Poor Degree Of Differentiation Research Articles

Molecular analysis of the sex chromosomes of the platyfish Xiphophorus maculatus: Towards the identification of a new type of master sexual regulator in vertebrates

In contrast to mammals and birds, fish display an amazing diversity of genetic sex determination systems, with frequent changes during evolution possibly associated with the emergence of new sex chromosomes and sex-determining genes. To better understand the molecular and evolutionary mechanisms driving this diversity, several fish models are studied in parallel. Besides the medaka (Oryzias latipes Temminck and Schlegel, 1846) for which the master sex-determination gene has been identified, one of the most advanced models for studying sex determination is the Southern platyfish (Xiphophorus maculatus, Günther 1966). Xiphophorus maculatus belongs to the Poeciliids, a family of live-bearing freshwater fish, including platyfish, swordtails and guppies that perfectly illustrates the diversity of genetic sex-determination mechanisms observed in teleosts. For X. maculatus, bacterial artificial chromosome contigs covering the sex-determination region of the X and Y sex chromosomes have been constructed. Initial molecular analysis demonstrated that the sex-determination region is very unstable and frequently undergoes duplications, deletions, inversions and other rearrangements. Eleven gene candidates linked to the master sex-determining gene have been identified, some of them corresponding to pseudogenes. All putative genes are present on both the X and the Y chromosomes, suggesting a poor degree of differentiation and a young evolutionary age for platyfish sex chromosomes. When compared with other fish and tetrapod genomes, syntenies were detected only with autosomes. This observation supports an independent origin of sex chromosomes, not only in different vertebrate lineages but also between different fish species.

Neoplastic Seeding After Radiofrequency Ablation for Hepatocellular Carcinoma

Neoplastic seeding reportedly occurs in up to 12.5% of patients treated with radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). The aim of this study is to assess the incidence, risk factors, and prognosis of neoplastic seeding after RFA among a large number of patients with a long-term follow-up. From February 1999 to December 2004, 1,031 patients underwent a total of 1,845 treatments with RFA for a total of 3,837 HCC nodules. The following variables were assessed to elucidate the risk factors of neoplastic seeding: age, sex, positivity for viral markers, tumor size, number of tumor nodules, number of RFA sessions, tumor location, percutaneous biopsy prior to RFA, alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin (DCP) and lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) levels, and the degree of tumor differentiation. Neoplastic seeding was detected in 33 patients (3.2% per patient) at intervals of 4.8-63.8 (median, 15.2) months after RFA. On multivariate logistic regression analysis, only the poor differentiation degree was associated with the risk of neoplastic seeding (P= 0.012). Of tumor factors, tumor size, and AFP, DCP, and AFP-L3 levels were significantly associated with the poor differentiation degree. The cumulative survival rates 1 and 2 yr after the detection of neoplastic seeding were 86% and 47%, respectively. Poor differentiation degree was the risk factor of neoplastic seeding after RFA for HCC. The surrogate markers for poor differentiation degree were larger tumor size and elevated tumor marker levels. Indication for RFA should be carefully considered for HCC patients under these conditions.

Expression of thymosin β10 and its role in non–small cell lung cancer

The exact role of thymosin beta10 in lung cancer progression remains unclear. We investigated by immunohistochemistry the expression of thymosin beta10 protein in tumors and tumor-adjacent tissues from 69 patients with non-small cell lung cancer. The relationship of thymosin beta10 expression with vascular endothelial growth factor, vascular endothelial growth factor-C, microvessel density, and lymphatic vessel density was determined; clinicopathologic factors and surgical treatment outcome were also studied. The results showed that thymosin beta10 was mainly expressed in the cytoplasm of lung cancer cells, and the overexpression of thymosin beta10 was correlated with advanced clinical stage (P = .026), distant metastases (P = .016), lymph node metastases (P = .007), poor degree of differentiation (P = .03), and poor postoperative survival (P = .004). Furthermore, thymosin beta10 overexpression was associated with vascular endothelial growth factor (P = .004), vascular endothelial growth factor-C (P = .017), microvessel density (P = .000), and lymphatic vessel density (P = .002). The lowest survival rate was observed in the patients with high thymosin beta10, positive vascular endothelial growth factor, and high microvessel density (P = .007) or in the patients with high thymosin beta10, positive vascular endothelial growth factor-C, and high lymphatic vessel density (P = .005). These results suggest that thymosin beta10 might induce microvascular and lymphatic vessel formation by up-regulating vascular endothelial growth factor and vascular endothelial growth factor-C in lung cancer tissues, thus promoting the distant and lymph node metastases and being implicated in the progression of non-small cell lung cancer.

Cyclooxygenase 2 Expression in Colorectal Cancer with DNA Mismatch Repair Deficiency

Cyclooxygenase 2 (COX-2) overexpression is a frequent but not universal event in colorectal cancer. It has been suggested that COX-2 protein expression is reduced in colorectal cancer with a defective mismatch repair (MMR) system, a phenomenon commonly associated with hereditary nonpolyposis colorectal cancer (HNPCC) but also present in up to 15% of sporadic tumors. To assess COX-2 expression in a large series of fully characterized colorectal cancer patients with respect to the MMR system and to dissect the mechanisms responsible for altered COX-2 expression in this setting. MMR-deficient colorectal cancer were identified in a nationwide, prospective, multicenter study (EPICOLON project). Control MMR-proficient colorectal cancer patients were randomly selected. COX-2 expression was evaluated by immunohistochemistry. Personal and familial characteristics, as well as MSH2/MLH1 expression and germ line mutations, were evaluated. One hundred fifty-three patients, 46 with MMR deficiency and 107 with MMR proficiency, were included in the analysis. Overall, tumor COX-2 overexpression was observed in 107 patients (70%). COX-2 overexpression was observed in 85 patients (79%) with a MMR-proficient system, but only in 22 patients (48%) with a MMR-deficient colorectal cancer (P < 0.001). The lack of COX-2 overexpression was independently associated with a MMR-deficient system (odds ratio, 3.89; 95% confidence interval, 1.78-8.51; P = 0.001) and a poor degree of differentiation (OR, 3.83; 95% CI, 1.30-11.31; P = 0.015). In the subset of patients with a MMR-deficient colorectal cancer, lack of COX-2 overexpression correlated with a poor degree of differentiation, no fulfillment of Amsterdam II criteria, absence of MSH2/MLH1 germ line mutations, presence of tumor MSH2 expression, and lack of tumor MLH1 expression. CpG island promoter hypermethylation of COX2 was observed in 6 of 18 (33%) tumors lacking COX-2 expression in comparison with 2 of 28 (7%) tumors expressing this protein (P = 0.04). Up to half of MMR-deficient colorectal cancer do not show COX-2 overexpression, a fact observed almost exclusively in patients with sporadic forms. COX2 hypermethylation seems to be responsible for gene silencing in one third of them. These results suggest the potential utility of nonsteroidal anti-inflammatory drugs in HNPCC chemoprevention and may explain the lack of response of this approach in some sporadic tumors.

Neoadjuvant therapies for hepatocellular carcinoma before liver transplantation: A critical appraisal

Hepatocellular carcinoma (HCC) is a major health problem, being the fifth most common cancer worldwide. The incidence of HCC is increasing in Europe and the United States, and it is currently the leading cause of death among patients with cirrhosis. The advent of surveillance programs has led to a change in the stage of tumors detected. In more than half of the cases, these tumors will be suitable for potentially curative treatments, such as resection, transplantation, and percutaneous ablation.

Expanding HCC criteria for liver transplant: The urgent need for prospective, robust data

Expanding HCC criteria for liver transplant: The urgent need for prospective, robust data

Survival of Young Patients after Gastrectomy for Gastric Cancer

It has been suggested that gastric cancer has a worse prognosis in young patients, but the data are controversial. The aim of this study was to compare the 5-year survivals after gastrectomy for gastric cancer in two groups of patients (those < or = 45 years of age and those (> 45 years) and to determine some of the prognostic factors. The 5-year survival was significantly better for patients < or = 45 years of age. Survival was also better for young patients with a curative resection and also for those with lymph node metastases. However, survival was not significantly different for the two groups when the resection was not curative and when the lymph nodes were not involved. Survival was no different for the two groups when compared at each stage, although a multivariate analysis showed that age > 45 years, moderate or poor degree of differentiation of the tumor, advanced tumors, the presence of lymph node involvement, and a noncurative resection were independent negative prognostic factors. Long-term survival after gastrectomy for gastric cancer depends on the stage of the disease; the age of the patient is not a decisive factor.

Prognostic factors and survival in endocrine tumor patients: comparison between gastrointestinal and pancreatic localization

Since gastro-entero-pancreatic endocrine tumors are rare and heterogeneous diseases, their prognosis and long-term survival are not well known. This study aimed at identifying prognostic factors and assessing long-term survival in gastro-entero-pancreatic endocrine tumors. A total of 156 patients enrolled. Prognostic factors were determined by univariate/multivariate analysis; survival rates were assessed by the Kaplan-Meier method. The tumors were non-functioning in 59.6% of patients, and originated from the pancreas in 42.9%. At diagnosis, 64.3% of patients had metastases. The tumors were well differentiated in 89.6% of patients. Ki67 was >2% in 39.6% of patients. Primary tumor size was >3 cm in 49.6% of cases studied. For the univariate analysis, the negative prognostic factors were: pancreatic origin (rate ratio 4.64, P = 0.0002), poorly differentiated tumor (rate ratio 7.70, P = 0.0001), primary tumor size >3 cm (rate ratio 4.26, P = 0.0009), presence of distant metastases (liver: rate ratio 5.88, P = 0.01; distant extra-hepatic: rate ratio 13.41, P = 0.0008). The pancreatic site, the poor degree of differentiation and the distant metastases were confirmed as negative prognostic factors at multivariate analysis. Overall 5-year survival rate was 77.5%. Survival rates differed according to: primary tumor site (62% for pancreatic vs 89.9% for gastrointestinal tract, P = 0.0001) and size (65.7% for >3 cm vs 88.8% for < or = 3 cm, P = 0.0003), degree of differentiation (22% for poor vs 86.8% for good, P < 0.0001), Ki67 (53.5% for > 2% vs 90.1% for < or = 2%, P = 0.003), metastases (96.1, 77, 73.3 and 50.1% for absent, local, liver and distant extra-hepatic metastases respectively), age at diagnosis (85.3% for < or = 50 years vs 70.3% for > 50 years, P = 0.03). Although 64.3% of gastro-entero-pancreatic endocrine tumors present metastases at diagnosis, the 5-year survival rate is 77.5%. Pancreatic site, a poor degree of tumor cell differentiation and distant extra-hepatic metastases are the major negative prognostic factors.

Expression of drs mRNA in human lung adenocarcinomas

The drs gene was originally isolated from a rat primary embryo fibroblast cDNA library as a suppressor gene against v-src transformation. We have previously shown that expression of drs mRNA was markedly reduced in a variety of human cancer cell lines, including those of the colon, bladder, and ovary. Furthermore, introduction of drs cDNA by retrovirus vector into these cancer cell lines caused suppression of anchorage-independent growth without affecting cell proliferation. These findings suggest that down-regulation of drs mRNA is closely correlated with expression of malignant phenotypes in development of human cancers. To clarify the correlation between down-regulation of drs mRNA and malignant tumor formation in human tumor tissues, we examined the expression of drs mRNA in well-differentiated, moderately differentiated, and poorly differentiated lung adenocarcinoma tissues by in situ mRNA hybridization. The results clearly indicated that expression of drs mRNA was markedly reduced in 5 of 5 poorly differentiated lung adenocarcinomas examined but significantly expressed in normal lung tissues and 5 of 7 moderately-differentiated and 3 of 5 well-differentiated lung adenocarcinoma tissues. Neither gross deletion nor rearrangement of the drs genome was detected in these tissues. Down-regulation of drs mRNA was also observed in human lung adenocarcinoma cell lines derived from poorly differentiated adenocarcinomas. Our results suggest that down-regulation of drs mRNA is correlated with a poor degree of differentiation and progression of lung adenocarcinoma. HUM PATHOL 33:615-619. Copyright 2002, Elsevier Science (USA). All rights reserved.

Increased risk of tumor seeding after percutaneous radiofrequency ablation for single hepatocellular carcinoma.

Radiofrequency (RF) ablation is an alternative to percutaneous ethanol injection (PEI) for single nonsurgical hepatocellular carcinoma (HCC) and is currently used as adjuvant therapy before liver transplantation. This phase II study assesses the treatment-related complications and response rate of RF for the treatment of single HCC < or = 5 cm. Percutaneous RF was performed under conscious sedation and ultrasound (US) guidance with an electrical generator connected to a single cooled-tip electrode. Neoplastic cells in peripheral blood (reverse transcription-polymerase chain reaction for alpha fetoprotein [AFP] messenger RNA) were analyzed before and after RF. Treatment response was assessed by spiral computed tomography (CT) at 1 month and every 3 months by US or spiral CT thereafter. Thirty-two patients (20 men; age 67 +/- 4 years; 78% hepatitis C virus; 24 Child-Pugh A) with a mean tumor size of 2.8 cm (25 patients < or = 3 cm) were treated by RF (1.25 sessions; mean time, 22.1 +/- 2 minutes). Adjuvant PEI was performed in 9 cases. Complete response was achieved in 21 patients (65%), being significantly higher for HCC < or = 3 cm (76% vs. 29%, P = .03). After a median follow-up of 10 months, 8 patients showed treatment-related morbidity. Four of them (12.5%) showed biopsy-proven needle-track seeding detected between 4 to 18 months. Neoplastic seeding was related to subcapsular location (P = .009), poor differentiation degree (P = .02), and baseline AFP levels (P = .02). Thus, RF ablation with cooled-tip needle for HCC is associated with a high risk of neoplastic seeding. Iatrogenic dissemination was related to subcapsular location or an invasive tumoral pattern, and has to be considered when selecting curative treatments for HCC or adjuvant therapies before liver transplantation.

Flow cytometric measurement of ploidy and proliferation in effusions of ovarian carcinoma and their possible prognostic significance

The cellular DNA pattern of ascites and pleural effusions from 81 patients with advanced ovarian carcinoma was prospectively studied by means of flow cytometric DNA analysis. The degree of ploidy and the proportion of S-phase values were correlated to histological differentiation, to status, and to the development of disease. According to DNA indices, the cell populations distributed in the diploid to peridiploid and in the tri- to tetraploid range. Aneuploidy was more frequently associated with poor degree of differentiation, with progressive disease, and with higher proportion of cells in S phase. Thus, although patients with stable disease had a significantly larger proportion of tumors with diploid DNA content, all except four patients were dead within a median survival period of 12 months. No correlation was observed between total survival period and ploidy; however a significantly shorter survival time was noted in patients whose ascites comprised cell populations with S-phase values exceeding 15%.

Hepatic resection of metastasis from colorectal carcinoma. Morbidity, mortality, and pattern of recurrence.

To identify the factors that determine the morbidity and mortality of liver resection of metastases from colorectal carcinoma and the variables that may influence the pattern of recurrence, the survival time and the disease-free rate, a univariate and-multivariate statistical analysis (30 variables using Student's t-test, Fischer's exact test, and chi square test) was performed. Intraoperative blood loss of greater than 3500 ml was found to be a significant risk factor to developing postoperative complications (p less than 0.05 by x2). After a mean follow-up of 25.8 months, 26 of the 35 patients studied (74%) had recurrent disease. In the univariate analysis, the following factors appear to be reliable predictors of early recurrence: poor degree of differentiation of the primary colorectal tumor, the presence of multiple liver metastases, the male gender, and the presence of tumor at the margin of the resected hepatic tissue (p less than 0.05). However, only the latter two factors appeared also to affect the survival time and the disease-free rates at 2 years after hepatic resection of metastases (p less than 0.05). In the multivariate analysis (factors tested simultaneously), presence of an advanced liver metastatic disease (Stage II or III) consistently indicated early recurrence and poor survival (p less than 0.005). The liver was the most common site of recurrence as the sole site of recurrence (54%) or in combination with other sites (88%)--followed by the lungs (31%) and the site of colonic resection (8%). Twenty-nine (83%), 14 (40%), and nine (26%) patients survived without recurrent disease at 1, 2, and 3 or more years, respectively, after hepatic resection of metastases. In six patients (17%), no significant palliation was noted, primarily because of early recurrence (less than 6 months). From this data, resection of hepatic metastases from colorectal cancer appears to offer a realistic therapeutic option to a selected group of patients, but only if the resective procedure can be performed with an operative mortality rate of less than 5%.

Surgical treatment of carcinoma of the clitoris

Thirty-eight consecutive patients were treated with either vulvectomy (14) or in combination with groin dissection (24) according to the same treatment protocol. The crude 5-year survival was 50% and the corrected 5-year survival was 66%. Three patients died post-operatively. Endophytic tumor, poor degree of differentiation, and involvement of lymph nodes resulted in higher mortalities. No patient with involvement of deep inguinal or pelvic nodes could be cured. The study concludes that invasive squamous cell carcinoma of the clitoris should be treated, in the same was as the same tumor in other areas of the vulva, with radical surgery.

Cancer of the urinary bladder category t2, t3, ( N XM 0) treated by interstitial radium implant: Second report

Three-hundred-twenty-eight patients with bladder cancer category T 2 N xM 0 and 63 patients with category T 3 N xM 0 have been treated by 3 times 3.5 Gy external irradiation followed by a radium implant. Overall 5- and 10-year survival in the T 2 category are 56 % and 37 %. In the T 3 category they are 39 % and 13 %, respectively. The intercurrent death (i.e. without evidence of bladder malignancy) corrected actuarial survival percentage in the T 2 category is 75 % at 5 years and 69% at 10 years. The corresponding percentages in the T 3 category are 62% and 59%. Prognosis is worsened by the following factors: more than 1 diagnostic transurethral resection, a pathological intravenous pyelography, non-papillary structure and poor degree of differentiation of the growth. Prognosis in category T 3 , as compared with category T 2 , is worse because of the prevalence of bad prognosticators in this T 3 category. Therapeutic adaptation to these findings might improve prognosis in the future.