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PubMed2004

[Clinical characteristics of and the related factors to the relapse of chronic hepatitis B after lamivudine withdrawal].

OBJECTIVES: To investigate the cases of chronic hepatitis B relapse after lamivudine withdrawal, and to find clinical characteristics and related factors to them. METHODS: 46 cases of chronic hepatitis B relapse after lamivudine withdrawal were investigated and followed up. The diagnosis and the course of the diseases before therapy with lamivudine, the dosage, effects, period of treatment, the reasons for lamivudine withdrawal, the biochemistry, immunological and virulogical data in each period, YMDD mutation, pre-C mutation and prognosis after relapse were recorded. RESULTS: The periods of treatment of 32.6% of patients in this group were shorter than 52 weeks. The HBV DNA of 93.6% of patients turned negative at the time of lamivudine withdrawal and returned to positive in all of those patients when relapsed; of the 6.4% of patients who did not turn negative at the time of lamivudine withdrawal, their HBV DNA was elevated more than 2 log when relapsed. A majority of patients (71.7%) did not ask their physicians when they decided to withdraw from lamivudine. There were 61.5% of the other patients who withdrew from lamivudine on the advice of physicians but they were not followed up. The state of their illness in 71.7% (33/46) patients was more severe than before their lamivudine therapy. In these cases, the YMDD mutation was detected in 78.8% of patients (chi2 = 23.23, P<0.01), and pre-C mutation was detected in 84.8% of patients (chi2 = 21.04, P<0.01), higher than that in the cases with aggrevation of their illnesses before the lamivudine therapy. The median time between lamivudine withdrawal and relapse was 12 weeks; it was negatively correlated with ALT (r = 0.32, P<0.05) detected at the time of lamivudine withdrawal. The severity of the illness at the time of relapse was related with age (r = 0.40, P<0.01) and YMDD mutation (r = 0.31, P<0.05). The prognosis was related with the age of the patient (r = 0.49, P<0.01), the diagnosis (r = 0.39, P<0.01), TBil (r = 0.46, P<0.05) and ALT (r = 0.32, P<0.05) detected before lamivudine therapy, HBeAg became negative when lamivudine was withdrawn (r = 0.31, P<0.05), TBil (r = 0.55, P<0.01) and PTA (r = 0.57, P<0.01) detected when relapsed. CONCLUSION: A majority of patients did not follow the lamivudine treatment recommendation of the experts group on lamivudine clinical practice in China. The major reason for relapse perhaps was revived HBV DNA multiplication, which induces damage of hepatocytes after lamivudine withdrawal. The YMDD mutation and/or pre-C mutation may be one of the factors that aggravate the damage of hepatocytes during the relapse. The factors including age of the patient, diagnosis before the treatment, TBil and ALT detected before lamivudine therapy, HBeAg turning to negative when lamivudine is withdrawn, and TBil and PTA detected during relapse may all impact the prognosis.

Adolescent↗
PubMed2005

A new human acute monocytic leukemia cell line SHI-1 with t(6;11)(q27;q23), p53 gene alterations and high tumorigenicity in nude mice.

BACKGROUND AND OBJECTIVES: Human leukemia cell lines are of great value in leukemia research. Thus far 36 leukemia cell lines carrying the 11q23 translocation and MLL rearrangements, including two cell lines with t(6;11)(q27;q23) and an MLL-AF6 fusion gene have been described. We have established a new monocytic cell line with t(6;11), designated SHI-1, and herein describe its biological characteristics. DESIGN AND METHODS: Mononuclear cells isolated from the bone marrow of a patient with acute monocytic leukemia (AML-M5b) at relapse were inoculated and passaged by liquid culture. The biological features of the cell line were characterized by morphological assays, flow cytometry, cytogenetic analysis, reverse transcription polymerase chain reaction (RT-PCR), direct sequencing, fluorescence in situ hybridization (FISH), clonogenic culture, quantitative fluorescent PCR, zymography, short tandem repeating sequences-PCR (STR-PCR), multiplex-FISH (M-FISH), and tumorigenic capacity in nude mice. RESULTS: The SHI-1 cell line has been maintained in continuous culture without any external cytokines for three years. The morphology and immunoprofile of the cells show typical features of monocytic lineage. Karyotypic analysis demonstrated a t(6;11)(q27;q23) translocation accompanied by a deletion of 17p, which are the same abnormalities as were seen in the leukemia cells of this patient in relapse. The MLL-AF6 fusion transcript and the loss of one p53 allele were proven by chromosome painting, FISH and RT-PCR analysis in both SHI-1 cells and the primary leukemia cells. A point mutation of ATC-->ACC at codon 195 of exon 6 in another p53 allele was found by direct sequencing of DNA in SHI-1 cells as well as in the primary leukemia cells. Neither Epstein-Barr virus nor mycoplasma was detected in SHI-1 cells. Tumor masses were found in all sixteen mice 9-19 days after subcutaneous injection of SHI-1 cells. DNA fingerprinting confirmed the authenticity of the cell line. INTERPRETATION AND CONCLUSIONS: SHI-1 is a new monocytic leukemia cell line with the t(6;11) translocation, p53 gene alterations, and high tumorigenicity in nude mice. It could be a valuable tool in the study of leukemogenesis.

Adult↗
PubMed1988

Relapse cell population differs from acute onset clone as shown by absence of the initially activated N-ras oncogene in a patient with acute myelomonocytic leukemia.

We have conducted a follow-up study of a patient with myelomonocytic leukemia exhibiting an N-ras mutation (Gln61----Lys61) using the polymerase chain reaction method and synthetic oligonucleotide hybridization probes. This method allowed us to detect as little as 3% of N-ras-mutated cells within a population. When the patient went into clinical remission, the mutation became undetectable. When a relapse occurred, the blasts did not carry the N-ras mutation. Analysis of M13 cloned amplified N-ras sequences from relapse DNA revealed exclusively the wild type allele of the N-ras gene. These findings suggest that the relapse cell population is derived from a different clone than the acute phase population. Furthermore, the data argue that N-ras mutation is not an initiating lesion in this case of acute myelomonocytic leukemia (AMML).

Cell Transformation, Neoplastic↗
PubMed1997

[Epidermal hamartoma and blaschkitis in an adult].

INTRODUCTION: Many inherited skin diseases and nevus malformations are distributed according to the Blaschko's lines. Some inflammatory skin diseases are also distributed according to these lines. OBSERVATION: In 1989 a 49-year-old woman presented with an epidermal nevus affecting the left hand and leg from the infancy. In 1994, inflammatory, linear papules occurred on the left leg, obscuring and continuing the previous lesions, on the left thigh and on the left clavicular region. On light microscopy, spongiosis of the epidermis and an infiltrate of lymphocytes and histiocytes in the superficial dermis were shown. Subintrant crops of new inflammatory lesions occurred for a period of two years, whereas the nevus lesions of the left hand persisted unchanged. These findings led to the final diagnosis of blaschkitis associated to epidermal nevus on the same Blaschko's lines. DISCUSSION: The distribution of a skin disease according to the Blaschko's lines underlines the presence in the affected skin of a mutant clone, with a different genetic material as compared with the normal skin. An early mutation giving raise to a mutant clone and affecting the left hemibody could be hypothesized in our case. The mutation probably involved a pleiotropic gene. The latter initially was responsible for thickening of the skin. Moreover, the mutation was also responsible for a particular proneness towards an exogenous factors, able to induce a persistent inflammatory skin eruption following the same lines.

Female↗
PubMed2005

Prognostic value of KIT mutation in gastrointestinal stromal tumors.

AIM: To examine the prevalence and prognostic significance of C-kit gene mutation and analysis the correlation of C-kit gene mutation and the clinicalpathologic parameters of GISTs. METHODS: Eighty-two GISTs were studied for the mutation of C-kit gene by PCR-SSCP, DNA sequence. Statistical comparison were used to analysis the correlation of C-kit gene mutation and clinicalpathology, clinical behavior, recurrence. RESULTS: (1) Mutation-positive and mutation-negative GISTs were 34 and 48,respectively; (2) Among these patients with C-kit mutation remained a significantly poor prognosis associated with 59% 3-year survival compared to those whose tumors did not; (3) Tumor size, PCNA index, mitotic cell number, presence of necrosis, microscopic invasion to adjacent tissues, recurrence and distant metastasis among mutation-positive and mutation-negative GISTs were significantly different. CONCLUSION: C-kit mutation is a undoubtedly pivotal event in GIST and may be associated with poor prognosis. Evaluation of C-kit gene mutation may have both prognosis and therapeutic significances.

Adult↗
PubMed1999

Recurrent molecular abnormalities in type VII collagen in Southern Italian patients with recessive dystrophic epidermolysis bullosa.

In this study we searched for mutations in the type VII collagen gene (COL7A1) in 10 families from Southern Italy with severe generalised recessive dystrophic epidermolysis bullosa using PCR amplification of genomic DNA, heteroduplex analysis and direct nucleotide sequencing. Our principal aim was to identify any recurrent mutations in COL7A1 that might facilitate future mutation detection strategies in this population. Three recurrent COL7A1 mutations were delineated in six of the 10 families: a frameshift mutation in exon 4, 497insA, was detected in three affected individuals from three families, a deletion mutation at the acceptor splice site of intron 114/exon 115, 8441-14del21, was found in five patients in three of the families, and an intron 49 acceptor splice site mutation, 4783-1 G-to-A, was identified in three subjects in two families (GenBank accession no, L02870). Haplotype analyses showed evidence for propagation of common ancestral mutant COL7A1 alleles for each of these recurrent mutations. These results contribute significantly to understanding the nature of COL7A1 pathology in patients from Southern Italy and in designing future approaches to mutation detection.

Alleles↗
PubMedDate not supplied

TP53 mutations do not correlate with locoregional recurrence in stage I tongue carcinomas.

BACKGROUND: The abrogation of the TP53 gene is considered to play a central role in the development of human cancers. Exons 5-8 harbor mutations most frequently, mainly of the missense type, resulting in accumulation of the p53 protein. The importance of these alterations as prognostic factors, are issues of controversy. MATERIAL AND METHODS: Thirty-four patients suffering from stage I tongue carcinoma had been treated with a local surgical excision of the tumor. Seventeen patients had developed a local recurrence in the tongue or cervical (regional) metastases while 17 patients, matched for age and gender to the former group, had no recurring disease within follow-up. Protein p53 was detected through immunohistochemical (IHC) analysis using antibody CM1. Exons 5-8 of the TP53 gene were amplified through the Polymerase Chain Reaction (PCR). The presence of mutations analyzed by CDGE (Constant Denaturant Gel Electrophoresis) and detected mutations were subjected to sequencing. RESULTS: 20 out of 34 tumors (59%) showed mutated TP53, 18 tumors were IHC p53 positive, but the correlation between CDGE and IHC was only 56%. Sequencing of the gene was possible in 8 cases. CONCLUSIONS: Neither the presence of mutations nor immunostaining had any impact on the risk of recurrence expressed as life-table analysis of time to recurrence.

Adult↗
PubMed1999

Malignant chondroblastoma presenting as a recurrent pelvic tumor with DNA aneuploidy and p53 mutation as supportive evidence of malignancy.

We report a rare case of malignant chondroblastoma, which presented in a 47-year-old man as a recurrent tumor, 18 years following wide excision of a typical pelvic chondroblastoma. Radiologic studies of the recurrent tumor showed a large, lytic, destructive lesion of the right pelvic bones and femur, with a pathologic fracture of the latter, a large pelvic soft tissue mass, and multiple pulmonary metastases. Biopsy tissue showed typical features of chondroblastoma, but also increased nuclear atypia, hyperchromasia, and pleomorphism, compared to the original tumor, and, most significantly, abnormal mitotic figures. Immunohistochemical studies of the recurrent tumor revealed p53 mutation and extensive proliferative activity, and flow cytometric studies showed DNA aneuploidy, none of which was present in the original tumor. The patient received chemotherapy and radiation, but died of disease eight months after presentation. We also review chondroblastoma in general, to assign this unusual lesion to a tumor subtype.

Aneuploidy↗
PubMed1996

The role of p53 mutation and protein expression in primary and recurrent adenoid cystic carcinoma.

Adenoid cystic carcinoma (ACC) is a malignant tumor of salivary gland origin having a propensity for spread by direct extension or perineural invasion with frequent recurrences. Previous reports have shown that tumor behavior is not always predicted by histological pattern or stage. Little is known of the role of p53 tumor suppressor gene mutation and altered protein expression with respect to ACC pathobiology and recurrence. The authors analyzed a group of 14 ACC specimens (seven primary; seven recurrent) from 13 patients treated between 1987 to 1993. Formalin-fixed, paraffin-embedded specimens were reviewed and subjected to, immunohistochemistry (p53, DO-7, DAKO, Nutley, NJ; and WAF-I, Ab-1, Oncogene Sciences, Uniondale, NY) on 4-microm-thick histological sections as a prelude to p53 genotyping. In one case, sequential material representing primary and recurrent tumor was analyzed. Each tumor specimen was topographically genotyped for p53 point mutational change. Minute tissue samples were removed from unstained sections, polymerase chain reaction (PCR) amplified for p53 exons 5 to 8, and then underwent direct DNA sequencing. Six of seven primary ACCs were p53 immunostain negative. Four of seven recurrent (57%) ACCs were p53 immunopositive. These tumors showed varying degrees of p53 immunopositivity ranging from diffuse, intense staining of most tumor cells (n = 1) to interspersed, strongly positive cells mixed with predominantly p53 immunonegative cells (n = 4). All tumors were WAF-I immunostain negative. Two of the most immunopositive recurrent tumors each manifested a single type of p53 point mutation detected by p53 DNA genotyping (p53 exon 5:codon 175 and p53 exon 6:codon 199). In the case in which both primary and recurrent tumor was available, only the recurrent tumor contained point mutational damage. Negative immunostaining for p53 in primary ACC suggests that p53 mutation is not important in early events involving development of this tumor. In contrast, the frequent presence of p53-positive cells and the detection of point mutations in recurrent ACC suggests that p53 alterations are involved in later stages of tumor progression, important in the phenomenon of ACC recurrence.

Adult↗
PubMed1999

Identification of the Chinese IVS-II-654 (C-->T) beta-thalassemia mutation in an immigrant Turkish family: recurrence or migration?

In this study we describe the Chinese IVS-II-654 (C-->T) beta-thalassemia mutation for the first time in an immigrant Turkish family living in Istanbul and originating from Xanthe, Greece. Four members of the family, representing 3 generations, are heterozygous for this mutation. A detailed family history demonstrated a Greek origin for members of 5 generations with no records of migration or consanguineous marriages. Analysis of polymorphic nucleotides located at the 5' end of the beta-globin chromosomes bearing the IVS-II-654 mutation in the family described carried the (AT)9(T)5 type of microsatellite sequence and the ACATCCCCA haplotype. These 2 haplotype components favor a non-Eastern Asian origin for this chromosome, hence suggesting an independent origin for the IVS-II-654 mutation described in this family.

Adult↗
PubMed2006

Polymorphism in the angiotensinogen gene, hypertension, and ethnic differences in the risk of recurrent coronary events.

The M235T mutation of the human angiotensinogen gene has been shown to be associated with elevated circulating angiotensinogen concentrations and essential hypertension. The frequencies of the 235T allele are significantly different in black and white subjects. We analyzed the independent contribution of the angiotensinogen M235T mutation to the development of recurrent coronary events (coronary-related death, nonfatal myocardial infarction, or unstable angina) in a cohort of 916 black (n=145) and white (n=771) postmyocardial infarction patients who were prospectively studied during an average follow-up of 28 months. The frequency of the 235T allele was significantly higher among black (82%) than among white (44%) patients (P<0.001). There was no evidence for Hardy-Weinberg disequilibrium. During follow-up, 41 cardiac events (28%) occurred in blacks and 197 (26%) in whites (P=0.49). Multivariate Cox proportional hazards regression analysis demonstrated that 235T homozygosity was independently associated with increased risk of coronary events among black (hazard ratio: 2.37; P=0.04) but not white (hazard ratio: 0.93; P=0.68) patients, with a significant ethnic-related interaction effect (P for the difference=0.04). Among hypertensive black patients, the TT genotype was associated with a 3.3-fold (P=0.02) increase in the risk of coronary events. Our findings suggest that homozygosity for the 235T mutation in the angiotensinogen gene is an independent risk factor for coronary events in black postmyocardial infarction patients. The presence of hypertension significantly augments the risk associated with this genetic mutation.

Aged↗
PubMed2024

LRP4 mutations promote tumor progression and resistance to anti-PD-1 therapy in recurrent hepatocellular carcinoma.

BACKGROUND AND AIMS: HCC recurrence is a major factor limiting long-term survival and the cause of most deaths in patients with HCC. However, molecular characterization and potential therapeutic targets of recurrent HCC remain mostly unknown. APPROACH AND RESULTS: We performed whole-exome sequencing in 63 matched primary and recurrent HCC tumors and combined the data with whole-genome sequencing results in 43 paired samples from our previous study. Sanger sequencing was used to identify all low-density lipoprotein receptor-related protein 4 ( LRP4 ) coding exons in 203 additional patients with recurrent HCC. We identified LRP4 somatic mutations in 7.8% (24/309) of recurrent tumors and only 0.97% (3/309) of primary tumors ( p <0.001). Prognosis after the second liver resection was poorer in patients with an LRP4 mutation. Biofunctional investigations demonstrated that inactivating LRP4 mutations promoted tumor progression and immunosuppression. Mechanistically, mutated LRP4 reduced intratumoral conventional type 1 dendritic cell and CD8 + T cell infiltration by repressing C-C motif chemokine ligand 4 expression and secretion through activation of &#x3b2;-catenin signaling, resulting in resistance to anti-programmed cell death protein-1 therapy. Patients with recurrent HCC carrying an LRP4 mutation did not benefit from anti-programmed cell death protein-1 treatment after their second resection surgery. A &#x3b2;-catenin inhibitor-reversed LRP4-induced resistance to anti-programmed cell death protein-1 therapy in humanized tumor-bearing mice. CONCLUSIONS: Our results identified novel LRP4 mutations important in recurrent HCC. Inactivating LRP4 mutations were associated with resistance to anti-programmed cell death protein-1 therapy and could be useful biomarkers for precision therapy in patients with recurrent HCC.

Humans↗
PubMedDate not supplied

Coexistence of factor V G1691A and factor II G20210A gene mutations in a thrombotic family is associated with recurrence and early onset of venous thrombosis.

Two G-to-A mutations at positions 1691 of the factor V (FV) gene and 20210 of the prothrombin (FII) gene have been associated with an increased risk of venous thromboembolism. We report a thrombosis-prone family in which one subject--the propositus who exhibited combined heterozygous FV G1691A and FII G20210A mutations--showed spontaneous and early clinical onset (at 23 years), recurrences of deep-vein thrombosis and pulmonary embolism. His asymptomatic father carried the FII G20210A substitution and his mother, characterized by an isolated thrombotic episode on occasion of surgery (at 48 years), carried the FV G1691A substitution. In the maternal lineage, one of the propositus' uncles had thrombosis on occasion of a bone fracture (at 65 years) despite the absence of known prothrombotic defects. A sister of the propositus carried the FII G20210A and the brother the FV G1691A mutation. They have been asymptomatic until now. The propositus' two children, 20 and 16 years old, both carry the FV G1691A substitution and have been asymptomatic until now. The plasma levels of FII were higher in carriers of the FII G20210A allele if compared with noncarriers, and the activated protein C resistance phenotype, associated with the FV Leiden mutation, showed a complete correlation with the FV G1691A mutation. Despite the very limited number of thrombotic cases involved in this survey, which does not allow statistically sound conclusions, the data obtained from this family suggest that the synergy of inherited factors and transient risk conditions could play a key role in the occurrence of thrombotic accidents.

Adolescent↗