Relationship between Eustachian tube dysfunction and otitis media with effusion in radiotherapy patients.

OBJECTIVE: This study evaluated the relationship between radiation and Eustachian tube dysfunction, and examined the radiation dose required to induce otitis media with effusion. METHODS: The function of 36 Eustachian tubes in 18 patients with head and neck cancer were examined sonotubometrically before, during, and 1, 2 and 3 months after, intensity-modulated radiotherapy. Patients with an increase of 5 dB or less in sound pressure level (dB) during swallowing were categorised as being in the dysfunction group. Additionally, radiation dose distributions were assessed in all Eustachian tubes using three dose-volume histogram parameters. RESULTS: Twenty-two of 25 normally functioning Eustachian tubes before radiotherapy (88.0 per cent) shifted to the dysfunction group after therapy. All ears that developed otitis media with effusion belonged to the dysfunction group. The radiation dose threshold evaluation revealed that ears with otitis media with effusion received significantly higher doses to the Eustachian tubes. CONCLUSION: The results indicate a relationship between radiation dose and Eustachian tube dysfunction and otitis media with effusion.

Effects of neoadjuvant chemotherapy with or without zoledronic acid on pathological response: A meta-analysis of randomised trials.

PURPOSE: The addition of bisphosphonates to adjuvant therapy improves survival in postmenopausal breast cancer (BC) patients. We report a meta-analysis of four randomised trials of neoadjuvant chemotherapy (CT) +/- zoledronic acid (ZA) in stage II/III BC to investigate the potential for enhancing the pathological response. METHODS: Individual patient data from four prospective randomised clinical trials reporting the effect of the addition of ZA on the pathological response after neoadjuvant CT were pooled. Primary outcomes were pathological complete response in the breast (pCRb) and in the breast and lymph nodes (pCR). Trial-level and individual patient data meta-analyses were done. Predefined subgroup-analyses were performed for postmenopausal women and patients with triple-negative BC. RESULTS: pCRb and pCR data were available in 735 and 552 patients respectively. In the total study population ZA addition to neoadjuvant CT did not increase pCRb or pCR rates. However, in postmenopausal patients, the addition of ZA resulted in a significant, near doubling of the pCRb rate (10.8% for CT only versus 17.7% with CT+ZA; odds ratio [OR] 2.14, 95% confidence interval [CI] 1.01-4.55) and a non-significant benefit of the pCR rate (7.8% for CT only versus 14.6% with CT+ZA; OR 2.62, 95% CI 0.90-7.62). In patients with triple-negative BC a trend was observed favouring CT+ZA. CONCLUSION: This meta-analysis shows no impact from the addition of ZA to neoadjuvant CT on pCR. However, as has been seen in the adjuvant setting, the addition of ZA to neoadjuvant CT may augment the effects of CT in postmenopausal patients with BC.

Development and external validation of a nomogram for overall survival after curative resection in serosa-negative, locally advanced gastric cancer.

BACKGROUND: Few nomograms can predict overall survival (OS) after curative resection of advanced gastric cancer (AGC), and these nomograms were developed using data from only a few large centers over a long time period. The aim of this study was to develop and externally validate an elaborative nomogram that predicts 5-year OS after curative resection for serosa-negative, locally AGC using a large amount of data from multiple centers in Japan over a short time period (2001-2003). PATIENTS AND METHODS: Of 39 859 patients who underwent surgery for gastric cancer between 2001 and 2003 at multiple centers in Japan, we retrospectively analyzed 5196 patients with serosa-negative AGC who underwent Resection A according to the 13th Japanese Classification of Gastric Carcinoma. The data of 3085 patients who underwent surgery from 2001 to 2002 were used as a training set for the construction of a nomogram and Web software. The data of 2111 patients who underwent surgery in 2003 were used as an external validation set. RESULTS: Age at operation, gender, tumor size and location, macroscopic type, histological type, depth of invasion, number of positive and examined lymph nodes, and lymphovascular invasion, but not the extent of lymphadenectomy, were associated with OS. Discrimination of the developed nomogram was superior to that of the TNM classification (concordance indices of 0.68 versus 0.61; P < 0.001). Moreover, calibration was accurate. CONCLUSIONS: We have developed and externally validated an elaborative nomogram that predicts the 5-year OS of postoperative serosa-negative AGC. This nomogram would be helpful in the assessment of individual risks and in the consideration of additional therapy in clinical practice, and we have created freely available Web software to more easily and quickly predict OS and to draw a survival curve for these purposes.

Factors related to postoperative delirium in patients with lower limb ischaemia: a prospective cohort study.

OBJECTIVES: To preoperatively determine candidates at definitive risk of postoperative delirium (POD), we identified relevant factors in patients with arteriosclerosis obliterans who underwent bypass surgery. DESIGN: A prospective cohort study. PATIENTS AND METHODS: 299 patients (age ≥ 60 years) who underwent bypasses in 1995-2006 were enrolled. Cognitive impairment was assessed by the Revised Hasegawa Dementia Scale, the Confusion Assessment Method was also used, and severity was graded as Grade I-III (mild to severe) based on the Delirium Rating Scale. All patients were followed for 3 years. RESULTS: POD occurred in 88 patients (29%), with a median age of 75 (10) years (IQR). Onset was 2 (1) days postoperatively, and a duration of 2 (2) days was observed. POD was hyperactive in 89% and was Grade I, II, and III in 11%, 68%, and 21% respectively. Multiple logistic regression analysis identified the following risk factors for POD: age ≥ 72 years (<0.0001), end-stage renal failure (0.001), multiple occlusive lesions (<0.0001), cognitive impairment (0.003), and critical limb ischaemia (0.034). The 3-year survival rate was similar when comparing POD and non-POD patients (84% vs. 88%, NS). CONCLUSIONS: This study identified 5 risk factors for POD in patients undergoing bypasses for limb ischaemia. Long-term outcomes were similar when comparing the patients who experienced POD with those who did not.

Recurrence risk score based on the specific activity of CDK1 and CDK2 predicts response to neoadjuvant paclitaxel followed by 5-fluorouracil, epirubicin and cyclophosphamide in breast cancers.

BACKGROUND: We established the cell cycle profiling (C2P) assay for specific activity (SA; activity/expression) of cyclin-dependent kinases (CDKs). C2P risk score (C2P-RS) based on CDK1 and CDK2 SAs was significantly associated with relapse in breast cancer (BC). This study was conducted to investigate the predictive value of C2P-RS for neoadjuvant chemotherapy (NAC). PATIENTS AND METHODS: Among 124 eligible patients, 122 were treated with weekly paclitaxel followed by 5-fluorouracil, epirubicin and cyclophosphamide (P-FEC) and 2 were treated with paclitaxel monotherapy. C2P-RS was determined via C2P using frozen biopsy samples before NAC. RESULTS: Negative estrogen receptor (ER), negative progesterone receptor (PR), positive human epidermal growth factor receptor 2 (HER2), high Ki-67 expression and intermediate + high C2P-RS were significantly associated with high pathological complete response (pCR) rates compared with positive ER (30% versus 9%), positive PR (25% versus 6%), negative HER2 (34% versus 11%), low Ki-67 expression (24% versus 7%) or low C2P-RS (24% versus 9%), respectively. The combination of C2P-RS and Ki-67 had a stronger impact on pCR than each parameter alone, and a multivariate analysis showed that the combination was an independent predictor of pCR (odds ratio 3.3, 95% confidence interval 1.1-9.5). CONCLUSIONS: C2P-RS was significantly associated with pCR after P-FEC and may be a useful predictor for chemotherapy in BCs.

Phase II trial of preoperative chemotherapy for breast cancer: Japan Breast Cancer Research Network (JBCRN)-02 trial.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is one of the main strategies for patients with locally advanced breast cancer. In our previous study, biological markers such as estrogen receptor (ER), progesterone receptor (PgR), and HER2 were essential predictors of the effectiveness of NAC to help individualize treatment. This study examined the effect of NAC on the disease-free survival (DFS) of breast cancer patients. Furthermore, the study was expanded by adding Ki-67 as a biological marker, and examined the correlation between Ki-67 and the prognosis. PATIENTS AND METHODS: Between September 2005 and September 2007, 43 patients with breast cancer received NAC and surgery. Four cycles of DC (doxorubicin: 60 mg/m(2) and cyclophosphamide: 500 mg/m(2)) were administered intravenously (i.v.) on day 1 every 21 days, followed by 12 cycles of paclitaxel i.v. (80 mg/m(2)) every 7 days, prior to surgery. The primary endpoint was the pathological complete response (pCR) rate and the secondary endpoint was DFS; the pCR rate was estimated for each groups stratified by the presence or absence of different factors (PcR, ER/PgR, and Ki-67). RESULTS: The clinical response (cCR+cPR) rate was 81.0%, and the pCR rate was 25.6%. The pCR rate was 75, 50, 9 and 0% in HER2(+)/ER(-), HER2(+)/ER(+), HER2(-)/ER(-), and HER2(-)/ER(+) patients, respectively. The 4-year DFS rate was estimated at 78% for all patients. The HER2 status was an independent predictor of pathological complete response (pCR). The DFS rate of patients with lower Ki-67 values (<15%) was higher than that of patients with higher Ki-67 values (≥15%). The treatment-related adverse events were manageable: the majority were mild, but five patients experienced grade 3 (neutropenia and sensory neuropathy) adverse events. CONCLUSION: DC followed by weekly paclitaxel is an active and manageable preoperative regimen for breast cancer patients. HER2 overexpression may be a good predictive marker of pCR, and the Ki-67 value after NAC may be a prognostic factor for DFS.

Association of GSTP1 expression with resistance to docetaxel and paclitaxel in human breast cancers.

AIMS: It has been reported that glutathione S-transferase P1 (GSTP1) expression is implicated in resistance to taxanes (docetaxel and paclitaxel) in human breast cancer cells in vitro. In the study presented here, we examine whether GSTP1 expression is associated with resistance to docetaxel or paclitaxel in human breast cancers. We also investigated the relationship between GSTP1 methylation status and response to these taxanes. MATERIAL AND METHODS: Sixty two primary breast cancer patients were treated with docetaxel or paclitaxel as primary systemic treatment (PST). GSTP1 expression was detected immunohistochemically and the hypermethylation status GSTP1 gene was identified with a methylation specific primer assay. RESULTS: The mean tumor reduction rate for all patients (n=62) was significantly (p<0.001) higher in GSTP1 negative (0.73+/-0.04; mean+/-standard error) than GSTP1 positive (0.31+/-0.09) tumors. The subset analysis showed that the mean reduction rate was significantly (p=0.005) higher in GSTP1 negative (0.59+/-0.06) than GSTP1 positive (0.11+/-0.13) tumors in the docetaxel group as well as in the paclitaxel group (p=0.006; GSTP1 negative tumors: 0.84+/-0.05; GSTP1 positive tumors: 0.56+/-0.08). On the other hand, GSTP1 methylation showed no significant association with the reduction rate. CONCLUSION: Our present study has suggested that GSTP1 protein expression, but not GSTP1 methylation status, might be associated with response to docetaxel and paclitaxel. This suggests that GSTP1 immunohistochemical expression might be a potentially clinically useful predictive factor for response to docetaxel and paclitaxel.

Multitensor tractography enables better depiction of motor pathways: initial clinical experience using diffusion-weighted MR imaging with standard b-value.

BACKGROUND AND PURPOSE: The purpose of this work was to test the feasibility of using high angular resolution diffusion imaging (HARDI)-based multitensor tractography to depict motor pathways in patients with brain tumors. MATERIALS AND METHODS: Ten patients (6 males and 4 females) with a mean age of 52 years (range, 9-77 years) were scanned using a 1.5T clinical MR unit. Single-shot echo-planar imaging was used for diffusion-weighted imaging (repetition time, 6000 ms; excitation time, 88 ms) with a diffusion-sensitizing gradient in 32 orientations and a b-value of 1000 s/mm(2). Data postprocessing was performed using both the conventional single- and multitensor methods. The depiction rate of the 5 major components of the motor pathways, that is, the lower extremity, trunk, hand, face, and tongue, was assessed. RESULTS: Motor fibers on both lesional and contralesional sides were successfully depicted by both the single-tensor and multitensor techniques. However, with the single-tensor model, the depiction of motor pathways was typically limited to the fibers of trunk areas. With the multitensor technique, at least 4 of 5 major fiber bundles arising from the primary motor cortex could be identified. CONCLUSION: HARDI-based multitensor tractography using a standard b-value (1000 s/mm(2)) can depict the fiber tracts from the face and tongue regions of the primary motor cortex.

Number of positive lymph nodes independently affects long-term survival after resection in patients with ampullary carcinoma.

AIM: The nodal status is an established prognostic factor in ampullary carcinoma. The aim of this study was to compare the prognostic power of the anatomic location of positive nodes with that of the number of positive nodes. METHODS: Of 73 consecutive patients treated for ampullary carcinoma, 62 underwent pancreaticoduodenectomy with regional lymphadenectomy. A survival analysis of these 62 patients by nodal status was conducted retrospectively. A total of 1942 lymph nodes taken from the patients were examined histologically for metastasis. The location of positive regional nodes was classified into 4 categories, according to the Japanese staging system. The number of positive regional nodes was recorded for each patient. The median follow-up period was 124 months. RESULTS: Nodal disease was found in 31 patients, of whom 23 had 1-3 positive regional nodes and 8 had >or=4 positive regional nodes. Univariate analysis revealed that both the location (p<0.0001) and the number (p<0.0001) of positive nodes were significant prognostic factors. Multivariate analysis revealed that the number of positive nodes was an independent prognostic factor (p=0.007), while the location failed to remain as an independent variable. The median survival time was 59 months with a 5-year survival rate of 48% in patients with 1-3 positive nodes, whereas all patients with >or=4 positive nodes died of the disease within 29 months of resection (p=0.0001). CONCLUSION: The number, not the location, of positive regional lymph nodes independently affects long-term survival after resection in patients with ampullary carcinoma.

A modified method of activity-based costing for objectively reducing cost drivers in hospitals.

OBJECTIVES: Activity-based costing (ABC) is widely used to precisely allocate indirect costs to medical services. In the ABC method, the indirect cost is divided among the medical services in proportion to the volume of "cost drivers", for example, labor hours and the number of hours of surgery. However, the workload of data collection of cost drivers can be time-consuming and a considerable burden if there are many cost drivers. The authors aim to develop a method for objectively reducing the cost drivers used in the ABC method. METHODS: In the ABC method, the cost driver is assigned for each activity. We assume that these activities and cost drivers are the best combination. Our method, that is cost driver reduction (CDR), can objectively select surrogates of the cost drivers for each activity in ABC from candidate cost drivers. Concretely, the total indirect cost of an activity is temporarily allocated to the medical services using each candidate of cost drivers. The difference between the costs calculated by each candidate and the proper cost driver used in ABC is calculated to evaluate the similarity by the evaluation function. RESULTS: We estimated the cost of laboratory tests using our method and revealed that the number of cost drivers could be reduced from seven in the ABC to four. Similarly, the results of cost estimation obtained by our method were as accurate as those calculated using the ABC. CONCLUSIONS: Our method provides two advantages compared to the ABC method: 1) it provides results that are as accurate as those of the ABC method, and 2) it is simpler to perform complicated estimation of hospital costs.

MYCN gene amplification is a powerful prognostic factor even in infantile neuroblastoma detected by mass screening.

MYCN is the most powerful prognostic factor in cases of older children. However, how MYCN is related to the prognosis of infantile cases is not clear. A mass screening program was carried out by measuring urinary catecholamine metabolites (VMA and HVA) from 6-month-old infants. Of 2084 cases detected by the screening program, MYCN amplification (MNA) was examined by Southern blot analyses in 1533 cases from 1987 to 2000. Of the 1533 cases examined, 1500 (97.8%) showed no MNA, 20 cases (1.3%) showed MNA from three to nine copies, and 13 (0.8%) cases showed more than 10 copies. The 4-year overall survival rates of these three groups (99, 89 and 53%, respectively) were significantly different (P<0.001), indicating that MYCN copy number correlates with the prognosis. Cases with MNA more than 10 copies were more advanced than those without amplification (stage III, IV vs I, II, IVs; P<0.001). Patients with MNA more than 10 copies had significantly higher serum levels of neuron-specific-enolase (NSE) and ferritin than non-amplified patients (P=0.049, P=0.025, respectively). MYCN amplification was strongly correlated with a poor prognosis in infantile neuroblastoma cases. Therefore, for the selection of appropriate treatment, an accurate determination of MNA is indispensable.

Interleukin-6 (IL-6)--373 A9T11 allele is associated with reduced susceptibility to chronic periodontitis in Japanese subjects and decreased serum IL-6 level.

We investigated whether interleukin-6 (IL-6) gene polymorphisms could be associated with chronic periodontitis (CP) and serum IL-6 level. One hundred and twelve CP and 77 non-CP Japanese subjects were analyzed for IL-6 -597 (G/A), -572 (C/G), -373 (A(n)T(m)), -190 (C/T), and -174 (G/C) polymorphisms. We could only detect -572 and -373 polymorphisms and found that the frequency and carriage rate of the -373 A9T11 allele were significantly higher in non-CP subjects. Enzyme-linked immunosorbent assay confirmed that the -572 and -373 G[A9T11] haplotypes were associated with lower serum IL-6 level. These findings suggest that IL-6 -373 A9T11 allele could be associated with reduced susceptibility to CP among Japanese subjects and decreased serum IL-6 level.

Clinical significance of mucin phenotype, beta-catenin and matrix metalloproteinase 7 in early undifferentiated gastric carcinoma.

BACKGROUND: The aim of this study was to examine the clinical significance of mucin phenotypes of early undifferentiated gastric carcinoma, and to identify variables that might be used to select patients suitable for minimally invasive surgery. METHODS: A total of 129 patients with early undifferentiated gastric carcinoma were studied. The mucin phenotype was determined immunohistochemically using markers for M1, apomucin (MUC) 6 and MUC2. Tumours were classified into gastric (G), intestinal, gastrointestinal (GI) or unclassified type. Undifferentiated carcinomas were classified into signet-ring cell carcinoma (SIG) and non-SIG. The immunoreactivity of matrix metalloproteinase (MMP) 7 and beta-catenin was also investigated. RESULTS: GI-type tumours more commonly expressed non-SIG than SIG histology. The GI phenotype was associated with a higher incidence of submucosal invasion, lymphatic invasion, MMP-7 expression and nuclear accumulation of beta-catenin than the G type. Non-SIG histology, and the combination of GI type and nuclear accumulation of beta-catenin were independent predictors of submucosal invasion. The combination of GI type and MMP-7 expression independently predicted lymphatic invasion. MMP-7 expression correlated with lymph node metastasis. CONCLUSION: GI-type early undifferentiated carcinomas and those with non-SIG histology had increased potential for invasion and metastasis. GI type, MMP-7 expression and nuclear accumulation of beta-catenin might prove useful markers in the selection of patients for less invasive surgery.

Case report: delayed post-contrast fluid-attenuated inversion recovery image for depicting meningeal carcinomatosis.

We present a case of intracranial meningeal carcinomatosis that was visualized more clearly on a delayed contrast-enhanced fluid-attenuated inversion recovery (FLAIR) MRI than on other regular post-contrast MRI.

Association between RCAS1 expression and clinical outcome in uterine endometrial cancer.

RCAS1, which acts as a ligand for a putative receptor on immune cells such as peripheral lymphocytes and natural killer cells, is strongly expressed in human cancers. RCAS1 can induce these cells to undergo apoptotic cell death, which suggests that RCAS1 expression may prohibit the stromal reaction occurring in a tumour. To clarify the clinical significance of RCAS1 expression in uterine endometrial cancer, we analysed the association between RCAS1 expression and clinicopathologic variables by statistical methods. With the use of immunohistochemical techniques, we performed a retrospective study of RCAS1 expression in resected tumour tissue from 147 patients with uterine endometrial cancer. We evaluated the statistical correlation between RCAS1 expression and clinicopathologic variables. RCAS1 was expressed in 106 of 147 patients with uterine endometrial cancer; 30 of these 147 patients showed RCAS1 overexpression. Overexpression of RCAS1 was significantly correlated with age at surgery, stage, extent of myometrial invasion, and positive peritoneal cytologic results. Multivariate analysis revealed that RCAS1 expression and metastasis were clinically significant prognostic factors for the overall survival. These findings indicated that analysis for RCAS1 expression can provide crucial information about the clinical behaviour of uterine endometrial cancer, which may be valuable for the management of patients with this disease.

Loss of motility-related protein 1 (MRP1/CD9) and integrin alpha3 expression in endometrial cancers.

BACKGROUND: MRP1/CD9 and integrin alpha3 have played crucial roles in cell adhesion, motility, and signaling events. The loss of MRP1/CD9 and integrin alpha3 has been involved in tumor growth and metastasis of cancer cells. The aim of the current study was to clarify the clinical significance of MRP1/CD9 and integrin alpha3 in endometrial cancer. METHODS: The expression of MRP1/CD9 and integrin alpha3 from the same tissue sample were examined immunohistochemically in 15 patients with normal endometrium and in 56 patients with uterine endometrioid adenocarcinoma. Disease-free survival curves were estimated using the Kaplan-Meier method and analyzed by the log-rank test between the positive and reduced expression statuses of both MRP1/CD9 and integrin alpha3. These expressions and clinicopathologic variables were analyzed univariately and multivariately. RESULTS: In normal endometrium, MRP/CD9 was expressed at the cell membrane of cell contact sites, and the expression of integrin alpha3 was detected also at the cell membrane of cell contact sites and at borders of stromal tissues. In patients with endometrioid adenocarcinoma, 17 cases showed reduced expression of MRP1/CD9, and 20 cases had reduced expression of integrin alpha3. Fourteen cases indicated a reduced expression of both MRP1/CD9 and integrin alpha3. Each reduced expression of MRP1/CD9 or integrin alpha3 was significantly correlated with histologic grade and metastasis. Multivariate analysis using the Cox regression model disclosed that age at surgery, metastasis, and expression status of MRP1/CD9 were significant prognostic factors for disease-free survival. CONCLUSIONS: These findings suggested that the analysis for the expression statuses of MRP1/CD9 and integrin alpha3 may provide important information on the clinical behavior of endometrial cancer.

Different characteristics of carcinoma in the gastric remnant: histochemical and immunohistochemical studies.

Seventy cases of cancer of the gastric remnant were divided into three groups: 33 cases following surgery for benign disease (group A), and 15 cases occurring more than 10 years and 22 cases occurring within 10 years after the first gastrectomy for malignant disease (groups B and C, respectively). Then mucin histochemical and immunohistochemical studies were undertaken. Billroth-II procedure for anastomosis was most frequently performed in group A. Intestinal metaplasia within the mucosa surrounding the carcinomas was more frequently present in groups A and C with a diffuse distribution. Intestinal-type surrounding mucosa was significantly more frequent in group C. The immunohistochemical expression of p53 protein was most frequently expressed in group B. We conclude that a different mechanism of carcinogenesis exists in these three groups; i) group A: the reflux of duodenal juice especially following B-II procedures leads to progression of the carcinoma. ii) group B: some genetic factor such as p53 may be related to the metachronous multiple carcinogenesis. iii) group C: metachronous multiple carcinogenesis within the short interval may be closely associated with diffuse intestinal metaplasia in the surrounding mucosa.

High dose chemotherapy as adjuvant treatment in operable breast cancer with 10 or more involved axillary lymph nodes.

BACKGROUND: it is well known that breast cancer patients with more than 10 axillary lymph nodes involved have poor prognosis even with extensive adjuvant chemotherapy. To improve this poor outcome, high-dose adjuvant chemotherapy has been applied to the these patients. This study was intended to clarify the efficacy and usefulness of high dose adjuvant chemotherapy (HDC) for high-risk breast cancer patients and its efficacy was compared with conventional adjuvant chemotherapy (non-HDC group). PATIENTS AND METHODS: Twelve patients with breast cancer involving more than 10 axillary nodes received high-dose chemotherapy with peripheral progenitor-stem cell transplantation (PBSCT). This regimen consists of BCNU (carmustine) 130 mg/m(2) x 3, CBDCA (carboplantin) 500 mg/m(2) x 3 and CPA (chyclophosphamide) 50 mg/kgx 2 after induction chemotherapy with 3 cycles of CE (chyclophosphamide 600 mg/m(2), epirubicin 60 mg/m(2)). RESULTS: Twelve patients completed the high-dose chemotherapy regimen as planned, no patient died of chemotherapy related toxicity. After a median follow-up period of 44 months, disease-free and overall survival at 48 months after the operation for 12 patients determined by Kaplan-Meier methods was 63 % and 83 %, respectively. Disease-free survival was superior in the high-dose chemotherapy group compared with the control group but a statistical difference was not observed. CONCLUSION: High-dose chemotherapy seems to be an effective and feasible treatment for high-risk breast cancer patients. However, the usefulness of high-dose adjuvant chemotherapy for high-risk breast cancer patients should be confirmed by a large-scale randomized trial.

Time trends of surgical treatment and the prognosis for Japanese patients with gastric cancer.

The incidence of gastric cancer is much higher in Japan than in other countries even though diagnostics and treatments of such patients have improved. The objective of this study was to present an overview of the past, present and future of surgical treatment for our patients with gastric cancer. We analysed data on 2152 Japanese men and women with gastric cancer who underwent surgical resection from 1965 to 1995 at Kyushu University in Fukuoka, Japan, based on a univariate and the multivariate analysis. We focused on time trends of surgical treatment and the postoperative outcome. Over the years, there have been favourable changes in the numbers of patients with early gastric cancer. In all cases of gastric cancer, the rate of 18% in the first six year period (group 1) was 57% in the last 5 year period (group 6). Size of the tumour was smaller, well-differentiated tumour tissue was more common, and lymphatic involvement was less frequent. Lymph node metastasis, liver metastasis and peritoneal dissemination all decreased. Extensive lymph node dissection was more frequently done and the rate of curative resection (curability A and B) increased. With increases in identifying the early stage of cancer and better perioperative care, mortality rates 30 days after the surgery greatly decreased. Multivariate analysis revealed that the 10 factors of depth of invasion, lymph node metastasis, lymph node dissection, tumour size, liver metastasis, peritoneal dissemination, lymphatic invasion, vascular invasion, lesion in the whole stomach and lesion in the middle stomach were independent factors for determining the prognosis. Detection of the tumour in an early stage, standardized surgical treatment, including routine lymph node dissection, close follow-up schedules and better perioperative management are expected to increase survival time for patients with this malignancy.

The impact of covariate imbalance on the size of the logrank test in randomized clinical trials.

This paper examines the baseline imbalance incidental to stratified random sampling in clinical trials. We assume that patients are randomly sampled from a stratum-specific population and assigned to either treatment or control groups. Prognostic factors not used for the stratification cause within-stratum patient heterogeneity. The patient heterogeneity is investigated with an analysis of the prognostic index, or the log-relative-hazard. An index V, used to measure the degree of baseline imbalance between the groups, is defined using the prognostic index. The degree of baseline imbalance resulting from the stratified random sampling of a population of heterogeneous patients is examined. A method to estimate the exact size of the stratified logrank test is developed and applied to data obtained from a cancer clinical trial.