterally by modified facial translocation or transpterygoid approach; intentional ligation of the internal carotid artery was performed after establishment of extracranial-intracranial (EC-IC) bypass in one patient; postoperative irradiation was given to the patients with positive pathological margins. RESULTS: Nine patients lived without disease for 20 to 93 months (mean interval, 52 mo) after surgery; among them, eight patients had T1 tumors that were resected totally by surgery via anteroposterior approaches and the other patient had postoperative irradiation to control the disease. Seven patients had local recurrence 8 to 21 months after treatment. Four patients developed distant metastases, including one patient with a T2b tumor that was totally resected through modified facial translocation approach with ligation of internal carotid artery. Eight patients died of other causes; internal carotid artery blowout was the cause of death in four of these eight patients. CONCLUSIONS: In most cases of recurrence, T1 nasopharyngeal tumors can be resected totally by anteroposterior approaches; for T2 or larger tumors, postoperative irradiation is usually necessary. Otherwise, facial translocation offers a better chance to completely resect the tumors. Internal carotid artery is better ligated if patients have received greater than 70 Gy irradiation or if the artery must be exposed during the surgery. We suggest that EC-IC bypass be used to avoid the possible complications (or cerebral ischemic stroke) caused by ligation of internal carotid artery. The transmaxillary approach is favored in the management of nasopharyngeal tumor recurrence with nasal cavity extension, and midline mandibulotomy is more suitable for resection of posterior margin of nasopharyngeal tumor recurrence. Facial translocation offers the widest operative field and is the most versatile approach for radical resection of nasopharyngeal tumor recurrence, but the surgeon should be skilled in the management of the facial nerves to reduce morbidity.

Salvage surgery for recurrent nasopharyngeal carcinoma in anterior marginal miss after radiotherapy.

Nasopharyngeal carcinoma (NPC) is treated primarily by radiotherapy. Marginal miss after radiotherapy is a potential cause for treatment failure in NPC. Anterior marginal miss after irradiation results in recurrent tumors in the nasal cavity outside the nasopharynx. From 1991 to January 1997, 6 recurrent NPCs arising in the anterior marginal miss zone after radiotherapy were confirmed by pathologic and radiologic evaluation. One patient had infiltrating growth of the original NPC tumor into the anterior part of nasal septum, and the other 5 had microscopic extensions from the original NPC tumors into the nasal cavity that were beyond detection by endoscopy or CT scan. In some cases the tumors extended further to include the hard palate or the lacrimal sac. Medial maxillectomy and partial maxillectomy with or without resection of the hard palate were necessary to encompass the extent of the tumors. Surgical margins were free of cancer cells in 5 patients. No further treatment was given in these 5 patients. Another patient with tumor extending to the lacrimal sac received postoperative radiotherapy. Five of the 6 patients survived with no evidence of disease for 8 to 65 months. One patient had distant metastasis 14 months after surgery but was free from tumor at the primary site. Radical surgery can result in good and sustained local control for anterior marginal miss of NPC after radiotherapy.

Ceramide inhibits lipopolysaccharide-mediated nitric oxide synthase and cyclooxygenase-2 induction in macrophages: effects on protein kinases and transcription factors.

The goal of this study was to elucidate whether triggering the sphingomyelin pathway modulates LPS-initiated responses. For this purpose we investigated the effects of N-acetylsphingosine (C(2)-ceramide) on LPS-induced production of NO and PGE(2) in murine RAW 264.7 macrophages and explored the signaling pathways involved. We found that within a range of 10-50 microM, C(2)-ceramide inhibited LPS-elicited NO synthase and cyclooxygenase-2 induction accompanied by a reduction in NO and PGE(2) formation. By contrast, a structural analog of C(2)-ceramide that does not elicit functional activity, C(2)-dihydroceramide, did not affect the LPS response. The nuclear translocation and DNA binding study revealed that ceramide can inhibit LPS-induced NF-kappaB and AP-1 activation. The immunocomplex kinase assay indicated that IkappaB kinase activity stimulated by LPS was inhibited by ceramide, which concomitantly reduced the IkappaBalpha degradation caused by LPS within 1-6 h. In concert with the decreased cytosolic p65 protein level, LPS treatment resulted in rapid nuclear accumulation of NF-kappaB subunit p65 and its association with the cAMP-responsive element binding protein. Ceramide coaddition inhibited all the LPS responses. In addition, LPS-induced PKC and p38 mitogen-activated protein kinase activation were overcome by ceramide. In conclusion, we suggest that ceramide inhibition of LPS-mediated induction of inducible NO synthase and cyclooxygenase-2 is due to reduction of the activation of NF-kappaB and AP-1, which might result from ceramide's inhibition of LPS-stimulated IkappaB kinase, p38 mitogen-activated protein kinase, and protein kinase C.

Thymoma is associated with an increased risk of second malignancy.

BACKGROUND: An association between thymoma and second malignancy has been suggested but has not been validated. Whether the relation is due to treatment or to other thymoma-associated conditions is unclear. METHODS: The authors studied 192 consecutive patients with thymoma and compared the incidence of second malignancies with those of 206 patients who underwent thymectomy for nonthymomatous conditions and 1426 patients with nasopharyngeal carcinoma (NPC). Detailed clinicopathologic features of thymoma patients with second malignancies were described. RESULTS: Additional malignancies were detected in 15 of 192 patients (8%) during their clinical courses. The risk for those patients was significantly greater compared with the risk for patients with nonthymomatous conditions (adjusted odds ratio [OR], 3.81; 95% confidential intervals [95%CI], 1.05-13.81; P = 0.042) and patients with NPC (adjusted OR, 4.89; 95%CI, 2.26-10.53; P < 0.0001) after adjustment for age, gender, length of follow-up, myasthenia gravis, and radiation therapy. The occurrence of second malignancies did not correlate with histologic type or stage of thymoma, radiation therapy, or myasthenia gravis. CONCLUSIONS: Thymoma is associated with an increased risk of second malignancy. The association cannot be attributed to the effect of thymectomy or radiation therapy. Patients with thymoma, even if it is benign, should be followed regularly to facilitate the early detection of other malignancies.

Prolonged survival in a nasopharyngeal carcinoma patient with multiple metastases: a case report and review of the literature.

Nasopharyngeal carcinoma is a common cancer in South East Asia. In the early stages, radiotherapy alone may achieve sustained control, but once metastasis occurs, it becomes an incurable disease with limited survival time. We report a case of nasopharyngeal carcinoma, initial stage T4N0M0, diagnosed in 1985 in a patient aged 36 years who received 70 Gy radiotherapy to the head and neck region. In 1988, relapse occurred with multiple lung metastases. The patient received many chemotherapy regimens with a very good response, including near complete remission with the first treatment regimen of cisplatin, 5-fluorouracil and leucovorin for lung metastases, and with the fifth chemotherapy regimen of ifosfamide as a single agent. After ifosfamide treatment, there was residual fibrotic change in the lung and complete disappearance, lasting for almost a year, of the liver and bone lesions. The patient eventually died in July 1995 due to progressive disease. Prolonged survival after mainly thoracic metastasis is possible in patients with nasopharyngeal carcinoma, especially if the tumor is chemo-responsive.

Management for patients with advanced T4 epidermoid carcinoma of the esophagus.

Available data concerning the treatment of patients with advanced T4 esophageal carcinoma are limited. A consecutive series of 42 patients with advanced T4M0 epidermoid carcinoma of the esophagus were studied from June 1987 to July 1992. The aim of this study was to evaluate the efficacy of various therapeutic modalities, and further evaluate the therapeutic options. The various therapeutic modalities included the following: Group I, feeding jejunostomy or endoesophageal intubation, 6 patients; Group II, palliative subtotal esophagectomy only, 8 patients; Group III, bypass procedures without tumor resection, 9 patients; Group IV, nutritional support and then treatment with irradiation (n=8) or concurrent radio-chemotherapy (n=4), 12 patients; Group V, subtotal esophagectomy, followed by aggressive concurrent radiochemotherapy, 7 patients. The total prescribed irradiation dose was 60 Gy (10 Gy/5 fractions/week). A combination regimen of chemotherapy consisted of cisplatin, 5-fluorouracil, and leucovorin (PFL regimen). For the patients undergoing esophagectomy or bypass procedures (n=24), the rates of operative complication and mortality were 45.8% and 25%, respectively. Side effects of adjuvant therapy (n=24) consisted of main airway irritation (100%), mucositis or gastrointestinal symptoms (83.3%), hematologic toxicity (79.2%), esophagitis or gastric ulcer (62.5%), alopecia (37.5%), and pneumonia (20.8%). The mortality due to toxicity of adjuvant therapy was 21.1% (4/19 patients). The mean survival times for each of the different groups was 1.9+/-0.5 months for Group I, 4.8+/-1.6 months for Group II, 5.2+/-1.2 months for Group III, 7.3+/-2.0 months for Group IV, and 20.3+/-2.5 months for Group V, respectively. Compared with patients of Groups I--IV, the Group V patients had a significantly superior one-year survival rate (P<0.01). Our results demonstrated that esophagectomy followed by concurrent irradiation and PFL combination chemotherapy may provide a significant improvement in the quality of life and survival for appropriate patients with advanced T4M0 epidermoid carcinoma of the esophagus. Furthermore, more than one cycle of PFL regimen chemotherapy may result in a better prognosis. During the performance of such an aggressive treatment, the utmost care must be taken with the patient's nutrition and to prevent pulmonary complications.

A phase II study of outpatient chemotherapy with cisplatin, 5-fluorouracil, and leucovorin in nasopharyngeal carcinoma.

BACKGROUND: Systemic disease progression occurs in the majority of patients with locally advanced nasopharyngeal carcinoma (NPC). Although a variety of chemotherapeutic drugs have had tumoricidal activity, the roles of chemotherapy and optimal regimens must be further defined. Based on high response rates of Cisplatin, 5-Fluororacil and Leucovorin (PFL) in patients with advanced squamous cell cancers of the head and neck, we tested a new outpatient PFL chemotherapy program in patients with advanced NPC. METHODS: Patients with NPC and 1) previously untreated, locally advanced disease; 2) local regional recurrence (LR) after radiotherapy; or 3) metastatic disease were eligible for study. Cisplatin 20 mg/m2/d, 5-FU 800 mg/m2/d and Leucovorin 90 mg/m2/d were administered simultaneously by continuous 96-hour intravenous infusion every three weeks. Patients were evaluated for response, survival, and toxicity. RESULTS: Thirty-five patients were studied. The response rates of PFL therapy were 100% (15% complete response [CR], 85% partial response [PR]) in 20 patients with locally advanced or locally recurrent disease, and 80% (13.3% CR, 67.7% PR) in 15 patients with metastatic disease. The overall median survival was 20 months after therapy (range, 2-21). The median survival rate for previously untreated, locally advanced patients was not reached. The median survival rate for previously treated, local recurrence was 34 months and for metastatic patients was 14 months. Mucositis and leukopenia were the dose-limiting toxicities (20-23%, grade III) and occurred more frequently in patients previously irradiated. No treatment-related deaths occurred. CONCLUSIONS: Outpatient PFL chemotherapy is active, safe, and convenient for advanced stage nasopharyngeal carcinoma patients, and the overall toxicities are tolerable.

Concomitant chemoradiation treatment in the management of patients with extrahepatic biliary tract recurrence of gastric carcinoma.

BACKGROUND: The aim of this study was to determine the role of concomitant chemoradiation in the alleviation of obstructive jaundice in patients with extrahepatic biliary tract metastases from gastric carcinoma. METHODS: Thirteen patients with good performance status who had obstructive jaundice resulting from extrahepatic biliary metastases after gastrectomy for gastric carcinoma were treated with palliative intent. Treatment consisted of insertion of a percutaneous transhepatic choledochal drainage (PTCD) catheter followed by external radiation up to a total dose of 40-60 grays in combination with chemotherapy (cisplatin 20 mg/m(2)/day, 5-fluorouracil 600 mg/m(2)/day, and leucovorin 90 mg/m(2)/day for 96 hours during the first and fifth weeks) on an outpatient basis. RESULTS: The concomitant chemoradiation produced a good palliative effect in all 13 patients. Hyperbilirubinemia continued to improve after treatment, patients' clay-colored stool resolved within an average of 4 weeks (range, 2-6 weeks), and bilirubin levels returned to normal. The PTCD catheter could be removed after treatment was completed (the seventh week); the mean duration of PTCD placement was 2 months. The entire treatment course was performed on an outpatient basis; hospital admission was necessary only for PTCD insertion and chemotherapy. Ten patients died of their disease, with an average survival of 14.4 months (range, 4-31 months) from the time of PTCD insertion. Three patients are still alive at 16, 21, and 8 months. Biliary tract patency was maintained until death. No serious treatment-related complications occurred, and no endoprothesis or intraluminal brachytherapy was needed in this study. CONCLUSIONS: Satisfactory palliation can be achieved by concomitant chemoradiation for patients with obstructive jaundice resulting from extrahepatic biliary metastases from gastric carcinoma, providing an alternative treatment choice for these patients.

Elimination of dose limiting toxicities of cisplatin, 5-fluorouracil, and leucovorin using a weekly 24-hour infusion schedule for the treatment of patients with nasopharyngeal carcinoma.

BACKGROUND: Cisplatin, 5-flourouracil (5-FU), and leucovorin (PFL) chemotherapy has been reported to be effective in the treatment of cancers but severe mucositis or neutropenia are dose limiting toxicities. This Phase II study evaluated the anticancer effect and the toxicities of a new weekly 24-hour infusional PFL chemotherapy in patients with nasopharyngeal carcinoma (NPC). METHODS: Forty-two patients with stage IV NPC were studied. Cisplatin 25 mg/m2/d, 5-FU 2200 mg/m2/d, and leucovorin 120 mg/m2/d were adminstered weekly by 24-hour intravenous continuous infusion in an outpatient setting. Clinical response and toxicity were evaluated weekly. RESULTS: The complete response rate (CR) was 30% and the partial response (PR) rate 60% in the localized previously untreated group. The CR rate was 22.7% and PR rate 45.5% in local recurrent/metastatic group. The overall response rate was 79%. Eighty-one percent of patients who had no previous chemotherapy and 67% of patients who had previous chemotherapy responded to weekly PFL. There were no dose limiting toxicities. No patient had grade 3 or 4 mucositis or neutropenia. Thirty-two patients (76%) had no oral mucositis. Seven patients (17%) had grade 1 mucositis and 3 patients (7%) had grade 2 mucositis. CONCLUSIONS: Elimination of dose limiting toxicities is possible using a weekly 24-hour infusion schedule of PFL chemotherapy while retaining significant anticancer activity as demonstrated in these patients with advanced NPC. To discover whether this schedule is superior to cisplatin and 5-FU or other PFL chemotherapy regimens requires further investigation.