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C Caldas

Publications and source records attributed to C Caldas.

69 records · Page 4Linked to original sources
PubMed1996

Frequent somatic deletion of the 13q12.3 locus encompassing BRCA2 in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) has consistent 13q chromosomal abnormalities detected by conventional cytogenetics. Using interphase cytogenetics we show deletion of a 1-megabase 13q12.3 locus, encompassing the BRCA2 gene, in 80% of 35 CLL cases studied. Homozygous deletion of BRCA2, located within the minimal deletion consensus, was detected in a significant population of cells in 60% of the cases. Deletion of the previously described 13q14 locus (analyzed with RB1 and D13S25 probes) was seen in 63% of the cases. Homozygous deletion of RB1 was seen in one case. Seven of the cases (32%) with D13S25 deletion had a population of cells with homozygous deletion. Deletions at the 13q12 and 13q14 loci result from distinct events because they were not contiguous. These data provide evidence for the existence of a new tumor suppressor locus in B-cell CLL located at 13q12.3. BRCA2, located within the minimal deletion consensus, is a candidate for the gene whose somatic inactivation could play a role in the initiation and or progression of B-cell CLL.

Alleles↗
PubMed1995

Allelotype of pancreatic adenocarcinoma using xenograft enrichment.

p53 and MTS1 are known to be mutationally inactivated in pancreatic adenocarcinoma. Other tumor suppressor genes are likely also to play a role. To define chromosomal arms which may harbor additional tumor suppressor genes, we performed an extensive allelotype on pancreatic cancer utilizing a xenograft enrichment technique. Eighty-eight percent (28/32) of primary tumors gave rise to xenografts. Eighteen cases were used in a PCR-based allelotype using 283 polymorphic markers, over 2800 informative assays, and an average coverage of 4.1 informative markers per chromosomal arm per case. Highly frequent allelic loss (> 60%) was seen at chromosomes 1p, 9p, 17p, and 18q. Moderately frequent allelic loss (40-60%) was seen at 3p, 6p, 6q, 8p, 10q, 12q, 13q, 18p, 21q, and 22q. The average fractional allelic loss was 0.36. Allelic and sequence stability was demonstrated among 64 parallel and second-passage xenografts derived from 12 cases of pancreatic adenocarcinoma with the ascertainment of over 3000 single alleles. The findings were confirmed in primary tumors. In only two instances were discrepancies revealed between the allelic loss data obtained from corresponding parallel xenografts, probably due to the xenografting of minor subpopulations, reflecting genetic heterogeneity of the primary tumor.

Adenocarcinoma↗
PubMed1995

Common occurrence of APC and K-ras gene mutations in the spectrum of colitis-associated neoplasias.

BACKGROUND/AIMS: Chronic colitis is associated with an increased risk of colorectal neoplasia, creating a need for early diagnosis in this population. Little is yet known of the genetic changes of early lesions. Cases of colitis-associated neoplasia were analyzed for APC and K-ras mutations with special emphasis given to the spectrum of noninvasive lesions. METHODS: Ten patients were studied. APC mutations were screened by an in vitro synthesized protein assay, and K-ras mutations were screened by a ligation assay. RESULTS: APC mutations were found in 5 patients, including dysplasias. K-ras mutations were present in 5 patients and in all classes of lesions, including 5 of 14 lesions indefinite for dysplasia. In only 2 patients were no mutations found. CONCLUSIONS: Mutations of APC and K-ras are common in colitis-associated neoplasia and can occur early in neoplastic progression. Serrated lesions and lesions indefinite for dysplasia may harbor genetic changes and thus are clonal, highlighting the importance of distinguishing them histologically. Assays for APC and K-ras mutations are promising as adjuncts to surveillance programs. Care will be needed in their application because the confident diagnosis of early lesions presumed to be of lesser clinical importance will raise new issues concerning prudent patient management.

Adult↗
PubMed1995

Epstein-Barr virus and bone marrow transplantation.

The development of Epstein-Barr virus-associated posttransplantation lymphoproliferative disease correlates with increased viral burden in lymphocytes. Patterns of viral gene expression in tumors are complex and heterogenous. Conventional chemotherapy for postransplantation lymphoproliferative disease is sometimes associated with long-term disease-free survival. A promising new approach involves adoptive cellular immunotherapy with donor lymphocytes or T-cell lines. Allogeneic bone marrow transplantation has been successful in patients with an inherited lack of immune response to Epstein-Barr virus.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

Detection of K-ras mutations in the stool of patients with pancreatic adenocarcinoma and pancreatic ductal hyperplasia.

Pancreatic adenocarcinoma is the fifth leading cause of cancer death in the United States. Mutations in the K-ras oncogene occur in 85% of pancreatic adenocarcinomas and have also been identified in 75% of pancreatic ducts with mucinous cell hyperplasia seen in association with chronic pancreatitis. We identified K-ras mutations in 65% of duct lesions associated not only with chronic pancreatitis but also with pancreatic adenocarcinoma and distal common bile duct carcinoma (cholangiocarcinoma). These observations make K-ras a potential candidate for a gene-based diagnostic test. Indeed, K-ras mutations have been demonstrated in the pancreatic secretions of patients with pancreatic carcinoma and pancreatic intraductal neoplasia. We analyzed stool specimens for mutated K-ras sequences using a plaque hybridization assay in patients with pancreatic adenocarcinoma, cholangiocarcinoma, and chronic pancreatitis. K-ras mutations were detected in stool specimens from 6 of 11 patients with pancreatic adenocarcinoma, from 2 of 3 patients with cholangiocarcinoma, and from 1 of 3 patients with chronic pancreatitis. The K-ras mutations found in stool specimens from patients with pancreatic carcinoma were identical to those in the primary cancer in five cases. Mutations found in the stool specimens from one patient with pancreatic cancer, one patient with chronic pancreatitis, and two patients with cholangiocarcinoma were the same as those identified in pancreatic ductal mucinous cell hyperplasia lesions present in the resected pancreas specimens. Our data suggest that the K-ras mutations originating from cells of pancreatic adenocarcinomas and from cells shed by abnormal pancreatic duct epithelium can be detected in the stool. These results support the further exploration of stool K-ras analysis as a potential screening assay for the early detection of pancreatic adenocarcinoma and precursor lesions such as pancreatic ductal mucinous cell hyperplasia.

Acute Disease↗
PubMed1994

p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions.

Pancreatic adenocarcinoma is a major cause of cancer death, and yet little is known about its molecular pathogenesis. We identified p53 mutations in 19 (70%) of 27 primary pancreatic adenocarcinomas. Most were missense point mutations, and the mutations were distributed primarily within the evolutionarily conserved domains. Transitions predominated over transversions, and many of the transitions were at CpG dinucleotides. Intragenic deletions accounted for 32% of mutations and were associated with decreased survival (P = 0.0016). A review of 1937 published p53 mutations revealed that the occurrence of small (1-2 base pairs) microdeletions varied among different types of human neoplasms and that pancreatic adenocarcinoma had one of the highest frequencies (13% of 47 mutations, P = 0.0036). Many small deletions occurred in iterations of single bases, but this did not fully account for their pattern of distribution, and there was evidence for the involvement of homocopolymer (polypurine:polypyrimidine) tracts. This may represent a more widespread phenomenon, because microdeletions occur in similar sequence patterns in reports of somatic and germ line mutations among genes other than p53.

Adenocarcinoma↗
PubMed1994

Allelotype of pancreatic adenocarcinoma.

Knowledge of the patterns of allelic loss has been useful in identifying the spectrum of the tumor suppressor genes involved in various tumor types. Such analyses in pancreatic carcinoma have been difficult due to the characteristic host desmoplastic reaction to the neoplasm. We have assembled the first allelotype of pancreatic adenocarcinoma, a survey for allelic loss among each chromosomal arm, using seven cryostat-dissected neoplasms. The fractional allelic loss in these seven neoplasms was 0.18, a value similar to that seen previously in colorectal carcinoma. Alleles of chromosome 18q (lost in five of six informative tumors) and of chromosome 17p (lost in four of five informative tumors) were commonly affected. Neither APC mutations (33 neoplasms), allelic shifts of dinucleotide repeats (26 neoplasms), nor immunohistochemical evidence of retinoblastoma protein underexpression (7 neoplasms) were found. Further evaluation of allelic loss in pancreatic cancer would benefit from improved methods for the analysis of lost genetic material which overcome the problems posed by the high admixture of nonneoplastic stromal and inflammatory cells in these tumors.

Adenocarcinoma↗
PubMed1994

Molecular genetic profiles of colitis-associated neoplasms.

BACKGROUND/AIMS: A major long-term risk for patients with chronic idiopathic colitis is the development of colorectal dysplasia and adenocarcinoma. The presence or absence of specific genetic changes in these lesions will provide important insights into the relationship of colitis-associated dysplasia and the development of carcinoma. METHODS: A case-study approach was used to develop detailed molecular genetic profiles of advanced dysplasias and carcinomas from six patients with ulcerative colitis or Crohn's colitis. RESULTS: Numerous genetic alterations were identified in each of the dysplasias and carcinomas profiled. These genetic alterations involved many of the same targets found in sporadic colorectal tumors and included multiple sites of allelic deletion, microsatellite instabilities, and mutations of the K-ras, p53, and APC genes. The progression of dysplasia to carcinoma was often accompanied by an accumulation of these mutations. CONCLUSIONS: Genetic alterations are common in colitis-associated neoplasia, just as in sporadic colorectal neoplasia. This could have important implications for the evaluation and treatment of patients with colitis.

Adenocarcinoma↗
PubMed1994

Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma.

The MTS1 gene on chromosome 9p21 encodes the p16 inhibitor of cyclinD/Cdk-4 complexes, and is deleted or mutated in a variety of tumour types. We found allelic deletions of 9p21-p22 in 85% of pancreatic adenocarcinomas. Analysis of MTS1 in pancreatic carcinomas (27 xenografts and 10 cell lines) showed homozygous deletions in 15 (41%) and sequence changes in 14 (38%). These included eight point mutations (four nonsense, two missense and two splice site mutations) and six deletions/insertions, all accompanied by loss of the wild-type allele. Sequencing of MTS1 from primary tumours confirmed the mutations. Coexistent inactivations of both MTS1 and p53 was common and suggests that abnormal regulation of cyclin-dependent kinases may play an important role in the biology of pancreatic carcinoma.

Adenocarcinoma↗
PubMed1994

Case report: transverse myelitis associated with Epstein-Barr virus infection.

Transverse myelitis is a rare complication of Epstein-Barr virus (EBV) infection. This article describes a case of a previously healthy patient with a subacute transverse myelopathy. The cerebrospinal fluid showed lymphocytic pleocytosis and protein elevation. A magnetic resonance imaging scan demonstrated abnormal spinal cord signal intensity over several cervical and thoracic segments, suggesting the diagnosis of transverse myelitis. The patient was treated with high-dose corticosteroids and had a rapid improvement. Serologic studies for other viruses were negative; antibody tests indicated acute EBV infection. It is thought this represents a case of transverse myelitis associated with acute EBV infection. Although a few similar patients have been reported previously, this case is the first where EBV serology suggested the etiology at the time of diagnosis, when EBV antibody titers and polymerase-chain reaction for EBV DNA in the cerebrospinal fluid were performed, and when a magnetic resonance imaging scan was used for diagnosis and follow-up.

Adult↗
PubMed1994

Salvage therapy in epithelial ovarian cancer.

Table 1 summarizes studies in which clinical or pathologic response rates can be determined. The majority of patients in these studies had macroscopic drug-resistant tumors, and most had received cisplatin-based chemotherapy. It is noteworthy that the response rate in this group of patients is considerably higher than the 30% to 36% seen with the most active salvage therapies, such as taxol (paclitaxel). Like most trials of salvage chemotherapy for refractory ovarian carcinoma, many responses were short-lived. Toxicity in these studies is comparable to that seen in trials of ASCT in other solid tumors. The promising results observed in these small studies of ASCT in ovarian carcinoma warrant further investigation focused on defining which groups of patients are likely to benefit from this approach. Based on evidence from the lymphohematopoietic malignancies, it would seem reasonable to use ASCT in patients early in the course of their disease before extensive pretreatment and preferably at a time of minimal tumor burden. Some groups have been exploring ASCT as consolidation therapy after surgery and limited debulking chemotherapy. Based on kinetic models of tumor growth, other investigators have suggested that multiple courses of high-dose chemotherapy with ASCT after debulking surgery may result in more cures than a single ASCT after conventional chemotherapy. The feasibility of performing sequential ASCT has been well documented. So far the best drug regimens, the number of cycles that should be used, and the patients who should be candidates for high-dose chemotherapy and ASCT remain undefined. Presently, there is no role for this therapeutic modality outside of well-designed clinical trials.

Antineoplastic Agents↗
PubMed1993

Taxol in epithelial ovarian cancer.

Epithelial ovarian cancer is the fifth most common cause of cancer death in women. The management of patients with advanced disease involves surgery followed by platinum-based chemotherapy, but most patients will have either residual or recurrent disease. Salvage therapy in these patients is poor, with response rates less than 20%. Taxol, a new antineoplastic agent, was first noted to have activity in platinum-resistant ovarian cancer in a phase I study. Since then, response rates of 20% to 35% have been noted in several phase II studies involving hundreds of patients. Major toxicities include neutropenia and peripheral neuropathy. Taxol dose escalation with granulocyte-colony stimulating factor support, and Taxol in combination with cisplatin, have been tested and shown to be feasible. Intraperitoneal administration of Taxol is possible and appears advantageous from a pharmacokinetic perspective. A phase III study of Taxol and cisplatin in suboptimal disease was completed, and toxicity data show that Taxol administration is safe in a multi-institutional setting. Planned clinical development of Taxol includes use in less bulky stage III disease and dose escalation in platinum-resistant disease. Taxol has already become a major treatment of platinum-resistant disease. Further investigation will determine its role in the overall management of ovarian cancer.

Cisplatin↗
PubMed1993

Paclitaxel (Taxol) therapy in ovarian carcinoma.

Ovarian carcinoma is the most common cause of death among the gynecologic malignancies. Primary therapy in advanced disease involves debulking surgery followed by platinum-containing chemotherapy. Despite such treatment, most patients die of residual or recurrent disease. Paclitaxel (TAXOL), a new antineoplastic agent, has response rates of 20% to 35% in phase II studies in patients with refractory ovarian cancer. Most women treated in these studies had platinum-resistant disease. Toxicity was primarily hematologic and neurologic. The findings from a large European-Canadian study suggest that hematologic toxicity is schedule dependent whereas neurologic toxicity is dose dependent. Dose escalation of paclitaxel with granulocyte colony-stimulating factor support and combinations of paclitaxel with cisplatin have been tested and shown to be feasible. Intraperitoneal administration of paclitaxel also is possible and advantageous from a pharmacokinetic perspective. In a multi-institutional randomized trial, primary treatment of patients with suboptimal disease with the combination of paclitaxel and cisplatin was compared with cyclophosphamide and cisplatin. Toxicity data from this completed trial show paclitaxel to be safe in this setting. Efficacy awaits maturity of survival data. Future clinical development of paclitaxel will include its use in less bulky disease and further evaluation of its dose escalation in advanced platinum-resistant disease. Paclitaxel currently is considered first-line treatment for platinum-resistant ovarian carcinoma. Further clinical investigation will determine its role in the primary management of ovarian cancer.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Synchronous mature teratomas of the ovary and liver: a case presenting 11 years following chemotherapy for immature teratoma.

Immature teratoma is a rare ovarian germ cell tumor with an aggressive clinical behavior. Treatment involves surgical resection, usually followed by chemotherapy. Since the introduction of postoperative chemotherapy several cases of "transformation" of this malignant tumor into mature teratoma (retroconversion) have been described. Usually retroconversion presents during the first year of diagnosis. We report a case of synchronous mature teratomas of the ovary and liver presenting 11 years following chemotherapy for stage III immature ovarian teratoma. The CT scan appearance, incidence, and biological significance of this phenomena are discussed.

Adult↗