Predictive factors of survival in patients treated with definitive chemoradiotherapy for squamous cell esophageal carcinoma

AIM: The aim of the study was to evaluate the predictive factors of survival in patients with locally advanced squamous cell esophageal carcinoma (LASCOC) treated with definitive chemoradiotherapy (CRT) regimen based on the 5FU/CDDP combination. METHODS: All patients with LASCOC treated with a definitive CRT using the 5FU/CDDP combination between 1994 and 2000 were retrospectively included. Clinical complete response (CCR) to CRT was assessed by esophageal endoscopy and CT-scan 2 mo after CRT completion. Prognostic factors of survival were assessed using univariate and multivariate analysis by the Cox regression model. RESULTS: A total of 116 patients were included in the study. A CCR to CRT was observed in 86/116 (74.1%). The median survival was 20 mo (range 2-114) and the 5-year survival was 9.4%. Median survival of responder patients to CRT was 25 mo (range 3-114) as compared to 9 mo (range 2-81) in non-responder patients (P < 0.001). In univariate analysis, survival was associated with CCR (P < 0.001), WHO performance status < 2 (P = 0.01), tumour length < 6 cm (P = 0.045) and weight loss < 10% was in limit of significance (P = 0.053). In multivariate analysis, survival was dependant to CCR (P < 0.0001), weight loss < 10% (P = 0.034) and WHO performance <2(P = 0.046). CONCLUSION: Our results suggest that survival in patients with LASCOC treated with definitive CRT was correlated to CCR, weight loss and WHO performance status.     

Lymph node dissection with cervical approach as a salvage surgery for locoregional failure after definitive chemoradiotherapy in a patient with recurrent esophageal carcinoma: report of a case

Salvage surgery is one important therapeutic option after locoregional failure of definitive chemoradiotherapy (dCRT) in patients with advanced or recurrent esophageal carcinoma. We have performed cervical lymph node dissection as a salvage surgery after chemoradiotherapy in a patient with recurrent esophageal carcinoma. A 54-year-old Japanese man was admitted to our hospital because of multiple lymph node metastases after endoscopic submucosal dissection (ESD) for early-stage esophageal carcinoma. The patient underwent a circumferential ESD of early-stage esophageal carcinoma in another hospital. The esophageal carcinoma, measuring 75 × 60 mm in size, was a superficial spreading type located in the middle portion of the thoracic esophagus. Histology of the resected specimen revealed a moderately to poorly differentiated squamous cell carcinoma, and the depth of invasion was limited within the mucosal layer associated with a small area being attached to the muscularis mucosae. Five months after ESD, lymph node metastases in the regions of right recurrent nerve and the left tracheobronchus were found, for which dCRT was performed. These metastatic lymph nodes disappeared in the chest CT scan images. Lymph node metastasis in the region of the right recurrent nerve then reappeared 8 months after the completion of CRT. Considering the solitary lymph node metastasis and surgical invasiveness, lymph node dissection using a cervical approach was selected as a salvage surgery. Cervical approach for the lymph node dissection in the region of right recurrent nerve may be one feasible option as a minimally invasive salvage surgery for patients with recurrent esophageal carcinoma after dCRT.     

Dose escalation study of docetaxel and nedaplatin in patients with relapsed or refractory squamous cell carcinoma of the esophagus pretreated using cisplatin, 5-fluorouracil, and radiation

Background Definitive chemoradiation with cisplatin (CDDP) and 5-fluorouracil (5FU) has been playing an important role in the treatment of esophageal cancer, but some patients are not curable or have recurrent lesions. However, few chemotherapeutic regimens are available for such patients. Docetaxel and nedaplatin are active for esophageal cancer. We conducted a dose-escalation study of docetaxel and nedaplatin as second line-chemotherapy after definitive chemoradiation in patients with relapsed or refractory squamous cell carcinoma of the esophagus after chemoradiation. Methods Nedaplatin was administered on day 1 and docetaxel was administered on days 1 and 15, every 4 weeks. Dose escalation was based on the dose-limiting toxicity (DLT) observed during the first cycle. Results Twelve patients were enrolled. At a docetaxel dose of 30 mg/m² and a nedaplatin dose of 80 mg/m², one grade 4 neutropenia occurred and caused one treatment break longer than 2 weeks, but there were few DLTs. At doses of 35 and 80 mg/m², respectively, two grade 4 neutropenias and one grade 2 thrombopenia occurred and caused three treatment breaks longer than 2 weeks. Therefore, the maximum tolerated dose was established at this dose level. Two grade 3 anorexias and one grade 3 nausea occurred, but other non-hematological toxicities were generally mild. Responses were seen in one-fourth of the 12 patients, including one complete remission. Conclusion The recommended doses of docetaxel and nedaplatin were 30 and 80 mg/m², respectively. This combination could be a potential second-line treatment for this target population.     

Patterning the neural crest derivatives during development of the vertebrate head: insights from avian studies

Studies carried out in the avian embryo and based on the construction of quail-chick chimeras have shown that most of the skull and all the facial and visceral skeleton are derived from the cephalic neural crest (NC). Contribution of the mesoderm is limited to its occipital and (partly) to its otic domains. NC cells (NCCs) participating in membrane bones and cartilages of the vertebrate head arise from the diencephalon (posterior half only), the mesencephalon and the rhombencephalon. They can be divided into an anterior domain (extending down to r2 included) in which genes of the Hox clusters are not expressed (Hox-negative skeletogenic NC) and a posterior domain including r4 to r8 in which Hox genes of the four first paraloguous groups are expressed. The NCCs that form the facial skeleton belong exclusively to the anterior Hox-negative domain and develop from the first branchial arch (BA1). This rostral domain of the crest is designated as FSNC for facial skeletogenic neural crest. Rhombomere 3 (r3) participates modestly to both BA1 and BA2. Forced expression of Hox genes (Hoxa2, Hoxa3 and Hoxb4) in the neural fold of the anterior domain inhibits facial skeleton development. Similarly, surgical excision of these anterior Hox-negative NCCs results in the absence of facial skeleton, showing that Hox-positive NCCs cannot replace the Hox-negative domain for facial skeletogenesis. We also show that excision of the FSNC results in dramatic down-regulation of Fgf8 expression in the head, namely in ventral forebrain and in BA1 ectoderm. We have further demonstrated that exogenous FGF8 applied to the presumptive BA1 territory at the 5-6-somite stage (5-6ss) restores to a large extent facial skeleton development. The source of the cells responsible for this regeneration was shown to be r3, which is at the limit between the Hox-positive and Hox-negative domain. NCCs that respond to FGF8 by survival and proliferation are in turn necessary for the expression/maintenance of Fgf8 expression in the ectoderm. These results strongly support the emerging picture according to which the processes underlying morphogenesis of the craniofacial skeleton are regulated by epithelial-mesenchymal bidirectional crosstalk.     

All-trans retinoic acid-induced ectopic limb and caudal structures: murine strain sensitivities and pathogenesis.

Treatment of pregnant mice at the egg cylinder stage with retinoic acid (RA) has caused ectopic hindlimbs in the offspring. Proposed causes of ectopic hindlimbs include homeotic transformation or multiple axis formation. Two mouse strains were determined to be divergent in susceptibility to this malformation (C57BL/6N, highly sensitive; SWV/Fnn, less sensitive). Ectopic limbs were hindlimbs (expressing Pitx1 and Tbx4 but not Tbx5), yet they also expressed the predominantly forelimb Hoxb8. Ectopic body axis formation was indicated by gene expression for ectopic primitive streaks, notochords, and nodes, as well as inhibition of anterior visceral endoderm and mesodermal migration. The earlier in development that embryos were examined, the higher the rate of ectopic hindlimb development and axis formation. Ectopic axis formation and cell migration inhibition had the same strain susceptibility as the dysmorphogenesis. We propose that all extra hindlimbs were derived from ectopic axis formation, perturbation of which is genetic background dependent.     

Contribution of foregut endoderm to tooth initiation of mandibular incisor in rat embryos

Classical transplantation experiments with various amphibian tissues have shown that tooth development requires not only oral ectoderm and neural crest but also foregut endoderm. In addition, histological observation of oral membrane showed that the tooth germs are initiated in some ectodermal cells and neural crest cells adjacent to foregut endoderm. These studies suggest that tooth initiation requires the presence and cooperation of these three components. In mammals, however, there is no direct evidence that tooth formation is involved in the region of oral ectoderm adjacent to foregut endoderm. In order to elucidate the contribution of foregut endoderm to tooth formation, we established a new type of endodermal cell tracing system with a recombinant adenovirus called Adex-lacZ, and performed endodermal cell tracing in a long-term culture system. Cells labelled with Adex-lacZ were seen next to non-labelled thickening epithelium, presumptive incisor epithelium. These findings show the first direct evidence in mammals that tooth formation takes place in the specified part of oral ectoderm adjacent to foregut endoderm, suggesting that foregut endoderm plays a role in tooth initiation.