Isolation of Dlx and Emx gene cognates in an agnathan species, Lampetra japonica, and their expression patterns during embryonic and larval development: conserved and diversified regulatory patterns of homeobox genes in vertebrate head evolution.

Agnathan cognates of vertebrate homeobox genes, Emx and Dlx, were isolated from embryonic cDNA of a Japanese marine lamprey, Lampetra japonica. Analyses of amino acid sequences indicated that the Dlx cognate was closely related to the common ancestor of gnathostome Dlx1 and Dlx6 groups and termed LjDlx1/6. Southern blot analyses could not rule out the possibility that L. japonica possesses more than one paralog for both LjDlx1/6 and LjEmx, the lamprey cognate of Emx. Expression of LjDlx1/6 was regulated spatially as well as developmentally, and its transcripts were mainly found in the craniofacial and pharyngeal mesenchyme and in the forebrain. The expression pattern of LjEmx changed dramatically during embryogenesis; expression was seen initially in the entire neural tube and mesoderm, which were secondarily downregulated, and secondarily in cranial nerve ganglia and in the craniofacial mesenchyme. No specific expression of LjEmx was seen in the telencephalon. Comparisons of Dlx and Otx gene expression patterns suggested a shared neuromeric pattern of the vertebrate brain. Absence of Emx expression implied that the patterning of the lamprey telencephalon is not based on the tripartite plan that has been presumed in gnathostomes. Expression domains of LjDlx1/6 in the upper lip and of LjEmx in the craniofacial mesenchyme were peculiar features that have not been known in gnathostomes. Such differences in expression pattern may underlie distinct morphogenetic pathway of the mandibular arch between the agnathans and gnathostomes.

Stage III thymoma: pattern of failure after surgery and postoperative radiotherapy and its implication for future study.

PURPOSE: With the conventional approach of surgery and postoperative radiotherapy for patients with Masaoka Stage III thymoma, progress has been slow for an improvement in the long-term survival rate over the past 20 years. The objective of this study was to evaluate the pattern of failure and survival after surgery and postoperative radiotherapy in Stage III thymoma and search for a new direction for better therapy outcome. METHODS AND MATERIALS: Between 1975 and 1993, 111 patients with thymoma were treated at Massachusetts General Hospital. Of these, 32 patients were determined to have Masaoka Stage III thymoma. The initial treatment included surgery for clinically resectable disease in 25 patients and preoperative therapy for unresectable disease in 7 patients. Surgical procedure consisted of thymectomy plus resection of involved tissues. For postoperative radiotherapy (n = 23), radiation dose consisted of 45-50 Gy for close resection margins, 54 Gy for microscopically positive resection margins, and 60 Gy for grossly positive margins administered in 1.8 to 2.0 Gy of daily dose fractions, 5 fractions a week, over a period of 5 to 6.6 weeks. In preoperative radiotherapy, a dose of 40 Gy was administered in 2.0 Gy of daily dose fractions, 5 days a week. For patients with large tumor requiring more than 30% of total lung volume included in the target volume (n = 3), a preoperative radiation dose of 30 Gy was administered and an additional dose of 24-30 Gy was given to the tumor bed region after surgery for positive resection margins. RESULTS: Patients with Stage III thymoma accounted for 29% (32/111 patients) of all patients. The median age was 57 years with a range from 27 to 81 years; gender ratio was 10:22 for male to female. The median follow-up time was 6 years. Histologic subtypes included well-differentiated thymic carcinoma in 19 (59%), high-grade carcinoma in 6 (19%), organoid thymoma in 4 (13%), and cortical thymoma in 3 (9%) according to the Marino and Müller-Hermelink classification. The overall survival rates were 71% and 54% at 5 and 10 years, respectively. Ten of the 25 patients who were subjected to surgery as initial treatment were found to have incomplete resection by histopathologic evaluation. The 5- and 10-year survival rates were 86% and 69% for patients (n = 15) with clear resection margins as compared with 28% and 14% for those (n = 10) with incomplete resection margins even after postoperative therapy, p = 0.002. Survival rates at 5 and 10 years were 100% and 67% for those with unresectable disease treated with preoperative radiation (n = 6) and subsequent surgery (n = 3). Recurrence was noted in 12 of 32 patients and 11 of these died of recurrent thymoma. Recurrences at pleura and tumor bed accounted for 77% of all relapses, and all pleural recurrences were observed among the patients who were treated with surgery initially. CONCLUSION: Incomplete resection leads to poor results even with postoperative radiotherapy or chemoradiotherapy in Stage III thymoma. Pleural recurrence is also observed more often among patients treated with surgery first. These findings suggest that preoperative radiotherapy or chemoradiotherapy may result in an increase in survival by improving the rate of complete resection and reducing local and pleural recurrences.

Development of cephalic neural crest cells in embryos of Lampetra japonica, with special reference to the evolution of the jaw.

Neural crest cells contribute extensively to vertebrate head morphogenesis and their origin is an important question to address in understanding the evolution of the craniate head. The distribution pattern of cephalic crest cells was examined in embryos of one of the living agnathan vertebrates, Lampetra japonica. The initial appearance of putative crest cells was observed on the dorsal aspect of the neural rod at stage 20.5 and ventral expansion of these cells was first seen at the level of rostral somites. As in gnathostomes, cephalic crest cells migrate beneath the surface ectoderm and form three major cell populations, each being separated at the levels of rhombomeres (r) 3 and r5. The neural crest seems initially to be produced at all neuraxial levels except for the rostral-most area, and cephalic crest cells are secondarily excluded from levels r3 and r5. Such a pattern of crest cell distribution prefigures the morphology of the cranial nerve anlage. The second or middle crest cell population passes medial to the otocyst, implying that the otocyst does not serve as a barrier to separate the crest cell populations. The three cephalic crest cell populations fill the pharyngeal arch ventrally, covering the pharyngeal mesoderm laterally with the rostral-most population covering the premandibular region and mandibular arch. The third cell population is equivalent to the circumpharyngeal crest cells in the chick, and its influx into the pharyngeal region precedes the formation of postotic pharyngeal arches. Focal injection of DiI revealed the existence of an anteroposterior organization in the neural crest at the neurular stage, destined for each pharyngeal region. The crest cells derived from the posterior midbrain that express the LjOtxA gene, the Otx2 cognate, were shown to migrate into the mandibular arch, a pattern which is identical to gnathostome embryos. It was concluded that the head region of the lamprey embryo shares a common set of morphological characters with gnathostome embryos and that the morphological deviation of the mandibular arch between the gnathostomes and the lamprey is not based on the early embryonic patterning.

[Prognosis and organ preservation in oropharyngeal cancer treated with radiotherapy].

The records of 102 patients with squamous cell carcinoma of the oropharynx treated at National Sapporo Hospital with external and/or interstitial radiotherapy between 1978 and 1996 were reviewed to evaluate the treatment results, focusing on primary control and functional preservation. Ninety-five patients had been primarily treated with curative intent initially. Of these 95 patients, 4% were in stage I, 19% in stage II, 42% in stage III and 34% in stage IV. Twenty-one patients (22%) had been treated with multidisciplinary chemotherapy, and 19 patients (20%) had been boosted with brachytherapy mainly using Au-198 grains. The cause-specific survival rates at 5 and 10 years were 63% and 52%, respectively. The local control rates at 5 and 10 years were 70% and 51%, respectively. The most important factors affecting local control were the subsite of the primary tumor and N stage. Based on these findings, it is considered that radiotherapy combined with/without chemotherapy except for N3 and the posterior wall type is an effective method of achieving tumor control and preserving organ function, compared with other methods including surgical procedures.

[Clinical evaluation for radiotherapy of metastatic brain tumors in lung cancer: prognostic analyses relevant to QOL].

From 1986 through 1992, 144 patients with metastatic brain tumors of lung cancer were treated with X-ray irradiation to whole brain or a comparatively wide field of the brain. To identify the subset of patients indicated for boost therapy like a stereotactic radiotherapy, we have analyzed the treatment results concerning both survival and performance status (PS). Median survival time of the patients in good PS (0-2) was 6.7 months, which was significantly better than 2.3 months in poor PS (3-4). Complete tumor-resectability, age, steroid therapy and condition within two months after the beginning of brain irradiation, seemed to be important prognostic indicators correlated with PS by both univariate and multivariates analyses.

[Importance of timing for radiation therapy in limited-stage small cell lung cancer].

We defined one group of patients who underwent radiotherapy within 75 days from the beginning of treatment as the early RT group, whereas another group of patients who underwent radiotherapy at least 75 days after the beginning of treatment was defined as the late RT group. The response rate (CR + PR) of the early RT group was 92.1% while that of the late RT group was 72.3%. The response rate for radiation therapy thus was significantly better in the early RT group. The 2 and 5-year actuarial survival rates of the early RT group were 22.1% and 9.2%, while those of the late RT group were 19.1% and 8.5%. Then respective median survival times (MST) were 14 months and 13 months. There was no significant difference in survival rates between the two groups. As much as the quality of life is concerned, early RT group would show here better results.

Results of prophylactic adjuvant chemotherapy for early stage non-Hodgkin's lymphoma of the head and neck.

Results were reviewed in 46 patients who had stage I and II head and neck non-Hodgkin's lymphoma, and received five to six cycles of CVP chemotherapy after regional irradiation. Disease-free survival, pattern of relapse, and time of relapse were compared with those of 64 patients, who received regional irradiation alone. Adjuvant, post irradiation CVP significantly improved five-year survival in stage I (and IE) disease, 49.6% to 81.9% (p less than 0.05), but was less successful in patients with heavier tumor burden, such as stage II disease or advanced loco regional disease in Waldeyer's ring (48.3% to 63.7%; p greater than 0.10 in stage II patients). In addition, in those who relapsed, the time and pattern of relapse were not altered by adjuvant CVP chemotherapy. This easily tolerated, mild adjuvant chemotherapy, we conclude, failed to prove significant in preventing relapse, especially in patients with heavier tumor burden.

[Relapse of the stage I & II non-Hodgkin's lymphoma of the head and neck--factors relating to the chance of long-term survival].

A review has been made of 36 patients who, after initial treatment for early non-Hodgkin's lymphoma originating in the head or neck, incurred a relapse, and factors relating to their chances of long-term survival, i.e., greater than three years, have been sought. Informatively, the overall 1-year and 5-year survival after such a relapse has been 18% and 15% respectively. The factor most significantly related to long-term survival was the site of the lymphoma and the extent of the initial relapse. For those affected in the neck region alone, four out of five survived for more than 48 months after the relapse (p less than 0.0001). The pathological subtype of the initial lymphoma was the second most significant factor (p less than 0.02). Another factor drawing our attention was the history of the prophylactic adjuvant therapy. No patient survived for more than a year after relapse if they had a history of prophylactic adjuvant therapy (0/10), whereas five long-term survivors were patients with no history of such therapy (0.1 less than p less than 0.2).