Preoperative induction of CPT-11 and cisplatin chemotherapy followed by chemoradiotherapy in patients with locoregional carcinoma of the esophagus or gastroesophageal junction

BACKGROUND: Patients with localized esophageal carcinoma often develop locoregional and distant disease recurrence. The current study investigated the outcome of a new chemotherapy combination as induction therapy before chemoradiotherapy. METHODS: Forty-three patients with resectable carcinoma of the esophagus or gastroesophageal junction were enrolled. Most of the tumors were endoscopic ultrasonography (EUS) (EUS)T3 (84%) and (EUS)N1 (63%). The patients received < or = 2 6-week cycles of CPT-11 and cisplatin followed by chemoradiotherapy (45 grays with 5-fluorouracil and paclitaxel). Five to six weeks after chemoradiotherapy, the patients underwent staging and surgery. The feasibility, curative resection rates, overall and disease-free survival rates, rate of significant pathologic response, and patterns of disease recurrence were assessed. RESULTS: Of the 43 patients, 39 (91%) underwent an R0 resection. Two patients (5%) died after surgery. A pathologic complete response (pathCR) was observed in 11 (28%) of the 39 patients (or 26% of the 43 patients). In addition, 16 patients (41% of 39 patients or 37% of 43 patients) had < 10% viable tumor in the surgical specimen (pathPR). A comparison of endoscopic ultrasonograpy T and N classifications with surgical T and N classifications demonstrated significant down-staging (P < 0.01). The median survival period of all 43 patients was 22.1 months. Patients who had achieved a pathCR or pathPR had a longer median survival (25.6 months) than those who achieved less than a pathPR (18.5 months; P = 0.52). None of the clinical parameters examined were found to correlate with survival or pathologic response. CONCLUSIONS: CPT-11-based induction chemotherapy resulted in substantial pathCR and pathPR rates, both of which lead to a favorable survival outcome. The three-step strategy needs to be developed further, with the investigation of targeted therapies with chemotherapy and radiotherapy.     

Cullin 3 promotes proteasomal degradation of the topoisomerase I-DNA covalent complex

DNA topoisomerase I (TOP1)-DNA covalent complexes are the initial lesions produced by antitumor camptothecins (CPTs). The TOP1-directed drugs stimulate degradation of TOP1 via the ubiquitin-proteasome pathway. We found that proteasome inhibition prevents degradation of DNA-bound TOP1 and sustains high levels of covalent complexes, thus enhancing CPT-induced cell death. Consistent with this, increased degradation of TOP1-DNA covalent complexes was seen in acquired CPT-resistant cells. We found that the resistant cells showed elevated expressions of Cul3, a member of the cullin family of E3 ubiquitin ligases. The reduction in Cul3 expression by small interfering RNA decreased degradation of TOP1-DNA covalent complexes. Conversely, Cul3 overexpression by stable transfection promoted covalent complex degradation and reduced CPT-induced cell death without affecting basal TOP1 expression levels. These results indicate that Cul3, by promoting proteasomal degradation of TOP1-DNA covalent complexes, becomes an important regulator for cellular CPT sensitivity.     

Evaluation of internal lung motion for respiratory-gated radiotherapy using MRI: Part II-margin reduction of internal target volume

PURPOSE: To analyze the relationship between lung motion and skin surface motion during respiration, determine the uncertainties and variability of such a relationship, and assess the potential of reducing internal target margin for gated radiotherapy. METHODS AND MATERIALS: Three healthy volunteers and four lung cancer patients were recruited in a prospective imaging study using MRI to track the internal lung and external skin motion during breathing. The relationship between the lung and skin motion was modeled using linear regression analysis. The slope of the linear fit and its confidence interval were analyzed for different lung locations, skin surface locations, and breathing patterns from separate imaging sessions. The margins of the internal target volume were calculated based on the residual lung motion during gating and its uncertainties from multiple treatment fractions for the gated treatment. RESULTS: The slope and confidence interval of the linear regression from the motion analysis were uniquely defined by the locations of the lung, skin surface, and breathing patterns. Statistically significant differences were observed among individuals and between different times of measurement. The normal free-breathing motion averaged from all volunteer and patient data was 13.4 +/- 7.4 mm along the superior-inferior (SI) direction and 6.9 +/- 2.6 mm along the anterior-posterior (AP) direction. With simulated respiratory gating, the average margin reduction was 5.5 +/- 4.8 mm and 1.6 +/- 1.0 mm, respectively, along the SI and AP directions (or 36% +/- 15% and 25% +/- 14%, respectively, relative to free-breathing motion). CONCLUSION: Because respiratory movement is rather complex, the relationship between the lung and skin surface motion is affected by many anatomic and physiologic factors. The reduction of internal target margin and efficacy of the free-breathing gating technique should be assessed for individual cases.     

Feasibility of sparing lung and other thoracic structures with intensity-modulated radiotherapy for non-small-cell lung cancer

PURPOSE: To investigate the possibility of using intensity-modulated radiotherapy (IMRT) to reduce the irradiated volumes of the normal lung and other critical structures in the treatment of non-small-cell lung cancer (NSCLC) and to investigate the effect of IMRT on the potential of spreading low doses to large volumes of normal tissues in such treatment. METHODS AND MATERIALS: A retrospective treatment planning study was performed to compare IMRT and conventional three-dimensional conformal radiation therapy (3D-CRT) for 10 NSCLC patients (Stage I-IIIB). In the IMRT plans, three to nine coplanar beams were designed to treat 95% of the planning target volume with 63 Gy and to minimize the volumes of the normal lung, esophagus, heart, and spinal cord irradiated above their tolerance doses. The two types of plans were compared with respect to the planning target volume coverage, dose-volume histograms, and other dosimetric indexes of the normal structures. RESULTS: Comparing the nine-beam IMRT plan with the 3D-CRT plan, the percentage of lung volume that received >20 Gy and the mean lung dose were reduced for all cases, with a median reduction of 8% and 2 Gy, respectively. An additional reduction of the >5-Gy volume and >10-Gy volume for the lung and thoracic tissue was more difficult with IMRT, although still possible using fewer beams in IMRT. The integral dose to the entire thorax was equivalent and even reduced for 8 of 10 cases using IMRT. CONCLUSION: It is possible to reduce the volumes of low doses (such as the >10-Gy volume and >20-Gy volume) for thoracic normal tissues using IMRT. The increased integral dose and low-dose volumes can be avoided for IMRT if such concerns are addressed carefully in the inverse planning process and with optimization of the IMRT beam configuration.     

Nationwide surveillance of parenteral antibiotics containing meropenem activities against clinically isolated strains in 2002

The antibacterial activity of meropenem (MEPM) and other parenteral antibiotics against clinical isolates of 899 strains of Gram-positive bacteria, 1500 strains of Gram-negative bacteria, and 158 strains of anaerobic bacteria obtained from 28 medical institutions during 2002 was measured. The results were as follows; 1. MEPM was more active than other carbapenem antibiotics against Gram-negative bacteria, especially against enterobacteriaceae and Haemophilus influenzae. MIC90 of MEPM against Pseudomonas aeruginosa was the lowest of the drugs tested. MEPM showed low cross-resistant rate against both imipenem-resistant P. aeruginosa and ciprofloxacin-resistant P. aeruginosa. MEPM was active against most of the species tested in Gram-positive and anaerobic bacteria, except for multi-drug resistant strains including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE). 2. The proportion of extended-spectrum beta-lactamase (ESBL) strains was 3.1% (4 strains) in Escherichia coli and 1.9% (2 strains) in Klebsiella pneumoniae. Carbapenems including MEPM were active against these ESBL strains. In conclusion, the results from this surveillance study suggest that MEPM retains its potent and broad antibacterial activity and therefore is a clinically useful carbapenem; at present, 7 years after available for commercial use.     

Tolnaftate spray treatment during pregnancy

Teratogenic studies of tolnaftate, an antifungal agent, in humans have not been published. The population-based data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996 contained 22843 fetuses or newborns with congenital abnormalities and 38151 matched controls without congenital abnormalities. The mothers of 13 cases and 13 controls were treated with tolnaftate spray during pregnancy. Four cases had congenital cardiovascular malformations in the group of cases (OR with 95% CI: 3.1, 1.0-9.7), but these cardiac defects were different. Thus, it is a signal for the potential teratogenic risk of tolnaftate in a case-control study, though the number of cases and controls were limited. Therefore, international collaboration is needed for the final conclusion.     

Epidermal growth factor receptor as a target to improve treatment of lung cancer

Despite considerable efforts to reduce tobacco use, lung cancer remains the most common cancer in both men and women. Recent advances in radiation therapy and chemotherapy for lung cancer have yielded encouraging results, but survival in patients with locally advanced non-small-cell lung cancer (NSCLC) remains poor. As more and more molecular changes and their importance in malignant tissues continue to be characterized, approaches to target those aberrant pathways are being actively explored. The epidermal growth factor receptor (EGFR) is commonly overexpressed in NSCLC, particularly squamous cell carcinoma, and has been implicated in the development and progression of this disease, although a clear correlation with prognosis has not been established. Several different strategies have been developed to target and block the EGFR and its downstream effects, and some of them have been intensively studied in preclinical and clinical studies as a single-agent approach or in combination with radiation therapy or chemotherapy. In this article, we review the role of EGFR in lung cancer, as well as preclinical and clinical data on strategies to interfere with EGFR signaling alone or in combination with chemotherapy, radiation, or both.     

Long-term outcome of phase II trial evaluating chemotherapy,chemoradiotherapy, and surgery for locoregionally advanced esophageal cancer

PURPOSE: To evaluate the long-term outcome of chemotherapy, chemoradiotherapy, and surgery for patients with locoregionally advanced esophageal cancer. METHODS AND MATERIALS: Thirty-eight patients with locoregionally advanced esophageal cancer were entered into a Phase II study between November 1996 and October 1998 at the University of Texas M. D. Anderson Cancer Center. Patients initially received two cycles of chemotherapy with paclitaxel (200 mg/m(2)), 5-fluorouracil (750 mg/m(2)/d for 5 days), and cisplatin (15 mg/m(2)/d for 5 days), followed by chemoradiotherapy, consisting of radiation (45 Gy during 5 weeks) with 5-fluorouracil (300 mg/m(2)/d during radiation) and cisplatin (15 mg/m(2)/d for 5 days). Surgical resection was performed 4-6 weeks after the completion of the chemoradiotherapy. RESULTS: Most patients had adenocarcinoma (n = 32; 84%). Pretreatment endoscopic ultrasonography revealed T3 tumors in 33 patients (87%) and N1 disease in 25 patients (66%). Thirty-seven patients (97%) completed the planned chemotherapy and chemoradiotherapy, and 35 patients (92%) underwent surgery, with a 30-day mortality rate of 6% (2 of 35 patients). A pathologic complete response or microscopic residual carcinoma (<10% viable) was found in 25 (71%) of 35 patients and was associated with a disease-free survival rate of 72% at 3 years and 51% at 5 years. On the basis of an intention-to-treat analysis and a median potential follow-up of 58 months, the 3- and 5-year overall survival rate for all 38 patients was 63% and 39%, respectively. CONCLUSION: The long-term results of this study suggest that the strategy of induction chemotherapy followed by chemoradiotherapy and surgery is safe and warrants further evaluation in the treatment of patients with locoregionally advanced esophageal cancer.