Survivin expression in colorectal carcinomas: correlations with clinicopathological parameters and survival.

BACKGROUND: Survivin is a new member of the Inhibitor of apoptosis protein family that has a dual function as a mitotic regulator and apoptosis inhibitor. Survivin is prominently expressed in transformed cell lines and in many human cancers, including colorectal carcinoma. The aim of this study is to investigate the expression of survivin in colorectal carcinomas and its possible associations with clinicopathological parameters and patient survival. MATERIALS AND METHODS: Sections of formalin-fixed paraffin-embedded tissues from 77 colorectal carcinomas were immunohistochemistry stained for survivin. RESULTS: Survivin was mainly detected in the bottom of the glands of normal mucosa with mainly cytoplasmic localization. No survivin expression was found in infiltrating lymphocytes, fibroblasts, smooth muscle cells or neural tissue. Survivin staining was detected in 68/77 (88.3%) colorectal carcinomas. Survivin expression was found to be significantly associated with tumor differentiation (P = 0.02) but not with gender, age or Dukes stage. Survival did not differ according to survivin expression. CONCLUSION: Survivin was found in the majority of colorectal carcinomas, suggesting that its expression is an early event in colorectal carcinogenesis. Its expression is statistically significantly associated with tumor differentiation but not with patient survival.

Expression of cyclin D1 and Ki-67 in squamous cell carcinoma of the penis.

BACKGROUND: Cyclin D1 plays an important role in regulating the progression of cells through the G1-phase of the cell cycle. The aim of the study was to investigate the expression of cyclin D1 and Ki-67 in squamous cell carcinomas (SCC) and in some premalignant lesions of the penis and to correlate it with clinicopathological parameters and patient survival. MATERIALS AND METHODS: Formalin-fixed paraffin-embedded tissues from 21 SCC, 7 lichen sclerosus, 5 condyloma acuminatum and 2 erythoplasia of Queyrat were stained by immunohistochemistry for cyclin D1 and Ki-67. RESULTS: Cyclin D1-positive nuclear staining was overexpressed in 13/21 SCC (61.9%) and in one case of erythoplasia of Queyrat. Strong reactivity for Ki-67 was found in 16 (76.2%) SCC, in 3 condyloma acuminatum and in one case of erythoplasia of Queyrat. A tendency for an association between cyclin D1 expression and tumour differentiation (p = 0.07) but not the level of tumour invasion (p = 0.50) was found. The Ki-67 expression was notably increased with the advance of tumour grade, but the difference did not reach a statistically significant level (p = 0.46). A slight tendency towards a relationship between Ki-67 and cyclin D1 protein expression was observed (p = 0.32). Two patients relapsed and one died from the disease over a median follow-up period of 4.6 years (range 0.1-10.3 years). CONCLUSION: Ki-67 antibody and cyclin D1 overexpression seem to parallel each other, supporting the concept that cyclin D1 serves as a cell cycle activator. Cyclin D1 overexpression may be used as a prognostic factor of poor outcome in penile carcinoma.

Expression of Smad4 and TGF-beta2 in colorectal carcinoma.

BACKGROUND: TGF-beta, a potent natural antiproliferative agent, is believed to play an important role in suppressing tumorigenicity. This effect is mediated through Smad4, a tumour-suppressor gene, at chromosome 18q21, which affects gene transcription and controls cell growth. The aim of the study was to investigate the expression of Smad4 and TGF-beta2 in colorectal carcinomas and to correlate them with pathological parameters and patient survival. MATERIALS AND METHODS: Formalin-fixed paraffin-embedded tissue from 49 cases of colon carcinoma was stained by immunohistochemistry for TGF-beta2 and Smad4 protein. RESULTS: Smad4 nuclear and cytoplasmic staining was absent in 9/49 (18.3%) or reduced in 18/49 (36. 7%) colorectal carcinoma, while in the remaining 22 (44.8%) Smad4 expression comparable with colonic mucosa was observed. TGF-P2 cytoplasmic staining was expressed in all cases and was overexpressed in 24/49 (48.9%) carcinoma. A statistically significant correlation was found between Smad4 expression and tumour grade (p =0.02) and between TGF-beta2 expression and Dukes' stage (p=0.03). A slight tendency for a relationship between Smad4 and TGF-beta2 (p=0.25) was also observed. No statistically significant relationship between the above markers and survival was detected. CONCLUSION: In poorly-differentiated carcinoma, Smad4 protein expression was retained and may be linked to TGF-beta2 overexpression, due to the activation or deregulation of the TGF-fl signalling pathway. Inactivation of the TGF-beta gene occurs at an early stage of colorectal carcinogenesis, while inactivation of Smad4 is probably a late event.

Age-related thymic activity in adults following chemotherapy-induced lymphopenia.

BACKGROUND: The potential role of the adult thymus in T-cell homeostasis subsequent to lymphopenia remains the subject of debate. We examined whether thymic activity contributes to reconstitution of the peripheral T-cell pool, a critical process for patients recovering from antineoplastic therapy. METHODS: In selected patients with various neoplastic diseases we assessed peripheral blood lymphocyte subsets by flow-cytometry, including thymus-derived, CD4+ T cells expressing the CD45RA molecule, and thymic size rebound by CT scan before, and 3, 6 and 12 months after completion of cytotoxic therapy. RESULTS: Adult patients (n = 21, mean age of 30 years, range 18-49) had higher baseline numbers of B and lower numbers of NK cells than elderly patients (n = 15, mean age of 79 years, range 70-91), while total T-cell numbers did not differ. Despite the reduction of lymphocyte counts being comparable in the adult (mean of 45%) and elderly (mean of 49%) groups, occurring at, or near, completion of treatment, an enlargement of the previously atrophic thymus was evident in 63% of the adult, but in none of the elderly, subjects. In 22 patients who remained active disease-free during the following year, B cells and NK cells recovered to pretreatment levels as soon as at 3 months, whereas overall T-cell recovery occurred at 6 months post-treatment. Thymic rebound, observed in 11 of 22 patients who were of younger age, correlated significantly with a faster and more complete recovery of CD45RA+ CD4+ (mainly helper-naïve) T cells. CONCLUSION: The adult thymus appears capable of regeneration, at least up to middle age, contributing significantly to the reconstitution of the peripheral T-cell pool following chemotherapy-induced lymphopenia. In advanced age, however, although peripheral homeostatic pathways appear intact, regeneration of the naïve repertoire is incomplete.

Adjuvant cytotoxic and endocrine therapy in pre- and postmenopausal patients with breast cancer and one to nine infiltrated nodes: five-year results of the Hellenic Cooperative Oncology Group randomized HE 10/92 study.

SUMMARY: The present randomized phase III trial was designed to detect a 15% benefit in relapse-free survival (RFS) or overall survival (OS) from the incorporation of adjuvant tamoxifen to the combination of CNF [cyclophosphamide, 500 mg/m2; mitoxantrone (Novantrone), 10 mg/m2; fluorouracil, 500 mg/m2 chemotherapy and ovarian ablation in premenopausal patients with node-positive breast cancer and conversely from the incorporation of CNF chemotherapy to adjuvant tamoxifen in node-positive postmenopausal patients. From April 1992 until March 1998, 456 patients with operable breast cancer and one to nine infiltrated axillary nodes entered the study. Premenopausal patients were treated with six cycles of CNF chemotherapy followed by ovarian ablation with monthly injections of triptoreline 3.75 mg for 1 year (Group A, 84 patients) or the same treatment followed by 5 years of tamoxifen (Group B, 92 patients). Postmenopausal patients received 5 years of tamoxifen (Group C, 145 patients) or 6 cycles of CNF followed by 5 years of tamoxifen (Group D, 135 patients). Adjuvant radiation was administered to all patients with partial mastectomy. After a median follow-up period of 5 years, 125 patients (27%) relapsed and 79 (17%) died. The 5-year actuarial RFS for premenopausal patients was 65% in Group A and 68% in Group B (p = 0.86) and for postmenopausal patients 70% in Group C and 67% in Group D (p = 0.36). Also, the respective OS rates were 77% and 80% (p = 0.68) for premenopausal and 84% and 78% (p = 0.10) for postmenopausal patients. Severe toxicities were infrequently seen, with the exception of leukopenia (18%), among the 311 patients treated with CNF. In conclusion, the present study failed to demonstrate a 15% difference in RFS in favor of node-positive premenopausal patients treated with an additional 5 years of tamoxifen after CNF adjuvant chemotherapy and ovarian ablation. Similarly, six cycles of CNF preceding 5 years of tamoxifen did not translate to a 15% RFS benefit in node-positive postmenopausal patients.

Algorithm for statistical detection of peaks--syndromic surveillance system for the Athens 2004 Olympic Games.

INTRODUCTION: No generally accepted procedure exists for detecting outbreaks in syndromic time series used in the surveillance of natural epidemics or biologic attacks. OBJECTIVES: This report evaluates the usefulness for syndromic surveillance of the Pulsar approach, which is based on removing long-term trends from an observed series and identifying peaks in the residual series of surveillance data with cutoffs determined by using a combination of peak height and width. METHODS: Simulations were performed to evaluate the Pulsar method and compare it with other approaches. The daily syndromic counts in emergency departments of four major hospitals in the Athens area during August 2002-August 2003 were analyzed for two common syndromes. A standardized residual series was generated by omitting trends and noise in the original data series; this series was examined for the presence of peaks (i.e., points having magnitude higher than at least one of three probabilistically determined cutoffs). The whole process was iterated, and the baseline was recalculated by assigning reduced weight to the identified peaks. RESULTS: For the specific simulation schema used, the Pulsar method fared well when compared with other approaches in meeting the performance criteria of sensitivity, specificity, and timeliness. CONCLUSIONS: Although the suggested algorithm needs further validation regarding the correspondence between detected peaks and true biologic alerts, the Pulsar technique appears effective for observing peaks in time series of syndromic events. The simplicity of the algorithm, its ability to detect peaks based not only on height but also on width, and its performance in the simulated data sets make it a promising candidate for further use in syndromic surveillance.

Survival and prognostic factors after initiation of treatment in Waldenstrom's macroglobulinemia.

BACKGROUND: Waldenstrom's macroglobulinemia (WM) is an unusual lymphoplasmacytoid lymphoma characterized by the presence of a serum monoclonal immunoglobulin M. Although several studies have evaluated possible prognostic factors of this disease, few have focused on the survival and prognosis of symptomatic patients after the initiation of treatment. PATIENTS AND METHODS: Our study included 122 previously untreated patients with a median age of 67 years who required systemic treatment. Multiple variables were analyzed for their prognostic value on survival after initiation of treatment using univariate and Cox regression multivariate analysis. RESULTS: The median overall survival was 106 months. Pretreatment factors associated with shorter survival were age >/=65 years, splenomegaly, B-symptoms (weight loss, fever or night sweats), hemoglobin <10 g/dl, platelets <100 x 10(6)/dl, albumin <3.5 g/dl and bone marrow lymphoplasmacytic infiltrate >/=50%. In the multivariate analysis, the two variables with independent prognostic value were age >/=65 years and hemoglobin <10 g/dl. Furthermore, we were able to divide our patients into three risk groups based on the presence of two, one or none of these two adverse prognostic factors. The median survival times in the high-, intermediate- and low-risk groups were 46 months, 107 months and 172 months, respectively (P <0.0001). DISCUSSION: Our findings suggest that advanced age and anemia appear to be the two dominant prognostic factors for survival after initiation of treatment in patients with WM. These two readily available parameters can stratify the patients into three distinct subgroups and may help the selection of appropriate treatment.

A phase II study with CPT-11 plus leucovorin and bolus IV 5-fluorouracil in patients with advanced colorectal carcinoma.

Standard chemotherapy in advanced colorectal carcinoma (CRC) has not yet been established. The present study was conducted to assess the efficacy and toxicity profile of CPT-11, leucovorin (LV), and bolus 5-fluorouracil (5-FU) in a weekly schedule. Fifty-five patients were entered with no prior chemotherapy for advanced disease or adjuvant treatment ended at least 6 months preceding study entry, and 45 were assessable for response. Patients were treated with CPT-11 80 mg/m2 (7 patients) or 70 mg/m2 (48 patients). After completion of CPT-11 infusion, LV 200 mg/m2 was administered over 2 hr followed immediately by 5-FU 450 mg/m2, IV bolus, weekly for 6 weeks followed by a 2-week rest period. Treatment was continued for four cycles. Because of grade 3 and 4 diarrhea in four of the first seven patients, the study was amended to reduce the starting dose of CPT-11 from 80 to 70 mg/m2 weekly. Four complete and 10 partial responses were observed (response rate: 25.5%), the median time to progression (TTP) was 7.7 months, 1-year survival rate was 62.3%, and the median overall survival was 15.0 months. Grade 3 and 4 diarrhea occurred in seven patients (12.7%), four of them treated with CPT-11 80 mg/m2. Grade 3 myelotoxicity occurred in five patients (9.0%). Toxic death because of diarrhea, neutropenia, bacteremia, and sepsis occurred in a patient treated with CPT-11 80 mg/m2. Our results confirm the efficacy of CPT-11, LV, and 5-FU in a weekly schedule in patients with advanced CRC. Further studies are needed to compare the present regimen with higher doses of CPT-11 with LV plus different schedules of 5-FU administration in the treatment of metastatic CRC.

Prognostic factors in Greek patients with small cell lung cancer (SCLC). A Hellenic Cooperative Oncology Group study.

BACKGROUND: Prognostic factors among Greek patients with SCLC were evaluated. PATIENTS AND METHODS: Data from 516 patients with SCLC treated by the Hellenic Cooperative Oncology Group were analyzed. Multivariate analysis was performed. RESULTS: Complete response (CR) was achieved in 26.8% and partial response in 40.1% of patients. The median duration of response was 7.4 months, the median survival 10.5 months and the 2-year survival rate 12%. The stage of the disease was a dominant prognostic factor for survival and response. PS 0-1 was a major prognostic factor for survival, duration of response and CR. Female gender was a favorable predictor for CR. Superior vena cava syndrome was a poor prognostic factor for survival and duration of response. Weight loss and age > or = 60 were poor predictors for response. The sites of metastases affected survival, duration of response and response. Normal alkaline phosphatase was a favorable prognostic factor for survival, duration of response and response. Normal lactate dehydrogenase and thoracic irradiation were favorable prognostic factors for survival and duration of response.

Randomized comparison of early versus late hyperfractionated thoracic irradiation concurrently with chemotherapy in limited disease small-cell lung cancer: a randomized phase II study of the Hellenic Cooperative Oncology Group (HeCOG).

BACKGROUND: Concurrent platinum etoposide chemotherapy given in combination with hyperfractionated thoracic radiation therapy (HTRT) in limited disease (LD) small cell lung cancer (SCLC) is associated with a high response rate and significant prolongation of survival. Given these results, the Hellenic Cooperative Oncology Group (HeCOG) performed a multicenter randomized phase II study in patients with LD SCLC to evaluate the timing of HTRT (early vs. late) when given concurrently with chemotherapy. PATIENTS AND METHODS: To be eligible for the study, patients were required to have histologically or cytologically proven LD SCLC, confined to one hemithorax and/or ipsilateral mediastinal or supraclavicular lymphnodes and absence of pleural effusion or controlateral supraclavicular lymphnode involvement. Moreover, patients had to have a good performance status and adequate haematological, liver and renal function. Patients with LD SCLC were randomized to receive HTRT either concurrently with the first (Group A) or with the fourth (Group B) cycle of chemotherapy. Chemotherapy consisted of carboplatin administered at an AUC of six given as an i.v. 1-hour-infusion immediately followed by etoposide at a dose of 100 mg/m2 i.v. as a two-hour infusion for three consecutive days every three weeks up to a total of six cycles. Prophylactic cranial irradiation was also given to patients achieving a complete response. RESULTS: 42 and 39 patients, were eligible for efficacy evaluation in group A and B respectively. The overall response rate was 76% in group A and 92.5% in group B (P = 0.07) with a complete response rate of 40.5% and 56.5%, respectively. After a median follow-up of 35 months, time to progression was 9.5 months in group A and 10.5 in group B (NS) while overall median survival was 17.5 and 17 months respectively (NS). The 2-year survival was 36% in group A and 29% in group B (NS) and the 3-year survival 22% and 13%, respectively (NS). The distant relapse rate was 38% in group A and 61% in group B (P = 0.046). Severe grade 3 4 anemia was recorded in 19% of group A and 12.5% of group B (NS), while severe leucopenia was recorded in 35.5% and 20.5% (P = 0.09) and neutropenic fever in 5% and 2.5% (NS), respectively. Severe thrombocytopenia did not differ significantly between the two treatment groups being 21.5% and 23%, respectively. Severe grade 2-3 esophageal toxicity was 19% in group A and 23% in group B (NS), while grade 3 lung toxicity was 5% and 7.5% (NS), respectively. No toxicity-related deaths were recorded. CONCLUSION: Concurrent administration of HTRT with carboplatin etoposide is associated with a high response and survival rate. Although a trend for higher response rate was recorded in the group of patients who received late HTRT, the overall median, 2-year and 3-year survival rates did not differ significantly between the two treatment groups. The toxicity of this promising therapeutic approach was acceptable. Comparative phase III studies with an adequate number of patients are recommended in order to answer this question.

Thalidomide and dexamethasone combination for refractory multiple myeloma.

BACKGROUND: Thalidomide is effective in approximately 30% of patients with refractory multiple myeloma. Dexamethasone is active in 25% of patients with disease resistant to alkylating agents. We investigated the combination of thalidomide with dexamethasone as salvage treatment for heavily pretreated patients with multiple myeloma, in order to assess its efficacy and toxicity. PATIENTS AND METHODS: Forty-four patients with refractory myeloma were treated with thalidomide, 200 mg p.o. daily at bedtime, with dose escalation to 400 mg after 14 days, and dexamethasone, which was administered intermittently at a dose of 20 mg/m2 p.o. daily for four days on day 1-4, 9-12, 17-20, followed by monthly dexamethasone for four days. Patients' median age was 67 years. All patients were resistant to standard chemotherapy, 77% were resistant to dexamethasone-based regimens and 32% had previously received high-dose therapy. RESULTS: On an intention-to-treat basis twenty-four patients (55%) achieved a partial response with a median time to response of 1.3 months. The thalidomide and dexamethasone combination was equally effective in patients with or without prior resistance to dexamethasone-based regimens and in patients with or without prior high-dose therapy. Toxicities were mild or moderate and consisted primarily of constipation, morning somnolence, tremor, xerostomia and peripheral neuropathy. The median time to progression for responding patients is expected to exceed 10 months and the median survival for all patients is 12.6 months. CONCLUSION: The combination of thalidomide with dexamethasone appears active in patients with refractory multiple myeloma. If this activity is confirmed, further studies of this combination as second-line treatment for patients resistant to conventional chemotherapy, and as primary treatment for patients with active myeloma, should be considered.

Anthracycline-based chemotherapy of primary non-Hodgkin's lymphoma of the testis: the hellenic cooperative oncology group experience.

Testicular non-Hodgkin's lymphoma is an uncommon disease and its outcome following chemotherapy and/or radiotherapy has been variable. A retrospective analysis was performed on 26 patients with primary testicular lymphoma treated predominantly with anthracycline-based chemotherapy between 1984 and 1999. The patients' median age was 60 years (range 19-82 years) with 17 (65.4%) patients being older than 60 years. Four (15.4%) patients had constitutional B symptoms. There were 11 (42.3%) patients with high grade lymphoma, 12 (46.2%) with intermediate grade, 1 (3.8%) with low grade and 2 (7.7%) were not classified. According to the Ann-Anbor staging system, 18 patients (69.2%) had early (stage I/II) and 8 (30.8%) advanced (stage III/IV) disease. Chemotherapy was administered to 24 patients including 22 patients who received anthracycline-based chemotherapy. Two stage IEA patients were treated with orchidectomy and adjuvant radiotherapy to the regional lymph nodes without systemic chemotherapy. Chemotherapy alone resulted in a complete remission (CR) in 14 (58.3%) of 24 patients and partial remission in 1 (4.2%), amounting to an overall response rate (RR) of 62.5%. Of the 5 stage I patients who had chemotherapy on an adjuvant basis, 4 (80%) had CR/no evidence of disease. Of the 11 stage II patients, 8 (72.7%) achieved CR and 1 (9.1%) PR (overall RR of 81.8%). CR was obtained in 2 (25%) of 8 stage III/IV patients. Both patients remain disease free for 26 and 65 months. Excluding the 5 stage I patients, chemotherapy resulted in a CR in 10/19 (52.6%) patients and a PR in 1/19 (5.2%), inducing an overall RR of 57.8%. The mean duration of response was 75 months (range 8-145.5+ months). After a median follow-up of 87 months (range 0.13-145.5+ months) the median survival time was 31 months (range 0.13-145.5+ months) and the median time to progression (TTP) 17 months (range 0.13-145.5+ months). The median TTP was significantly higher in early disease compared to that of advanced disease (52 vs. 3 months, p = 0.02). Of the 3 patients who relapsed following disease-free status, CNS involvement occurred in 2 stage II patients and contralateral testis involvement in 1 stage IEA, respectively. The latter remained disease free for 2 years following orchidectomy alone. The other 2 patients who relapsed did not respond to salvage chemotherapy and died. There was no significant relationship between the values of LDH and beta(2)-microglobulin with the outcome except for ESR which was significantly related with the CR (p = 0.005) or RR (p = 0.005). In conclusion, patients with primary testicular lymphoma have a poor outcome, despite the treatment with anthracycline-containing regimens. Treatment with anthracycline-based chemotherapy is recommended in patients at early stages. In advanced disease, more intensive or investigational regimens should be considered. Because the relapse rate in the CNS and contralateral testis is quite high in most studies, prophylactic CNS treatment and radiotherapy to the other testis should be included in the management of testicular lymphoma.

Induction chemotherapy in non small cell lung cancer stage IIIa-b and IV and second-line treatment.

This study investigates the treatment management and survival of inoperable advanced non-small cell lung cancer (NSCLC) patients. The objective was to treat all patients with induction chemotherapy and then to stratify them for surgery, radiotherapy, second-line chemotherapy or supportive treatment. Of the 359 patients enrolled in the study, 336 fulfilled the study criteria and were classified as follows: 90 stage IIIa, 135 stage IIIb and 111 stage IV. Histological types included 131 squamous cell, 123 adenocarcinomas, 53 undifferentiated non-small, 15 large cell, 3 adenosquamous, 3 bronchoalveolar and 8 unclassified. For all patients induction therapy involved Cisplatin (CDDP) combined chemotherapy and 84% of the patients were also treated with Vindesine and Epirubicin. The mean number of courses was 4 (minimum 2, maximum 11). The result of induction therapy was 49% complete and partial for at least 8 weeks; with minor response included, the total response rate was 67.6%. Fourteen patients (4.16%) achieved analytically complete response, 151 (45%) partial response and 62 (18.5%) minor response. The second-line treatment implemented was as follows: surgical excision, 22 patients (Group A); radiotherapy, 106 patients (Group B); chemotherapy, 91 patients (Group C) and supportive treatment, 117 patients (Group D). Median survival in months was 72 (range 5-120+), 12 (range 2-118), 15 (range 3-48) and 7 (range 3-120) for Groups A-D respectively. There was a statistically significant difference in survival in Group A patients (p < 0.001) but no difference was observed between Groups B and C. Group D patients had significantly lower survival than the other three groups. In conclusion, induction chemotherapy renders a reasonably high response rate in operable NSCLC patients and second-line radiotherapy treatment is not superior to second-line chemotherapy.