Detection of human papillomavirus DNA by polymerase chain reaction and southern blot hybridization in colorectal cancer patients.

PURPOSE: The molecular mechanisms related to colorectal carcinogenesis are controversial. The purpose of this study was to evaluate the possible role of high-risk oncogenic human papillomavirus (HPV) types in the pathogenesis of colorectal cancer. PATIENTS AND METHODS: Tumor, and corresponding normal mucosal tissue specimens were obtained soon after surgery from 56 patients with colorectal adenocarcinoma. We studied both neoplastic and normal colon tissues for the presence of HPV types 6, 11, 16, 18, and 33. After the isolation of DNA, the presence of specific types of HPV DNA was determined by polymerase chain reaction (PCR) and southern blot hybridization. RESULTS: HPV DNA was detected in 46 (82.14 %) of 56 colorectal adenocarcinomas and in 18 (32 %) of 56 normal colonic mucosal tissue samples. Two or more HPV types were detected in 32 carcinoma samples. HPV type 18 (n= 40) and 33 (n= 32) were the most frequently detected types of HPVs in the tumor tissues. None of the normal mucosal specimens revealed HPV 18 DNA. The expression rate of HPV DNA in tumor tissue was significantly higher than that encountered in normal colonic mucosa (p <0.001). CONCLUSION: Detection of HPV DNA types 18 and 33 in most of the colorectal adenocarcinoma specimens suggests that HPVs may be related to carcinogenesis in glandular cells of the colorectal mucosa of our patient population.

Chemotherapy as an adjunct to radiotherapy in locally advanced nasopharyngeal carcinoma.

BACKGROUND: A previous meta-analysis investigated the role of chemotherapy in head and neck locally advanced carcinoma. This work had not been performed on nasopharyngeal carcinoma. OBJECTIVES: The aim of the project was to study the effect of adding chemotherapy to radiotherapy on overall survival (OS) and event-free survival (EFS) in patients with nasopharyngeal carcinoma. SEARCH STRATEGY: We searched MEDLINE (1966 to October 2003), EMBASE (1980 to October 2003) and the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 3, 2003) and trial registers. Handsearches of meeting abstracts, references in review articles and of the Chinese medical literature were carried out. Experts and pharmaceutical companies were asked to identify trials. SELECTION CRITERIA: Randomised trials comparing chemotherapy plus radiotherapy to radiotherapy alone in locally advanced nasopharyngeal carcinoma were included. DATA COLLECTION AND ANALYSIS: The meta-analysis was based on updated individual patient data. The log rank test, stratified by trial, was used for comparisons and the hazard ratios (HR) of death and failure (loco-regional/distant failure or death) were calculated. MAIN RESULTS: Eight trials with 1753 patients were included. One trial with a 2 x 2 design was counted twice in the analysis. The analysis was performed including 11 comparisons based on 1975 patients. The median follow up was six years. The pooled hazard ratio of death was 0.82 (95% confidence interval (CI) 0.71 to 0.95; P = 0.006) corresponding to an absolute survival benefit of 6% at five years from chemotherapy (from 56% to 62%). The pooled hazard ratio of tumour failure or death was 0.76 (95% CI 0.67 to 0.86; P < 0.00001) corresponding to an absolute event-free survival benefit of 10% at five years from chemotherapy (from 42% to 52%). A significant interaction was observed between chemotherapy timings and overall survival (P = 0.005), explaining the heterogeneity observed in the treatment effect (P = 0.03) with the highest benefit from concomitant chemotherapy. AUTHORS' CONCLUSIONS: Chemotherapy led to a small but significant benefit for overall survival and event-free survival. This benefit was essentially observed when chemotherapy was administered concomitantly with radiotherapy.

Bcl-2 gene rearrangements and apoptosis rates in patients with non-Hodgkin's lymphoma during chemotherapy.

OBJECTIVES: Overexpression of the bcl-2 gene as a result of the t(14,18) translocation leads to neoplastic transformation by suppressing apoptosis. However, apoptotic cell death in response to chemotherapy has not been investigated. This study was planned with the aim to investigate the association between bcl-2 gene rearrangements and apoptotic changes during chemotherapy in patients with non-Hodgkin's lymphoma. DESIGN AND METHODS: Lymphocytes from 33 patients were collected before and during chemotherapy. Bcl-2 gene rearrangements were investigated by PCR. Apoptotic cell death was analyzed by enzyme immunoassay. RESULTS: In 24 cases, mbr gene rearrangements were detected. Apoptosis was successfully induced by chemotherapy in 48% of patients. Two characteristic, clearly distinguishable apoptotic response patterns with transient peaks either following the first or the third course were observed. It was found that apoptosis rates measured after the first course exactly reflect the final response. No correlation was found between bcl-2 gene rearrangements and apoptosis. CONCLUSIONS: Apoptotic cell death rates show transient changes during chemotherapy. Because the midterm response can be misleading, the apoptotic response should be evaluated following the first course of chemotherapy.

The efficacy of a five-drug antiemetic combination during chemotherapy regimens containing cisplatin or cyclophosphamide-doxorubicin.

A five-drug combination, including metoclopramide, thiethylperazine, diphenhydramine, dexamethasone, and diazepam, was given to 32 patients during three consecutive treatments with chemotherapy. Eighteen patients (group A) were treated with a cisplatin-containing regimen, and 14 patients (group B) were treated with a cyclophosphamide- and doxorubicin-containing chemotherapy. In group A, complete responses were lower on the first day than on the second and third days (P < 0.015 and P < 0.041, respectively), during the first and second courses. The five-drug antiemetic regimen seems safe and effective. These results show that clinical trials that evaluate antiemetic efficacy in cisplatin-containing chemotherapy regimens should evaluate at least two consecutive courses.

Treatment of aggressive non-Hodgkin's lymphoma with dose-intensified epirubicin in combination of cyclophosphamide, vincristine, and prednisone (CEOP-100): a phase II study.

Epirubicin is an agent with a lower incidence of cardiotoxicity and myelotoxicity compared with doxorubicin; and it is active in patients with non-Hodgkin's lymphoma (NHL). Our aim was to define the therapeutic efficacy and toxicity of dose-intensified epirubicin in combination with cyclophosphamide, vincristine, and prednisone (CEOP) in patients with diffuse large-cell NHL. Previously untreated patients aged between 15 and 75 years, with at least one measurable lesion, adequate liver, renal, cardiac functions, and no central nervous system involvement were included in the study. The planned chemotherapy regimen CEOP consisted of cyclophosphamide 750 mg/m2, epirubicin 100 mg/m2, and vincristine 1.4 mg/m2 intravenously on day 1 and 100 mg prednisone taken orally on days 1 to 5. Courses were repeated every 21 days. Patients with stage I and II received four cycles of chemotherapy followed by involved-field radiotherapy, and patients with stage III and IV received six cycles of chemotherapy followed by radiotherapy to bulky lymph node sites. Seventy-five patients were enrolled in the study. The complete response rate was 83.8%, and 72 patients were assessable for toxicity. The most common toxicity was myelosuppression; 13.9% of the patients had grade III-IV neutropenia. Severe mucositis, diarrhea, and emesis were uncommon (<10%). At a median follow-up period of 41 months, the 5-year progression-free survival and overall survival rates were 63.5% and 65.3%, respectively. Increasing the dose intensity of epirubicin can yield a similar complete response rate compared with the regimens used in NHL without significantly increasing the toxicity rate associated with chemotherapy. The role of dose-intensive epirubicin should be investigated further in future randomized trials.

High-dose epirubicin and cisplatin in locally advanced undifferentiated nasopharyngeal carcinoma.

AIM: Undifferentiated nasopharyngeal carcinoma (UNPC) is a chemosensitive tumour; a randomized study evaluating neoadjuvant chemotherapy with bleomycin/epidoxorubicin/cisplatin (BEC) in addition to conventional radiotherapy has resulted in a better disease-free survival in the chemotherapy arm. The bleomycin infusion in the BEC regimen has necessitated hospitalization for the infusion, and resulted in serious pulmonary toxicity. This study has aimed to omit the bleomycin, and test the efficacy and toxicity of cisplatin (C) and a higher dose of epidoxorubicin (EPI) in patients with locally advanced UNPC. METHODS: Seventy-one patients with locally advanced UNPC were treated with three cycles of C 100 mg/m2 day 1, and EPI 100 mg/m2 day 1 every 3 weeks followed by conventional radiotherapy of 70 Gy. RESULTS: Neoadjuvant chemotherapy was well tolerated. There was only 1-week delay in 14.3% of the patients and no dose modification. Grade III-IV neutropenia occurred in 18.9% of the cycles: none of the patients developed neutropenic fever. No patient progressed during chemotherapy, the complete response rate was 26.8% (95% CI = 16.9-38.6) and the partial response rate was 59.1% (95% CI = 46.8-70.7) for an objective response rate of 85.9% (95% CI = 75.6-93.0) at the end of the three cycles of chemotherapy. After the completion of radiotherapy, the complete response rate increased to 81.7% (95% CI = 70.7-89.9) and the objective response increased to 91.5% (95% CI = 82.5-96.8). The median disease-free interval and the median survival have not been reached. The 5-year disease-free and overall survival rates are 53.0% (95% CI = 43.7-62.0) and 57.2% (95% CI = 48.3-65.2), respectively. CONCLUSION: Neoadjuvant C and EPI, easily administered in the outpatient setting, is an effective and well-tolerated regimen in the treatment of locally advanced UNPC.

A phase II study of paclitaxel and cisplatin combination chemotherapy in recurrent or metastatic head and neck cancer.

The taxanes are the most active new agents for squamous-cell carcinoma of the head and neck (SCCHN) since the discovery of cisplatin. Our aim was to define the therapeutic efficacy and toxicity of paclitaxel and cisplatin combination therapy in patients with recurrent SCCHN. Patients with locally recurrent or metastatic SCCHN were enrolled in the study. Patients were required to be chemotherapy-naive, and should have completed radiation therapy at least 6 weeks prior to enrollment. A World Health Organization (WHO) performance status of less than 3 was required. Paclitaxel (Taxol, Bristol Myers Squibb Company, Princeton, NJ) and cisplatin therapy (PC) consisted of prophylaxis with pheniramine 50 mg i.v., ranitidine 150 mg i.v. and dexamethasone 20 mg i.v. given prior to paclitaxel 175 mg/m2 as a 3-hour i.v. infusion, followed by cisplatin 75 mg/m2 as a 1-hour infusion with an additional 3000 cc of saline for hydration. This treatment was repeated every 3 weeks for a maximum of six cycles. Patients were evaluated for response after the third and sixth cycles, or at the time of clinical progression. Fifty patients were enrolled in the study. The overall response rate was 32% with a 10% complete response rate. Forty-eight patients were assessable for toxicity. A total of 221 cycles of chemotherapy was given and the most common toxicity was myelosuppression; 7.7% of cycles had grade III-IV neutropenia. Severe neuropathy, nephropathy, mucositis, and emesis were uncommon (<10 %). At a median follow-up period of 25 months, the median overall survival was 10 months and the 1-year progression-free and overall survival rates were 16.7% and 35.2%, respectively. We conclude that patients with recurrent SCCHN have a moderate response to combination chemotherapy with cisplatin and paclitaxel. Given this moderate response rate, it is unlikely that this combination (PC) might ultimately prove to be superior to standard treatment regimens in terms of significant survival advantage.

Osteocalcin: a valuable bone metastasis marker.

Osteocalcin (BCG) in an osteoblast product which reflects the bone formation rate. It could be a valuable bone metastasis marker. To investigate this, we measured serum osteocalcin levels by using radioimmunoassay method in 11 healthy subjects and in 79 cancer patients. The cancer patients consisted of 36 non-metastatic, 29 with only bone metastasis and 14 with extraosseous metastases. Significance was found only between bone metastatic patients and non-metastatic patients in both sexes (p. 0.05). There was no significance between non-metastatic patients and patients with other than bone metastases. This study shows that osteocalcin measurements reflect bone formation rates in bone metastasis and could be used as a bone metastasis marker in suspicious cases.

Serum values of CA72.4 in patients with gastrointestinal system tumors comparison with CEA and CA 19.9.

Serum CA 72.4 levels of patients with malignant gastrointestinal disorders (n = 77) were determined in parallel with the CEA and CA 19.9 levels. The values related to healthy individuals were 1.7 U/ml, with a median of 1.7 U/ml, whereas an average of 12.1 U/l (median 2 U/ml) was measured in malignancy. Among all three markers CEA showed the highest positive rate while the values for CA 19.9 and CA 72.4 were lower. Although positive rates among the healthy group were observed with CEA and CA 19.9, no false positives were found with CA 72.4. Elevated CA 72.4 levels were found in 17.6% of patients with gastric carcinoma and 56.3% with colorectal carcinoma. All markers showed significant sensitivity for the malignant state when used alone. However, the regression analysis revealed that only the combination of CA 72.4 and CEA may contribute significantly to the diagnostic potential. Our results indicate that complementation of CEA with CA 72.4 can significantly increase the sensitivity in the serodiagnosis of gastrointestinal system cancers. Combination of positive information from these two sources is likely to lead to a more accurate diagnosis and may therefore improve the efficiency of the follow-up and therapeutic response.

Detection of HPV 16 and HPV 18 infection in patients with cervical neoplasia.

Definite types of human papillomaviruses (HPV) are considered an etiological factor in the occurrence of cervical carcinoma. Determining the persistence of some HPV types associated with cervical carcinoma is important in defining and following precancerous lesions. The most sensitive method in the determination of these viruses is polymerase chain reaction (PCR). Because of the convenience and the fastness it provides, cytological cervical material is preferred for the analysis. In our study infection with HPV 16 and HPV 18 was investigated in the cervical scrapes of 33 subjects with cervical carcinoma. The DNAs isolated from the samples were amplified by PCR. HPV 16 and HPV 18 types were identified by Southern Blot hybridization. The positivity rates for HPV 16 and HPV 18 in 33 subjects with cervical carcinoma were 54.5% and 45.4%, respectively. The corresponding value in the control group was only 5.5%. PCR combined with Southern Blot is the most sensitive method for scanning programmes and in defining and monitoring the risk groups for developing cervical neoplasia.

Menstrual cycle values of tumor marker in healthy women and in patients with non-gynecological tumors.

The aim of the present study is to investigate whether the values of CA 12-5 which is considered a specific ovarian tumor marker can be used in patients with non-gynecological tumors whose values in menstrual cycle phases were not previously investigated. In order to determine whether a particular phase or a combination of phase are important, CA 12-5 values were determined by radioimmunoassay technique in a limited number of patients belonging to three different age groups. CA 12-5 were found to be unrelated to age. No statistically significant difference in CA 12-5 values was noted between samples obtained from patients with tumor and healthy women on the first and second days of menstruation. In both cases the normal value exceeded 35 U/ml. The mean values was 42 U/ml in healthy women and 49 U/ml in tumor patients. Mean CA 12-5 values determined between the 12th and 14th days on which estrogen hormone is at its highest level, were found to be 23 U/ml in healthy women and 40 U/ml in patients with tumors. These values are statistically significant, while CA 12-5 values determined in samples obtained on the 20th-25th days are within the normal range. Values of the CA 12-5 tumor marker during the estrogenic phase are important in the diagnosis, management and follow-up of cancer. Determination of estrogen hormone levels as an additional parameter may provide a significant correlation.

Survival outcomes in aggressive non-Hodgkin's lymphoma according to the International Prognostic Index.

PURPOSE: To retrospectively analyse the disease-free survival (DFS) and overall survival (OS) according to the International Prognostic Index (IPI) risk groups in patients with aggressive non-Hodgkin's lymphoma (A-NHL) treated at the Institute of Oncology, Istanbul University between 1989-1998. PATIENTS AND METHODS: The records of 201 patients with A-NHL and aged 15 years and over were retrospectively analysed. Features evaluated for potential prognostic importance for DFS and OS included sex, age, tumor stage, performance status (PS), "B" symptoms, bone marrow infiltration, number of extranodal disease sites, size of the largest tumor, histologic grade, erythrocyte sedimentation rate (ESR), and serum levels of lactate dehydrogenase (LDH), albumin and beta2-microglobulin. The International Working Formulation system and the Ann Arbor staging system were used for histologic and staging classifications, respectively. Kaplan-Meier, log-rank and Cox's methods were used for statistical analyses. RESULTS: Sixty-six percent of the patients were classified in the low risk group; 23% in the low-intermediate risk group; 9% in the intermediate-high risk group; and 2% in the high risk group. The median follow-up was 25.9 months (range 1-150 months). Five-year DFS and OS were 41% and 47%, respectively, in all patients. According to IPI, based on the age, tumor stage, LDH level, PS, and extranodal involvement in the identified 4 risk groups of all patients and all ages, the 5-year DFS and OS rates were 66-51%, 49- 43%, 40-34%, and 0%, respectively. Patients in the lowintermediate and intermediate-high risk groups had a worse survival outcome than low risk patients (p=0.001). CONCLUSION: The IPI can be used in the selection of appropriate therapeutic strategy for individual patients. IPI is the most acceptable prognostic system, but being not the ideal one, is still being under critical discussion.

An atypical presentation of metastatic gestational choriocarcinoma with maxillary sinus and subcutaneous involvement; report of a case with literature review.

Extragonadal germ cell tumors are rare neoplasms with histologic features comparable to those of gonadal origin. In this case report we present a 21-year-old female patient with an atypical localization of metastatic gestational choriocarcinoma. She was admitted to our hospital with recurrent epistaxis, abnormal vaginal bleeding, rectal bleeding, subcutaneous nodules on both thighs and forearms and left maxillary mass with intranasal cavity invasion. Laboratory analysis revealed significant elevation in serum beta-human chorionic gonodotropin (beta-HCG) level. Abdominal computerized tomography (CT) revealed left renal and retroperitoneal masses and thoracic CT displayed multiple bilateral lung metastases. Histopathological evaluation of the biopsy specimen obtained from the maxillary sinus showed choriocarcinoma. Based on WHO criteria she was classified as high-risk metastatic choriocarcinoma and treated with combination chemotherapy. We believe that in young women with recurrent epistaxis, gross abnormal vaginal and rectal bleeding and atypical maxillary sinus tumor with multiple lung metastases, choriocarcinoma should be included in the differential diagnosis and previous history of pregnancy or abortion should be obtained.

Investigation of the molecular changes during chemotherapy in non-Hodgkin's lymphoma.

In the present study the changes in the detection rate of bcl-2 and IgH gene rearrangements in relation to chemotherapy and therapeutic response in patients with diffuse large B-cell lymphoma have been investigated. Immunoglobulin gene rearrangements were detected in almost all patients during all stages of treatment. Persistence of bcl-2 rearrangements reflected the effect of chemotherapy better. Bcl-2 rearrangements were initially detected in 64% of the patients. Cells bearing the translocation disappeared during therapy in a significant group of cases. In 10 patients bcl-2-rearranged cells were detected for varying periods of time. However, no correlation was found between the molecular persistence or disappearance of cells as detected by PCR and the therapeutic response or recurrence rates.

Prognostic significance of marker half-life during chemotherapy in non-seminomatous germ cell testicular tumors.

Decrease in serum alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) levels is considered as a response during chemotherapy of non-seminomatous germ cell testicular tumors, but data on the prognostic significance of marker half-life remains inconclusive. Serum marker half-life was evaluated in 34 patients with elevated markers, receiving chemotherapy (CT). Marker half-life was calculated from the natural logarithm of the sequential AFP or HCG concentrations. The correlation between event-free (EFS) and overall survival (OS) with unfavorable half-lives of AFP and HCG was evaluated. Median actual half-life (AHL) AFP was 3.9 days (range, 1.4-21.5) and median AHL HCG was 4.4 days (range, 1.4-21.0); 82% of the patients had a satisfactory initial decline in AFP, and 71% had a satisfactory initial decline in HCG. There was a significant difference in EFS and OS between the two groups of patients with an AFP half-life < 7 days and > 7 days. HCG half-life did not adversely affect EFS and OS. The correlation of better EFS and OS with appropriate AFP marker half-life during chemotherapy could provide a dynamic method, which could complement the standard baseline prognostic factors, for the prediction of prognosis.

Turkish Heart Study: lipids, lipoproteins, and apolipoproteins.

We examined the plasma lipids, lipoproteins, and selected apolipoproteins in approximately 9,000 men and women from six different regions of Turkey with markedly different diets, ranging from an Aegean coast diet high in olive oil (plasma cholesteryl ester fatty acids enriched in monounsaturated fatty acids) to an inland Anatolian diet high in meat and dairy products (plasma cholesteryl esters enriched in saturated fatty acids). The rural population consuming an olive oil-rich diet had the lowest plasma cholesterol levels (men, 149 mg/dl; women, 150 mg/dl). The urban populations of Istanbul and Adana had higher plasma cholesterol levels (men, 202 and 184 mg/dl, respectively; women, 181 and 190 mg/dl, respectively). Affluent men had the highest cholesterol levels (207 mg/dl). The low density lipoprotein (LDL) cholesterol levels tended to parallel the total cholesterol levels (highest for Istanbul men at 136 mg/dl and lowest for Aegean coast men and women at approximately 100 mg/dl). Strikingly, the Turkish people were found to have very low levels of high density lipoprotein (HDL) cholesterol (HDL-C) (mean values for all six regions: men, 34-38 mg/dl; women, 37-45 mg/dl) and total cholesterol/HDL-C ratios that were high (mean values for all six regions: men, 4.5-5.5; women, 3.9-5.0). The low HDL-C levels appear to be caused, at least in part, by a genetic factor. Triglyceride levels also tended to be high in Turkish men (approximately 120-150 mg/dl) and women (approximately 90-110 mg/dl). Thus, even though the total plasma cholesterol levels are not excessively elevated in comparison to those in other populations, the presence of low HDL-C or low HDL-C coupled with mildly elevated triglyceride levels may represent a significant risk factor for heart disease in the Turkish population. Affluence and higher education were associated with higher cholesterol levels. Lack of physical activity, smoking, and alcohol consumption also tended to be associated with a detrimental lipid profile. Lipoprotein[a] levels were identical among the regions surveyed (mean: 11-15 mg/dl) and displayed the typical distribution with an increased number of individuals with low levels. The 90th percentile value for lipoprotein[a] was about 30 mg/dl for both men and women. Smoking, a major risk factor for heart disease, was very prevalent in the Turkish population, especially in men (50-70% smokers) and women in urban areas (30-40% smokers). Hypertension, defined as a systolic pressure > 140 or a diastolic pressure of > 90 occurred in approximately 17% and 26% of the men and women surveyed, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)