Independent Prognostic Factor In Stage Research Articles

Proliferating Cell Nuclear Antigen as a Prognostic Factor After Total Mesorectal Excision of Stage II–III Rectal Cancer

Proliferating cell nuclear antigen (PCNA) is an auxiliary protein of DNA polymerase delta that is tightly associated with sites of DNA replication; whether PCNA is a definite prognostic factor remains controversial. This study determined the clinicopathological factors associated with the long-term oncological outcome after radical resection of stage II-III rectal cancer, focusing on PCNA. We retrospectively reviewed 135 consecutive patients who underwent curative surgery for stage II-III rectal cancer between August 2001 and April 2004. Prognostic factors including immunohistochemical PCNA expression and the clinical outcome were evaluated. The PCNA index correlated with lymph node metastasis (P = 0.010). A multivariate analysis identified two independent factors that significantly affected both disease-free and overall survival: lymph node metastasis and PCNA index. With a median follow-up period of 60 months (range 8-87 months), both 5-year disease-free and overall survival of the low PCNA group were significantly higher than those of the high PCNA group (71.8% versus 32.0%, P < 0.001; 83.9% versus 50.0%, P < 0.001, respectively). For patients undergoing curative resection for rectal cancer, pathological N stage and high PCNA expression can provide valuable prognostic information about survival. This study suggests that the PCNA index may be used as an independent prognostic factor in stage II-III rectal cancer patients.

Prognostic factors of stage III endometrial carcinoma

To investigate the prognostic factors of surgery-pathological stage III endometrial cancer. The clinical data of 102 patients with stage III endometrial cancer, aged 54.9 (27-79), 71 with endometrioid adenocarcinoma, 31 with non-endometrioid adenocarcinoma, 9 undergoing simple surgical treatment, and 42 receiving radiation, 16 receiving chemotherapy, and 35 receiving chemoradiation after surgery, were analyzed retrospectively. Follow-up was conducted for 56 (3-192) months. Cox risk model analysis showed that the risk factors for the prognosis of stage III endometrial cancer were pathological types, method of treatment, vascular thrombosis, and age (all P < 0.05). The average survival time of stage III a endometrial cancer patients purely positive in peritoneal cytology was 74.4 months, significantly longer than that of the patients with serosa and/or annex involvement (53.8 months, P < 0.05). The independent prognostic factors of stage III endometrial cancer are pathological type, method of treatment, vascular thrombosis, and age. The patients with, the prognosis of stage III a endometrial cancer simply positive in peritoneal cytology is better than that with serous and/or annex involvement.

Impact of MDM2 SNP309 genotype on progression and survival of stage 4 neuroblastoma

Circumvention of the p53 checkpoint in neuroblastoma (NB) might arise from increased expression of its main negative regulator MDM2. The SNP309, a T-to-G substitution in the MDM2 promoter, was associated with higher levels of MDM2 mRNA and protein, with consequent attenuation of the p53 pathway. The association between MDM2 SNP309 and disease progression and survival was evaluated in a cohort of 142 children with stage 4 NB. The SNP309 GG patients had a worse overall survival and a worse survival after relapse than the TT ones, whereas the heterozygotes showed an intermediate behaviour ( p = 0.043 and p = 0.049, respectively, log-rank test for trend). No evident association between SNP309 and event free survival was found. The lack of association between SNP309 and MYCN status indicates that MDM2 SNP309 may be a new independent prognostic factor for stage 4 NB.

Growth patterns of osteosarcoma predict patient survival

In this retrospective study, we assessed tumor growth patterns as visualized on MR images, and examined whether tumor growth patterns correlate with clinicopathologic variables. In addition, we also evaluated the relationship between patient outcome and tumor growth pattern in the whole study cohort and in subsets of AJCC IIA and IIB patients. We retrospectively reviewed 347 patients with Enneking stage IIB and AJCC stage II osteosarcoma that was treated with surgery and neoadjuvant chemotherapy at our institute. Patients were divided into three groups based on tumor growth pattern, namely, concentric, eccentric, and longitudinal groups. Fisher's exact test was performed to analyze correlations between tumor growth patterns and clinicopathological variables. Five-year metastasis-free survival and overall survival were evaluated using univariate and multivariate analyses. In terms of tumor growth patterns, 225 patients (64.8%) had a concentric, 71 (20.5%) an eccentric and 51 (14.7%) a longitudinal tumor. Eccentric tumors were usually small and responded well to chemotherapy, whereas concentric tumors were large and responded poorly. The prognostic significances of tumor growth patterns were confirmed by univariate and multivariate analyses. Among AJCC stage IIA patients, no survival difference was found according to growth pattern, whereas in AJCC stage IIB patients, longitudinal tumors were associated with significantly better survival than concentric tumors. Tumor growth pattern was found to be an independent prognostic factor in stage II osteosarcoma. Moreover, longitudinally growing tumors were associated with better survival in AJCC stage IIB patients. Our results suggest that tumor growth pattern could be used as an indicator of risk-adapted therapy when combined with other prognostic factors.

Prognostic value of immunohistochemical stain pattern for carcinoembryonic antigen in patients with completely resected pathologic stage I lung adenocarcinoma

7553 Background: Surgery alone remains the standard therapy for patients with stage I NSCLC based on the recent results of randomized control trials. There is, however, a subgroup of patients with stage I disease who have a poor prognosis, for whom adjuvant chemotherapy can be as effective as that for patients with more advanced disease. Preoperative serum CEA level has been reported to be an independent prognostic factor for stage I NSCLC. Nevertheless, adjuvant therapy is not performed based on the serum CEA level, because it can be influenced by smoking or other lung conditions. Therefore, a more definitive indicator is considered necessary. We hypothesized that immunohistochemical (IHC) CEA expression would be a more reliable and effective prognostic marker than serum CEA levels. Methods: Between 1986 and 2000, 219 patients who underwent complete resection at our hospital were diagnosed as having stage I lung adenocarcinoma. Immunohistochemical staining with the antibody for CEA was carried out on paraffin embedded sections of those tumors using the avidin-biotin- peroxidase complex method. Preoperative serum CEA levels and other clinicopathologic factors were also investigated by univariate and multivariate analysis. Results: IHC CEA was positive in 186 patients (85%). The membrane pattern, in which only the cell membrane was stained, was observed in 92 patients; the cytoplasmic pattern (CP), in which cytoplasm was diffusely stained, was observed in 94 patients; and a negative stain pattern was shown in 33 patients. We combined the cell membrane pattern and negative stain pattern as the non- cytoplasmic pattern (NCP) on the basis of survival analysis. Survival analysis demonstrated that CEA IHC patterns and serum CEA levels as well as age and blood vessels invasion were significant prognostic factors on both univariate and multivariate analysis. The 5-year survival for patients with a high serum CEA level and CP was only 38%, compared to 79% for normal serum CEA levels and CP, 78% for high serum CEA levels and NCP, and 93% for normal serum CEA levels and NCP. Conclusions: Both CEA IHC patterns and serum CEA levels were independent prognostic factors for patients with pathologic stage I lung adenocarcinoma. No significant financial relationships to disclose.

Transection of vaginal cuff is an independent prognostic factor in stage I endometrial cancer

Aims The objective was to identify prognostic factors of disease-free and overall survival in stage I endometrial carcinoma, thereby potentially facilitating the selection of patients who are on high risk for recurrence and who may benefit from transection of a vaginal cuff. Methods In a retrospective review between 1994 and 2004, 340 patients with stage I endometrial carcinoma were managed surgically at two different hospitals in Rostock. The median follow-up was 79 (range 12–161) months. Clinical and histological parameters were compared using the SPSS software package. Results In the univariate analysis the factors associated with poor disease-free survival in stage I carcinoma were higher tumor grade ( P = 0.013), and no removed vaginal cuff ( P = 0.025). The corresponding factor for impaired overall survival was no removed vaginal cuff ( P = 0.003). All parameters with a P-value < 0.25 in the univariate setting were entered into a multivariate analysis. The factors that maintained associated with poor disease-free and overall survival were higher tumor grade and lack of vaginal cuff. Conclusions The removal of a vaginal cuff during abdominal hysterectomy was found to be an independent prognostic factor in stage I endometrial carcinomas. A prospective surgical trial is needed to validate our results before changing current clinical practice.

Use of a Cytokine Gene Expression Signature in Lung Adenocarcinoma and the Surrounding Tissue as a Prognostic Classifier

A 17-cytokine gene expression signature in noncancerous hepatic tissue from patients with metastatic hepatocellular carcinoma (HCC) was recently found to predict HCC metastasis and recurrence. We examined whether the cytokine gene expression profile of noncancerous lung tissue could predict the metastatic capability of adjacent lung adenocarcinoma. We analyzed a 15-cytokine gene expression profile in noncancerous lung tissue and corresponding lung tumor tissue from 80 US lung adenocarcinoma patients using real-time quantitative reverse transcription-polymerase chain reaction. We then used unsupervised hierarchical clustering and Prediction Analysis of Microarray classification to test the prognostic ability of the 15-cytokine gene profile in the US patients and in an independent validation set comprising 50 Japanese patients with stage I disease. Survival was analyzed by the Kaplan-Meier method using the log-rank test, and univariate and multivariable Cox proportional hazards modeling were used to analyze the association of clinical variables with patient survival. All statistical tests were two-sided. A 15-cytokine gene signature in noncancerous lung tissue primarily reflected the lymph node status of 80 lung adenocarcinoma patients, whereas the gene signature of the corresponding lung tumor tissue was associated with prognosis independent of lymph node status. Cytokine Lung Adenocarcinoma Survival Signature of 11 genes (CLASS-11), a refined 11-gene signature, accurately classified patients, including those with stage I disease, according to risk of death from adenocarcinoma. CLASS-11 prognostic classification was statistically significantly associated with survival and was an independent prognostic factor for stage I patients (hazard ratio for death in the high-risk CLASS-11 group compared with the low-risk CLASS-11 reference group = 7.46, 95% confidence interval = 2.14 to 26.05; P = .002). CLASS-11 also classified patients in the validation set according to risk of recurrence. CLASS-11, which consists of genes for pro- and anti-inflammatory cytokines, identifies stage I lung adenocarcinoma patients who have a poor prognosis.

Prognostic value of preoperative serum tumor markers, including CEA, Cyfra21–1, SCC, CA19–9, SCC, CA125, TPA, NSE, and SLX, in patients with completely resected pathological stage I non-small cell lung cancer

7681 Background: Recent randomized control trials have shown a survival benefit of adjuvant chemotherapy in patients with stage II or more advanced NSCLC, while surgery alone is still the standard therapy for stage I patients. There is, however, a subgroup of patients among the stage I patients who have a poor prognosis, for whom adjuvant chemotherapy can be as effective as has been observed for the patients with more advanced disease. Preoperative serum CEA level has been reported to be an independent prognostic factor for stage I NSCLC. However, many other tumor markers have also been reported as prognostic indicators in different studies using different tumor markers. It is unknown which tumor marker is the most effective for selecting poor prognostic subgroup of patients with stage I NSCLC for which adjuvant chemotherapy can be applied. Methods: A total of 355 patients underwent complete resection, and were diagnosed as having stage I NSCLC from 1995 to 2003. Analyzed tumor markers included CEA, Cyfra21–1, SCC, CA19–9, SCC, CA125, TPA, NSE, and SLX. Cut-off values for each tumor marker are listed in the table . Clinicopathologic factors including age, gender, histology, vessel invasion, pleural invasion, and pathologic T indicator are also analyzed in the multivariate analysis. Results: Among the 355 patients, 211 patients were male, 249 had adenocarcinoma, 82 had squamous cell carcinoma, and 253 had pathologic T1 tumors. Percentages of elevated value for each tumor marker are listed in the table in combination with related survival data. Cox proportional hazard model demonstrated age, pleural invasion, histology, and CEA were significantly independent prognostic factors. Conclusions: CEA is thought to be the best tumor marker for selecting the poor prognostic subgroup of patients with resected stage I NSCLC because of its high percentage of abnormal value and high ability to differentiate prognostic subgroups. No significant financial relationships to disclose. [Table: see text]

The number of analyzed lymph nodes – a prognostic factor in colorectal cancer

The prognostic significance of the number of lymph nodes examined in surgical specimen of colorectal cancer was determined. One thousand and twenty five patients with colorectal cancer stage II and III were included in the study. These patients underwent surgery from 1991 to 1997 and were enrolled in clinical trials to evaluate the efficacy of adjuvant 5-fluorouracil (5FU) based chemotherapy. The median number of examined lymph nodes was five. Only 13% of the patients had≥12 lymph nodes analyzed. The number of examined lymph nodes was an independent prognostic factor for overall survival in the entire group of patients with stage II and III colorectal cancer (p=0.009). Patients with a higher number of lymph nodes examined had a longer overall survival. In stage III colorectal cancer the ratio of the number of metastatic lymph nodes to the number of examined lymph nodes (lymph node ratio, LNR) was an independent prognostic factor for overall survival. A decreasing LNR was correlated with a longer overall survival (p<0.0001). Increasing age was associated with a reduction of lymph node harvest (p=0.04). Patients with rectal cancer treated with preoperative radiotherapy had a lower number of lymph nodes analyzed compared with non-radiated (p<0.001). The number of examined lymph nodes in the surgical specimen is an independent prognostic factor for overall survival in colorectal cancer. The LNR is an independent prognostic factor in stage III colorectal cancer.

Clear cell carcinoma of the ovary: a retrospective multicentre experience of 254 patients with complete surgical staging

A retrospective analysis was performed to evaluate the clinical characteristics and prognostic factors in the patients with clear cell carcinoma (CCC) of the ovary. After central pathological review and scanning of the medical records of nine Japanese institutions between 1992 and 2003, a total of 254 patients with CCC of the ovary were enrolled in the present study. Mean age was 52.4 years (range 23–73 years). Tumours were 13% (33/254) stage Ia, 36% (92/254) stage Ic, 13% (33/254) stage II, 30% (80/254) stage III, and 6% (16/254) stage IV. Five-year progression-free survival and overall survival was 84 and 88% in stage I, 57 and 70% in stage II, 25 and 33% in stage III and 0 and 0% in stage IV, respectively. Retroperitoneal lymph node metastasis was observed in 9% in pT1a tumours, 7% in pT1c tumours, 13% in pT2 tumours, and 58% in pT3 tumours, respectively. There was no survival benefit according to chemotherapeutic differences in the patients who received complete surgical staging procedures and conventional chemotherapy. Peritoneal cytological status was an independent prognostic factor in stage Ic patients (P=0.03) and only residual tumour diameter was an independent prognostic factor in stage III, IV patients (P=0.02). Our results suggest that cytoreductive surgery resulting in no residual tumour only could improve the prognosis of advanced CCC patients.

Smoking Status as a Prognostic Factor in Patients with Stage I Pulmonary Adenocarcinoma

Cigarette smoking is a well-known risk factor for lung carcinogenesis; however, its effect on tumor progression is still unclear. We herein investigated the influence of cigarette smoking on postoperative prognosis in patients with non-small cell lung cancer (NSCLC). The postoperative survival and pathologic stage of 999 patients with NSCLC who underwent a curative resection were retrospectively investigated in relation to the pack-year index (PYI). Adenocarcinoma patients with a PYI of less than 20 showed a more favorable prognosis than those with a PYI of 20 or more, whereas no difference was observed among the subgroups of squamous cell carcinoma patients. In adenocarcinoma, stage I disease was a significantly larger population in never-smokers than in smokers. A multivariate analysis revealed that the smoking habit (yes or no) and stage (IA or IB), but not gender or histologic subtype (bronchioloalveolar type or not), are independent prognostic factors in stage I adenocarcinoma with hazard ratios of 1.8 and 2.3, respectively. The smoking status is a significant prognostic factor for stage I pulmonary adenocarcinoma.

Prognostic Factors of Resected Stage IV Gastric Cancer Patients

Purpose: The prognosis of stage IV gastric cancer is poor with the 5-year survival rate still being about 10%. We investigated the prognostic factors of stage IV gastric cancer patients who underwent resection. Materials and Methods: A retrospective study of 383 patients with stage IV gastric cancer who underwent surgery in our department between September 1983 to December 2000 was conducted. We classified the 383 patients into two groups: patients surviving 2 years or more (n=77) and those surviving less than 2 years (n=306). Clinicopathologic differences were analyzed between the two groups. We also performed univariate and multivariate analyses of various clinicopathologic factors concerning survival. Results: Statistically significant clinicopathologic differences between the two groups were observed in regard to macroscopic type, distant metastasis, lymph node dissection, curability, and histology. Curability and histology were significant survival factors in 2-year survival. The 5-year survival rate was 5.4% in stage IV gastric cancer. Significant differences in survival among macroscopic type, distant metastasis, lymph node dissection, curability and histology were observed in the univariate analysis. In the Multivariate analysis, Curability, lymph node dissection, and histology were significantly beneficial factors for survival. Conclusion: Lymph node dissection, curability, and histology were independent prognostic factors in stage IV gastric cancer, and radical treatment is recommended to improve survival.

Outcome of patients with early ovarian cancer undergoing three courses of adjuvant chemotherapy following complete surgical staging

We conducted the present study to determine the outcome of patients with early ovarian cancer who underwent three courses of adjuvant chemotherapy after complete surgical staging. One hundred consecutive patients with stage I-II epithelial ovarian cancer who had undergone complete surgical staging and received three courses of platinum-based chemotherapy were entered in this study. Twenty-one patients were low risk, defined as stage IA-B, grade 1 and histologic types except for clear cell adenocarcinoma, and remaining 79 were high risk. All patients with stage IA or IB, whatever histologic type and histopathologic grade, were alive without disease. The 5-year survival rate was 89.4% for patients with stage IC and 76.2% for those with stage II. The 5-year survival rate for low- and high-risk patients was 100% and 89.4%, respectively. The survival rate for grade 1 was significantly better than that for grade 2 or 3. Multivariate analysis revealed that histologic grade was an independent prognostic factor in stage IC-II ovarian cancer. The outcome of patients with early ovarian cancer undergoing three courses of chemotherapy after complete surgical staging was favorable even in high-risk patients.

Role of Surgery in Ovarian Cancer: An Update

Rupture of an ovarian malignant tumor should be avoided at the time of surgery for an early ovarian cancer. Laparoscopic removal of ovarian cysts should be restricted to patients with preoperative evidence that the cyst is benign. Degree of differentiation is the most important independent prognostic factor in stage I disease and should be used in decisions on therapy in clinical practice and the future FIGO-classification of Stage I. In early ovarian cancer staging adequacy and tumor grade were the only 2 statistical significant prognostic factors for survival in the multivariate analysis of the EORTC ACTION-trial. According to the present data there is no scientific basis to rely only on adjuvant chemotherapy or on optimal staging procedure in medium and high risk stage I ovarian cancer. Primary debulking surgery by a gynecologic oncologist remains the standard of care in advanced ovarian cancer. Optimal debulking surgery should be defined as no residual tumor load. Interval debulking is defined as an operation performed after a short course of induction chemotherapy, usually 2 or 3 cycles. Based on the randomized EORTC-GCG trial, interval debulking by an experienced surgeon improves survival in some patients who did not undergo optimal primary debulking surgery. Based on the GOG 152 data, interval debulking surgery does not seem to be indicated in patients who underwent primarily a maximal surgical effort by a gynecological oncologist. Open laparoscopy is probably the most valuable tool for evaluating the operability primarily or at the time of interval debulking surgery. In retrospective analyses neoadjuvant chemotherapy followed by interval debulking surgery does not seem to worsen prognosis compared to primary debulking surgery followed by chemotherapy. However, we will have to wait for the results of the EORTC-GCG/NCI Canada randomized trial to know whether neoadjuvant chemotherapy followed by interval debulking surgery is as good as primary debulking surgery in some or all stage IIIc and IV patients. The most suitable candidates for secondary debulking surgery are those who had an initial complete response to chemotherapy, a long treatment-free interval (e.g. more than 12 months), and resectable disease (without diffuse carcinomatosis).

Controversies in surgery in ovarian cancer — what is its real role?

Rupture of an ovarian malignant tumour should be avoided at the time of surgery for an early ovarian cancer. Laparoscopic removal of ovarian cysts should be restricted to patients with preoperative evidence that the cyst is benign. Degree of differentiation is the most important independent prognostic factor in stage I disease and should be used in decisions on therapy in clinical practice and the future FIGO (International Federation of Gynecology and Obstetrics) classification of stage 1. In early ovarian cancer, staging adequacy and tumour grade were the only two statistically significant prognostic factors for survival in the multivariate analysis of the EORTC (European Organisation for Research and Treatment of Cancer) ACTION (Adjuvant ChemoTherapy In Ovarian Neoplasms) trial. According to the present data there is no scientific basis to rely only on adjuvant chemotherapy or on optimal staging procedure in medium and high risk stage I ovarian cancer. Primary debulking surgery by a gynaecological oncologist remains the standard of care in advanced ovarian cancer. Optimal debulking surgery should be defined as no residual tumour load. Interval debulking is defined as an operation performed after a short course of induction chemotherapy, usually 2 or 3 cycles. Based on the randomised EORTC GCG (Gynaecological Cancer Group) trial, interval debulking by an experienced surgeon improves survival in some patients who did not undergo optimal primary debulking surgery. Based on the GOG (Gynecologic Oncology Group) 152 data, interval debulking surgery does not seem to be indicated in patients who underwent primarily a maximal surgical effort by a gynaecological oncologist. Open laparoscopy is probably the most valuable tool for evaluating the operability primarily or at the time of interval debulking surgery. In retrospective analyses, neoadjuvant chemotherapy followed by interval debulking surgery does not seem to worsen prognosis compared to primary debulking surgery followed by chemotherapy. However, we will have to wait for the results of the EORTC-GCG/NCI (National Cancer Institute) Canada randomised trial to know whether neoadjuvant chemotherapy followed by interval debulking surgery is as good as primary debulking surgery in some or all stage IIIc and IV patients. The most suitable candidates for secondary debulking surgery are those who had an initial complete response to chemotherapy, a long treatment-free interval (e.g. more than 12 months), and resectable disease (without diffuse carcinomatosis).

Comorbidity and Karnofksy performance score are independent prognostic factors in stage III non-small-cell lung cancer: an institutional analysis of patients treated on four RTOG studies

Purpose: To determine the prognostic role of comorbidity in Stage III non-small cell lung cancer (NSCLC) treated definitively with radiotherapy alone.Methods and Materials: A total of 112 patients with clinical Stage III NSCLC (American Joint Commission on Cancer 1997) enrolled in four Radiation Therapy Oncology Group studies (83-11, 84-03, 84-07, and 88-08 nonchemotherapy arms) at a single institution were analyzed retrospectively for overall survival (OS) and comorbidity. Of the 112 patients, 105 (94%) completed their assigned radiotherapy. The median assigned dose was 50.4 Gy to the lymphatics (range 45–50.4 Gy) and 70.2 Gy to the primary tumor (range 60–79.2 Gy). Comorbidity was rated retrospectively using the Cumulative Illness Rating Scale for Geriatrics (CIRS-G) and Charlson scales. Karnofsky performance scores (KPSs) and weight loss were prospectively recorded. Because only 8 patients had a KPS of <70, these patients were combined with patients who had a KPS of 70. The OS of this group was compared with that of the patients with better KPSs (>70).Results: The median survival was 10.39 months (range 7.87–12.91). The 2-, 3-, and 5-year OS rate was 20.5%, 12.5%, and 7.1%, respectively. On univariate analysis, clinical stage (IIIA vs. IIIB) was found to be a statistically significant factor influencing OS (p = 0.026), and the histologic features, grade, tumor size as measured on CT scans, age, tobacco use, weight loss ≥5%, and total dose delivered to the primary tumor were not. A KPS of ≤70 (p = 0.001), the presence of a CIRS-G score of 4 (extremely severe; p = 0.0002), and a severity index of >2 (p <0.0001) were associated with statistically significant inferior OS. Multivariate analysis with clinical stage, KPS, and comorbidity (severity index) of all patients showed that a KPS ≤70 and severity index >2 were independently associated with inferior OS; clinical tumor stage was not found to be an independent prognostic factor.Conclusion: KPS and comorbidity are important independent prognostic factors in Stage III NSCLC. Comorbidity should be included in protocols studying advanced stage NSCLC and used for stratification.

New WHO histologic classification predicts prognosis of thymic epithelial tumors: a clinicopathologic study of 200 thymoma cases from China.

In 1999, a World Health Organization (WHO) committee published histologic criteria for distinct thymoma entities (labeled as Type A, AB, B1, B2, B3 thymomas) and for the heterogeneous group of thymic carcinomas, collectively called Type C thymomas. Whether WHO-defined histologic thymoma subtypes are of independent prognostic relevance has yet to be proved. Two hundred thymomas from the Shanghai Chest Hospital with a mean follow-up time of 15 years (range, 1-246 months) were studied for the relevance of WHO histologic subtype and other factors (stage, therapy, and myasthenia gravis [MG]) for survival. In order of frequency, 68 patients (34.0%) had Type AB, 39 (19.5%) had Type B2, 36 (18.0%) had Type C, 27 (13.5%) had Type B3, 17 (8.5%) had Type B1, and 8 (4.0%) had Type A thymoma. Five cases (2.5%) were rare thymomas not mentioned in the WHO classification. Survival data showed significant differences among the histologic subtypes (log rank test: P < 0.001). Among patients with Type A and AB thymomas, none died of tumor; of the Type B1 thymoma patients, only one (5.9%) died at 22 months. Type B2, B3, and C thymomas had a significantly worse prognosis with 5-year survival rates of 75.0%, 70.0%, and 48.0%, respectively. Ninety-six patients (48.0%) were in Masaoka Stage I, 26 (13.0%) were in Stage II, 65 (32.5%) were in Stage III, and 13 (6.5%) were in Stage IV. Stage was highly significant in predicting survival (log rank, test P < 0.001). The association between histologic subtype and invasive behavior (stage) was statistically significant (P < 0.001). However, histology was an independent predictive factor of survival in Stage I and II thymomas: Type B2, B3, and C thymomas had a worse prognosis than Type A, AB, and B1 thymomas (log rank test: P < 0.003). Thirty patients (15.0%) presented with MG. MG was significantly more frequent in Type B2 and B3 than in Type A, AB, and B1 thymomas (P < 0.01). On multivariate analysis, MG had no adverse effect on survival (P = 0.17). Radiation or chemotherapy improved patients' survival at 5 and 10 years in Type B2, B3, and C thymomas (log rank test: P < 0.003). Tumor stage is the most important determinant of survival in thymoma patients, but the WHO histologic subtype is an independent prognostic factor in Stage I and II thymomas, among which WHO Type A, AB, and B1 thymomas form a low-risk group. Patients with high-risk thymomas might profit from novel adjuvant radiochemotherapy regimens.

Comorbidity and KPS are independent prognostic factors in stage I non-small-cell lung cancer

Purpose: To determine the prognostic role of comorbidity in Stage I non-small-cell lung cancer (NSCLC) treated with surgery or radiotherapy (RT).Methods and Materials: One hundred sixty-three patients with clinical Stage I NSCLC were analyzed for overall survival (OS) and comorbidity. One hundred thirteen patients underwent surgery (surgical group) and 50 patients received definitive radiotherapy (RT group). Ninety-six percent of the surgical group had lobectomy or pneumonectomy, and negative margins were achieved in 96% of the patients. The median dose to the tumor for the RT group was 61.2 Gy (range 30.8–77.4). The Cumulative Illness Rating Scale for Geriatrics (CIRS-G) and the Charlson scale were used to rate comorbidity. Karnofsky performance scores (KPS) were available in 42 patients; the rest of the scores were determined retrospectively by two physicians independently, with 97% agreement.Results: The OS was 44% for the surgical group and 5% for the RT group at 5 years. Noncancer-related mortality was observed in 31% and 62% of the surgical and RT patients, respectively. On univariate analysis, performed on all patients (n = 163), squamous cell histologic type (p <0.001), clinical Stage T2 (p = 0.062), tumor size >4 cm (p = 0.065), >40 pack-year tobacco use (p <0.001), presence of a CIRS-G score of 4 (extremely severe, CIRS-G4: [+]) (p <0.001), severity index of >2 (p <0.001), Charlson score >2 (p = 0.004), KPS <70 (p <0.001), and treatment with RT (p <0.001) were associated with a statistically significant inferior OS. Multivariate analysis with histologic features, clinical T stage, age, tobacco use, KPS, comorbidity [CIRS-G(4)] and treatment group on all patients showed that squamous cell histology, >40 pack-year tobacco use, KPS <70, and presence of CIRS-G(4) were independently associated with an inferior OS. Treatment modality, T stage, and age did not have any statistically significant effect on OS. Statistically significant differences were found between the surgical and RT groups in Charlson score (p = 0.001), CIRS-G total score (p = 0.004), severity index (p = 0.006), CIRS-G4(+) (p <0.001), KPS (p <0.001), amount of tobacco use (p = 0.002), clinical tumor size (p <0.001), clinical T stage (p = 0.01), forced expiratory volume in 1 s (p = 0.001), and age (p = 0.008), in favor of the surgical group.Conclusion: The presence of significant comorbidity and KPS of <70 are both important prognostic factors, but were found to be independent of each other in Stage I NSCLC. Therefore, comorbidity and KPS assessment are recommended when analyzing the prognostic effects of tumor or treatment-related factors on OS.

Angiogenic co‐operation of VEGF and stromal cell TP in endometrial carcinomas

Vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP) are important angiogenic enzymes, inducing new blood vessel formation in many human malignancies. In this study, the immunohistochemical expression of the two molecules was analysed in a series of 121 endometrial carcinomas. VEGF was expressed exclusively in cancer cells, while TP expression was shown in cancer cells (TPcc) and in stromal cells (TPsc) of both fibroblastic and myometrial origin. In all cases, enzymatic detection was particularly evident at the invading tumour front. At this site, TPsc, but not VEGF, expression was associated with non-endometrioid-type carcinomas, high tumour grade, deep myometrial invasion, and advanced stage. VEGF, but not TP, expression was related to increased angiogenesis (p=0.01). Double stratification of the two factors, however, marked VEGF/TPsc co-expression as the most potent angiogenic phenotype (p=0.008), suggesting a synergistic function. Survival analysis revealed that VEGF and TPsc, whether expressed alone or in combination, define poor prognosis. In multivariate analysis, however, stage of disease (p<0.0001, t-ratio 4.4) and VEGF expression (p=0.01, t-ratio 2.4) were the most important prognostic variables. Furthermore, VEGF expression emerged as the only independent prognostic variable in stage I endometrial carcinomas (p=0.04, t-ratio 1.9). This was not shown for TP, probably because of its close association with histopathological parameters. In conclusion, VEGF is a major angiogenic factor in endometrial carcinomas and an independent prognostic factor in stage I endometrial disease. TP is not an effective contributor to the angiogenic process, but is associated with aggressive histological features. The two factors, when co-expressed, play a co-operative role in the induction of angiogenesis.

Prognostic significance of thrombomodulin expression and vascular invasion in stage I squamous cell carcinoma of the lung

Thrombomodulin (TM) is an important modulator of intravascular coagulation. TM exists on endothelial cells and on several types of tumor cells, especially squamous cell carcinoma cells. Tumor cell TM is thought to be associated with progression and metastasis of the tumor. To evaluate the prognostic significance of TM in lung cancer, we examined TM expression and vascular invasion in surgical specimens obtained from 90 patients with completely resected stage I non-small cell lung cancer (NSCLC). In addition, we correlate these pathologic data to other clinicopathologic data, including the outcome of the patients. Squamous cell carcinomas had a significantly higher incidence ( P<0.0001) of TM expression (22/36 cases, 61%) than adenocarcinomas (9/54 cases, 17%). In 36 squamous cell carcinoma patients, both vascular invasion ( P=0.0153; risk ratio 6.507) and TM non-expression ( P=0.0282; risk ratio 3.584) were significant for a poor prognosis. Univariate analysis of patient survival rates also revealed that vascular invasion and TM expression were significant prognostic factors ( P=0.0036 and 0.012, respectively). Further, combination analysis of vascular invasion and TM expression in the squamous cell carcinoma patients showed that the 5-year survival rate was 90% in patients with TM expression and without vascular invasion, but 21% in patients with vascular invasion and without TM expression ( P=0.0004). Since our results suggest that vascular invasion and TM expression are independent prognostic factors of stage I squamous cell carcinoma of the lung, and since the two factors play different roles in the metastatic process of cancers (promotion of metastasis by vascular invasion and inhibition of metastasis by TM expression), the combination evaluation of vascular invasion and TM expression may be very significant in evaluating the prognosis of patients with completely resected stage I squamous cell carcinoma.