Phase II study of twice-daily high-dose thoracic radiotherapy alternating with cisplatin and vindesine for unresectable stage III non-small-cell lung cancer: Japan Clinical Oncology Group Study 9306.

PURPOSE: To evaluate the efficacy and toxicity of high-dose thoracic radiotherapy (TRT) alternating with chemotherapy (CH) for unresectable stage III non--small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Forty-one patients received TRT with 1.5 Gy twice daily, 5 days a week, on weeks 1, 2, 5, 6, and 9, up to a total dose of 66 to 72 Gy, alternating with cisplatin 80 mg/m(2) on day 1 and vindesine 3 mg/m(2) on days 1 and 8, repeated every 4 weeks, for two or three courses beginning on week 3. RESULTS: The median (range) total dose of TRT and number of CH courses were 72 Gy (16.5 to 72 Gy) and three (zero to three), respectively. Delay in TRT > or = 5 days was observed in 24 (75%) of 32 patients who completed the projected treatment, due to leukopenia in 12, esophagitis in seven, infection in two, and other causes in three patients. Partial responses were obtained in 36 patients (88%). The median survival time and 3- and 5-year survival rates were 18.4 months, 24%, and 10%, respectively. Grade 3 or 4 leukopenia and esophagitis developed in 32 and seven patients, respectively. Grade 3 or 4 late esophageal toxicity developed in two patients. CONCLUSION: Alternating high-dose TRT and CH for stage III NSCLC produced a high response rate with median and long-term survival comparable to prior trials utilizing standard approaches in this population. Acute and late esophageal toxicity was observed and interruption of TRT was required in most of the patients.     

Immunohistochemical assessment of localization and frequency of micrometastases in lymph nodes of colorectal cancer.

PURPOSE: Micrometastases are often found in regional lymph nodes of colorectal cancer (CRC). The aim of this study is to examine the extent and distribution of such lymph nodes. EXPERIMENTAL DESIGN: We immunohistochemically assessed localization and frequency of micrometastases in 878 lymph nodes from 98 patients with CRC. The anatomical position of lymph nodes was defined as level 1 to level 3 according to distance from the main tumor. RESULTS: The frequency of micrometastasis increased through observation of the 4-microm-thick lymph node sections, from one to two to five slices. With five slices, micrometastasis was frequently and extensively present in 49.1, 35.7, and 53.3% patients of histologically node-negative patients, node-positive patients at level 1, and node-positive patients at level 2, respectively. We then assessed the value of the presence of micrometastasis in node-negative patients with regard to prognosis, but no significant impact was obtained. To examine the reproducibility of the results obtained with immunohistochemistry, serial sectioning (four consecutive slices at seven different levels) of lymph nodes was additionally performed in lymph nodes initially diagnosed as micrometastasis positive. Immunohistochemical detection revealed that the sectioning level highly affected the results. CONCLUSIONS: Our results indicated frequent presence of micrometastasis in lymph nodes of CRC and that micrometastasis in node-negative CRC patients did not help in predicting the outcome, in part because of the limited reproducibility with immunohistochemistry.     

Close Association between Fas Ligand (FasL; CD95L)-positive Tumor-associated Macrophages and Apoptotic Cancer Cells along Invasive Margin of Colorectal Carcinoma: A Proposal on Tumor-Host Interactions

Anti-tumor immune responses are considered to be one of the key host reactions in human colorectal cancer, with T cells as important effector cells. For the induction of tumor-specific immunity, processing of cancer cells and pruning of T cells by antigen-presenting cells are important. The present study was designed to clarify the relationship between Fas ligand (FasL; CD95L) expression and apoptotic cancer cells. Immunohistochemistry using frozen sections taken from 58 patients with colorectal cancer revealed that stromal cells composed mainly of tumor-associated macrophages expressed FasL, leaving cancer cells negative for FasL. These macrophages were abundantly distributed along the invasive margin. In situ hybridization revealed that these macrophages as well as cancer cells expressed FasL mRNA, whereas macrophages in the normal colon mucosa rarely expressed FasL. Apoptotic cancer cells recognized by monoclonal antibody M30 CytoDEATH were localized not only in cancer cell nests, but also in the stroma along the invasive margin showing a dissociated pattern, which was particularly evident in the areas of FasL⁺ macrophages. Furthermore, these macrophages, phenotypically similar to dendritic cells, occasionally contained M30⁺ apoptotic cancer cells in the cytoplasm. Clinicopathologic analyses in 123 cases revealed 1) a positive correlation between the degree of dissociated M30⁺ apoptotic cancer cells and the number of macrophages along the invasive margin and 2) an inverse association between the degree of dissociated M30⁺ apoptotic cancer cells and the occurrence of hematogenous metastasis after surgical resection of the primary tumor. In conclusion, the present study shows the impor- tance of FasL⁺ activated macrophages as one of the host defense mechanisms against cancer cell spread in human colorectal cancer.     

Establishment and application of criteria for the elective transfer of two good-quality embryos to reduce high-order multiple pregnancies

Aim  This study was carried out to establish criteria for the elective transfer of two good-quality embryos to reduce high-order multiple pregnancy rates. The pregnancy and multiple pregnancy rates per transfer were retrospectively analyzed in 128in vitro fertilization and embryo transfer (IVF-ET) cycles. Results  The analysis revealed that the pregnancy and multiple pregnancy rates were 26.6% (34 of 128) and 23.5% (eight of 34), respectively. Five twin and three triplet pregnancies were included. The pregnancy rates in women 29 years old and younger, 30–34 years, 35–39 years, and 40 years and older were 21.2 (seven of 33), 37.0 (17 of 46), 25.8 (eight of 31), and 11.1% (two of 18), respectively. There was a significant difference of the pregnancy rates between 30 and 34-year-old and 40-year-old and older women (P < 0.05). The multiple-pregnancy rate in women 40 years and older was 0%. Three triplet pregnancies were established only in the first attempt of IVF-ET. The pregnancy rates in women, to whom good-quality embryos (0–4) were transferred, were 0% (none of 12) for 0, 17.2% (five of 29) for one, 41.2% (seven of 17) for two, 30.8% (12 of 39) for three, and 32.3% (10 of 31) for four and more embryos, respectively. The multiple pregnancy rates in women who had good-quality embryos of one, two, three, and four and more transferred were 0% (none of five), 23.5% (four of seven), 16.7% (two of 12), and 20.0% (two of 10), respectively. Conclusion  The criteria for the elective transfer of two good-quality embryos were established as follows: age < 40 years, a first treatment cycle, and more than three good-quality embryos available for transfer. After the application of the established criteria, the overall pregnancy and multiple pregnancy rates were 30.4% (14 of 46) and 14.3% (two of 14), respectively, which was satisfactory as compared with those in the 128 IVF-ET cycles before application of the criteria. An elective transfer of two good-quality embryos can be highly recommended to avoid high-order multiple pregnancies in subjects with the established criteria.     

Annual report of perioperative mortality and morbidity for the year 1999 with a special reference to anesthetic methods at Certificated Training Hospitals of Japanese Society of Anesthesiologists

The Committee on Operating Room Safety of Japanese Society of Anesthesiologists (JSA) sends annually confidential questionnaires of perioperative mortality and morbidity to Certificated Training Hospitals of JSA. This report is on perioperative mortality and morbidity in 1999 with a special reference to anesthetic methods. Four hundred and sixty-seven hospitals reported the number of cases referred to anesthetic methods and total numbers of cases were 727,723. The incidences of cardiac arrest per 10,000 cases due to all etiology are estimated to be 6.77 cases in average, 5.33 cases in inhalation anesthesia, 34.26 cases in total intravenous anesthesia (TIVA), 5.26 cases in inhalation anesthesia plus epidural or spinal or conduction block, 5.29 cases in TIVA plus epidural or spinal or conduction block, 0.73 cases in spinal with continuous epidural block (CSEA), 2.85 cases in epidural anesthesia, 1.63 cases in spinal anesthesia, 2.53 cases in conduction block and 46.51 cases in other methods. However, the incidences of cardiac arrest per 10,000 cases totally attributable to anesthesia are estimated to be 0.78 case in average, 0.51 case in inhalation anesthesia, 1.35 cases in TIVA, 0.97 case in inhalation anesthesia plus epidural or spinal or conduction block, 1.51 cases in TIVA plus epidural or spinal or conduction block, 0.73 case in CSEA, 1.71 cases in epidural anesthesia, 0.54 case in spinal anesthesia, 2.52 cases in conduction block and 1.08 cases in other methods. The incidences of severe hypotension per 10,000 cases due to all etiology are estimated to be 16.64 cases in average, 13.61 cases in inhalation anesthesia, 100.36 cases in TIVA, 13.32 cases in inhalation anesthesia plus epidural or spinal or conduction block, 9.07 cases in TIVA plus epidural or spinal or conduction block, 3.65 cases in CSEA, 6.26 cases in epidural anesthesia, 7.31 cases in spinal anesthesia, 2.52 cases in conduction block and 28.12 cases in other methods. On the other hand, the incidences of cardiac arrest per 10,000 cases totally attributable to anesthesia are estimated to be 2.40 cases in average, 1.65 cases in inhalation anesthesia, 0.81 cases in TIVA, 3.92 cases in inhalation anesthesia plus epidural or spinal or conduction block, 2.77 cases in TIVA plus epidural or spinal or conduction block, 2.56 cases in CSEA, 3.42 cases in epidural anesthesia, 2.71 cases in spinal anesthesia, zero case in conduction block and zero case in other methods. The incidences of severe hypoxia per 10,000 cases due to all etiology are estimated to be 5.32 cases in average, 6.7 cases in inhalation anesthesia, 9.17 cases in TIVA, 5.16 cases in inhalation anesthesia plus epidural or spinal or conduction block, 4.53 cases in TIVA plus epidural or spinal or conduction block, 2.56 cases in CSEA, zero case in epidural anesthesia, 1.08 cases in spinal anesthesia, zero case in conduction block and 1.08 cases in other methods. On the other hand, the incidences of severe hypoxia per 10,000 cases totally attributable to anesthesia are estimated to be 2.39 cases in average, 3.22 cases in inhalation anesthesia, 2.43 cases in TIVA, 2.26 cases in inhalation anesthesia plus epidural or spinal or conduction block, 2.77 cases in TIVA plus epidural or spinal or conduction block, zero case in CSEA, zero case in epidural anesthesia, 0.54 cases in spinal anesthesia, zero case in conduction block and 1.08 cases in other methods. The mortality rates of cardiac arrest per 10,000 cases due to all etiology are estimated to be 3.56 cases in average, 2.82 cases in inhalation anesthesia, 24.55 cases in TIVA, 1.4 cases in inhalation anesthesia plus epidural or spinal or conduction block, 1.51 cases in TIVA plus epidural or spinal or conduction block, zero cases in CSEA, 0.57 cases in epidural anesthesia, 0.27 cases in spinal anesthesia, zero case in conduction block and 42.18 cases in other methods. On the other hand, the mortality rates of cardiac arrest per 10,000 cases totally attributable to anesthesia are estimated to be 0.08 case in average, 0.09 case in inhalation anesthesia, 0.27 case in TIVA, 0.05 case in inhalation anesthesia plus epidural or spinal or conduction block, zero case in TIVA plus epidural or spinal or conduction block, zero case in CSEA, 0.57 case in epidural anesthesia, zero case in spinal anesthesia, conduction block and other methods. The outcomes of cardiac arrest totally attributable to anesthesia are 70.2% of full recovery without any sequelae, 10.5% of death within 7 days, 1.8% of vegetative state and 17.5% of unknown results while the outcome of critical events including severe hypotension and severe hypoxia totally attributable to anesthesia is 94.9% of full recovery without any sequelae, 0.4% of death within 7 days, 0.2% of vegetative state and 4.5% of unknown results. These results indicate that there are no differences in mortality and morbidity totally attributable to anesthesia among anesthetic methods in 1999 at Certificated Training Hospitals of Japan Society of Anesthesiologists.     

Surgery did not improve the subjective neuropsychological symptoms of patients with incidentally detected mild primary hyperparathyroidism

Primary hyperparathyroidism (PHPT) is known to cause diverse subjective symptoms, in addition to those related to osteitis fibrosa cystica and kidney stones. The treatment of the disease ameliorates the subjective symptoms and improves the patients’ quality of life. In this prospective study, patients undergoing surgery for incidentally detected, mild, asymptomatic PHPT were assessed to determine whether subjective neuropsychological symptoms are improved even in patients with “asymptomatic” PHPT. From October 1995 to March 2004, 25 patients who had one or more neuropsychological symptoms preoperatively and were followed up 1 year after parathyroidectomy were enrolled. The subjective symptoms were identified using questionnaires distributed to patients; eight questions were used to determine the presence or absence of psychoneurological symptoms. Compared to their preoperative status, patients responded that their general health perceptions 1 year after surgery were improved (13 cases, 52%), unchanged (11 cases, 44%), or aggravated (1 case, 4%). There were no statistically significant differences in the patients’ responses before and after surgery with respect to individual neuropsychological symptoms, such as “tiring easily, “forgetfulness,” “decreased concentration,” “depression,” “irritability,” “uneasiness,” and “sleeplessness.” Therefore, subjective neuropsychological symptoms did not improve in otherwise asymptomatic PHPT patients following parathyroidectomy. However, patients’ questionnaire responses may not reflect their actual status as accurately as laboratory examination results. Overall, 52% of patients were subjectively satisfied with surgery; this may result from patients’ expectations of treatment.     

Smoking trends before, during, and after pregnancy among women and their spouses

Background: Pregnancy and childbirth can act as strong factors motivating parents to spontaneously quit smoking. The aim of the present survey was to establish smoking cessation guidelines for this group. The objectives were to clarify the smoking status of parents before, during and after pregnancy, as well as the factors associated with continuous smoking during pregnancy and post-partum smoking relapse among women who had stopped smoking during pregnancy.
Methods: A cross-sectional survey with self-administered questionnaires was conducted for the parents of the 908 infants who participated in the official medical and dental examination for 18-month-old infants in Itabashi ward, Tokyo, Japan.
Results: The prevalence of smoking among women before, during pregnancy, and at post-partum 18 months at 95% confidence intervals was 29.3% (23.3–35.3%), 9.8% (3.0–16.6%), and 23.1 (16.8%–29.4%), and among their spouses it was 64.3% (60.0–68.6%), 58.1% (53.4–62.7%), and 58.2% (53.5–62.8%), respectively. The positive factors associated with smoking among pregnant women were marriage to a smoker, less education, under stress, and part-time employment rather than unemployment. The positive factors associated with smoking relapse after childbirth among women were breast-feeding <6 months and age under 30 years.
Conclusion: Compared with Western countries, the rate of smoking cessation during pregnancy was relatively high in Japan. It is necessary that smoking cessation intervention and support for men be initiated at the early stages of their spouses' pregnancies. These observations could influence the targeting and design of maternal smoking intervention.     

Quantitative analysis of estrogen receptor-alpha and -beta messenger RNA expression in breast carcinoma by real-time polymerase chain reaction

BACKGROUND: Estrogen action is mediated not only through a classic estrogen receptor (ER) (ER-alpha) but also through a second ER (ER-beta) that has a structure and function similar to ER-alpha. A correlation between ER-beta mRNA expression with ER and progesterone receptor (PR) protein levels as well as prognostic factors remains to be established in breast carcinoma. METHODS: The authors conducted a quantitative analysis of ER-alpha and ER-beta mRNA expression in 116 breast tumors using real-time polymerase chain reaction (PCR), and investigated a possible correlation between ER-alpha and ER-beta mRNA expression and ER and PR status as determined by enzyme immunoassay as well as with various prognostic factors. RESULTS: ER-alpha mRNA levels were significantly (P < 0.01) higher in ER positive compared with ER negative tumors. Conversely, ER-beta mRNA levels were significantly (P < 0.01) lower in ER positive compared with ER negative tumors. Accordingly, the ratio of ER-beta to ER-alpha was significantly (P < 0.01) higher in ER negative compared with ER positive tumors. A subset analysis based on ER and PR status showed that ER-beta mRNA levels as well as the ratios of ER-beta to ER-alpha mRNA level were highest in ER negative and PR negative tumors (P < 0.05). ER-alpha mRNA levels were significantly (P < 0.05) higher in postmenopausal compared with premenopausal tumors. Histologic Grade 3 tumors showed a significant decrease in ER-alpha mRNA levels compared with Grade 1 and 2 tumors (P < 0.01 and P < 0.05, respectively). No significant correlation between ER-alpha and ER-beta mRNA levels and histologic type, tumor size, or lymph node status was observed. CONCLUSIONS: An absolute and relative increase in ER-beta mRNA levels in ER negative and PR negative breast tumors, which rarely respond to endocrine therapy, suggests the possible involvement of up-regulation of ER-beta mRNA in the development of estrogen-independent tumors.     

Activation of the beta-catenin gene by interstitial deletions involving exon 3 as an early event in colorectal tumorigenesis

beta-Catenin has been identified as an oncogene in several tumors including colorectal cancers. beta-Catenin gene is activated by interstitial deletions involving exon 3 in colorectal carcinomas of Japanese population, in contrast to amino acid substitutions detected among Caucasian population. The aim of this study was to examine the type and frequency of beta-catenin gene mutation during early stages of colorectal tumorigenesis. We screened 100 colorectal adenomas for somatic mutations in the beta-catenin gene by single-strand conformation polymorphism method, as well as polymerase chain reaction amplification. In cases with mutations, sequencing analyses and immunohistochemical staining were also performed. Somatic interstitial deletions of 272-413 bp, each of which included all parts of exon 3, were detected in three tumors. However, no adenoma carried missense mutations. We confirmed accumulation of aberrant beta-catenin protein in cytoplasm and nuclei of adenoma cells by immunohistochemical analysis. Our results suggested that activation of the beta-catenin gene by interstitial deletions involving exon 3 might be less frequent compared with frequent alterations of adenomatous polyposis coli (APC) gene, but could be an early event in colorectal tumorigenesis equivalent to APC gene alterations in the Japanese population.