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Biomedical subjects

Yoshiyuki Kakehi

Publications and source records attributed to Yoshiyuki Kakehi.

At least 19 recordsLinked to original sources

[Temporary inferior vena cava filter applied to 4 patients with urological disease].

A temporary inferior vena cava (IVC) filter was placed in 4 patients. Patient 1 had an advanced testicular germ cell tumor with IVC tumor thrombosis, patient 2 presented with a large adrenal tumor with IVC tumor thrombosis, patient 3 was found to have deep vein thrombosis following grade 3b renal injury, and patient 4 was suffering severe SLE with renal vein thrombosis. The temporary inferior vena cava filter prevented pulmonary thromboembolism in all cases, and no adverse reaction was observed. Temporary inferior vena cava filter is safe and useful to prevent pulmonary thromboembolism associated with urological disorders.

Adolescent↗

[Treatment strategy for advanced prostate cancer with bone metastases].

The introduction of PSA screening has led to confirming a shift towards an earlier pathological stage in the diagnosis of prostate cancer. Consequently, the proportion of detecting early stage prostate cancer has clearly been increasing. On the other hand, progressive cancers in the form of distant metastases and locally advanced ones that have been confirmed at the initial diagnosis exhibit a constant rate. In addition, there have been a lot of cases where hormonal resistance was acquired during hormonal therapy which resulted in advanced metastases of the prostate. Prostate cancer has a tendency to be metastatic to bones. Combining the fact that the survival period of patients undergoing treatment is prolonged after metastases, the length of suffering caused by complications, such as ostealgia, pathological fracture and myelopathy, becomes an issue in which QOL and ADL of the patient are sacrificed for a long time. As for treatment of prostate cancer with metastases, a palliative treatment is common in the clinical scene. However, we can extend a life prognosis with use of radiotherapy and surgical treatment in addition to the palliative treatment at an appropriate time. It appears that a combination of new chemotherapy and hormonal therapy will be promising. In the future, we believe that the appearance of new anticancer drugs, endocrine therapies, bisphosphonates and strontium treatment could be used as a part of the treatment strategy for prostate cancer with bone metastases.

Activities of Daily Living↗

Biochemical and molecular characterization of a novel choline-specific glycerophosphodiester phosphodiesterase belonging to the nucleotide pyrophosphatase/phosphodiesterase family.

Nucleotide pyrophosphatases/phosphodiesterases (NPPs) are ubiquitous membrane-associated or secreted ectoenzymes that release nucleoside 5'-monophosphate from a variety of nucleotides and nucleotide derivatives. The mammalian NPP family comprises seven members, but only three of these (NPP1-3) have been studied in some detail. Previously we showed that lysophospholipase D, which hydrolyzes lysophosphatidylcholine (LPC) to produce lysophosphatidic acid, is identical to NPP2. More recently an uncharacterized novel NPP member (NPP7) was shown to have alkaline sphingomyelinase activity. These findings raised the possibility that other members of the NPP family act on phospholipids. Here we show that the sixth member of the NPP family, NPP6, is a choline-specific glycerophosphodiester phosphodiesterase. The sequence of NPP6 encodes a transmembrane protein containing an NPP domain with significant homology to NPP4, NPP5, and NPP7/alkaline sphingomyelinase. When expressed in HeLa cells, NPP6 was detected in both the cells and the cell culture medium as judged by Western blotting and by enzymatic activity. Recombinant NPP6 efficiently hydrolyzed the classical substrate for phospholipase C, p-nitrophenyl phosphorylcholine, but not the classical nucleotide phosphodiesterase substrate, p-nitrophenyl thymidine 5'-monophosphate. In addition, NPP6 hydrolyzed LPC to form monoacylglycerol and phosphorylcholine but not lysophosphatidic acid, showing it has a lysophospholipase C activity. NPP6 showed a preference for LPC with short (12:0 and 14:0) or polyunsaturated (18:2 and 20:4) fatty acids. It also hydrolyzed glycerophosphorylcholine and sphingosylphosphorylcholine efficiently. In mice, NPP6 mRNA was predominantly detected in kidney with a lesser expression in brain and heart, and in human it was detected in kidney and brain. The present results suggest that NPP6 has a specific role through the hydrolysis of polyunsaturated LPC, glycerophosphorylcholine, or sphingosylphosphorylcholine in these organs.

Amino Acid Sequence↗

Inhibition of prostate carcinogenesis in probasin/SV40 T antigen transgenic rats by raloxifene, an antiestrogen with anti-androgen action, but not nimesulide, a selective cyclooxygenase-2 inhibitor.

The chemopreventive efficacies of raloxifene and nimesulide, an anti-estrogen but with anti-androgen action and a cyclooxygenase-2 (COX-2) selective inhibitor, respectively, were evaluated in probasin/SV40 T antigen (Tag) transgenic (TG) rats. The treatment groups were placebo, nimesulide (400 p.p.m. in basal diet p.o.), raloxifene (slow-release pellets implanted s.c., 5 mg/kg/day), raloxifene (5 mg/kg/day) plus nimesulide (400 p.p.m.), and raloxifene (10 mg/kg/day) plus nimesulide (400 p.p.m.). Animals were killed at 17 weeks of age, and prostate tissues were harvested and weighed by lobes. Tissues were evaluated by histology, immunohistochemistry, and western blot analyses and blood was collected to measure the testosterone levels. All the animals in the placebo group had tumors in each lobe compared with only 43% each in the dorsolateral (DLP) and anterior prostate (AP) of the animals treated with raloxifene (10 mg/kg/day) plus nimesulide. The total prostate weights and adenocarcinoma portions were significantly reduced in the three raloxifene-treated groups, whereas atrophic glands were increased. There were no significant differences between the nimesulide alone and placebo groups or between the raloxifene (5 mg/kg/day) alone and raloxifene (5 mg/kg/day) plus nimesulide group, suggesting a lack of cancer preventive effects of the COX-2 inhibitor in this animal model. PCNA positive rates in ventral prostate (VP) and DLP, and androgen receptor (AR) levels in VP were significantly reduced in the three raloxifene-treated groups. Furthermore, circulating testosterone was decreased after raloxifene (10 mg/kg/day) plus nimesulide treatment. These results demonstrate that raloxifene, but not nimesulide, inhibits prostate carcinogenesis in SV40 Tag TG rats associated with a decline in circulating testosterone levels and a loss of AR expression, as well as an inhibition of cell proliferation.

Adenocarcinoma↗

Cavernous nerve reconstruction during radical prostatectomy by sural nerve grafting: surgical technique in nerve harvesting and grafting.

The authors performed cavernous nerve reconstruction by nerve grafting in 22 patients (unilateral-16, bilateral-6) between August 2001 and June 2004. Harvesting of the sural nerve was unexpectedly more difficult than nerve grafting in the extremities or the head and neck, because a knee and lumbar bending position was impossible due to the pelvic surgical field. Suture of the grafted nerve on the distal side required great effort, because there was only sufficient space for one hand at the maximum in a deep region of the pelvic cavity, and the nerve ends easily become invisible by inflow of even a small amount of urine or blood. The mean time of the nerve harvesting and grafting was 1 hr 50 min for unilateral grafting and 2 hr 40 min for bilateral grafting. Recovery of erectile function was observed in about half the patients who had undergone surgery nearly 1 year before. Since harvesting of the sural nerve and nerve grafting were more difficult than expected, modification and improvement of many surgical elements, such as improvement of surgical devices and application of endoscopic techniques, are necessary.

Aged↗

Randomized controlled trial to evaluate radiotherapy +/- endocrine therapy versus endocrine therapy alone for PSA failure after radical prostatectomy: Japan Clinical Oncology Group Study JCOG 0401.

A randomized controlled trial has started in Japan to evaluate radiotherapy and endocrine therapy for prostate-specific antigen (PSA) failure after radical prostatectomy. Patients who have PSA failure after radical prostatectomy for localized prostate cancer (T1-2N0M0) are randomized into treatment groups of either radiotherapy +/- endocrine therapy or endocrine therapy alone. The Urologic Oncology Study Group (UOSG) in the Japan Clinical Oncology Group (JCOG) composed of 36 specialized institutions will recruit 200 patients. The primary end-point is time to treatment failure (TTF) of bicalutamide, and secondary end-points are TTF of protocol treatment, progression-free survival, overall survival, adverse events and quality of life (QOL). The Clinical Trial Review Committee of the JCOG approved the protocol on April 13, 2004, and the study was activated on May 17, 2004.

Adult↗

Association of a genetic polymorphism of the E-cadherin gene with prostate cancer in a Japanese population.

The E-cadherin gene has been identified as having a physiological role in cellular attachment, and is hypothesized to participate in carcinogenesis. A polymorphism (an A to C substitution) in the 5'-untranslated region has a direct effect on E-cadherin gene transcriptional regulation. We explored the association between E-cadherin gene polymorphism and the risk of prostate cancer in a Japanese population. The subjects consisted of 236 patients with prostate cancer, 209 benign prostatic hyperplasia (BPH) patients and 139 male controls. A marginally significant difference was found between prostate cancer patients and male controls (P = 0.053). No significant difference was observed between prostate cancer and BPH patients. When patients with prostate cancer were divided into two groups, stage A+B and stage C+D, a significant difference was observed between progressive cancer patients (stage C+D) and male controls (odds ratio = 1.93, P = 0.016). It is possible that the presence of one A allele resulted in an increased risk of cancer progression.

Aged↗

Expression of a novel biomarker, EPCA, in adenocarcinomas and precancerous lesions in the prostate.

PURPOSE: EPCA, a nuclear matrix protein, has been identified as a novel prostate cancer marker through protein profiling analyses comparing prostate cancer and its normal counterpart. A recent study of prostate biopsy specimens revealed that EPCA stained positive in the cancer negative biopsy cores of individuals with cancer at later biopsy. We clarified the relationship between EPCA expression and clinicopathological parameters, including grade and stage. Morphological characteristics of EPCA positive cells in noncancerous tissues were also analyzed. MATERIALS AND METHODS: Prostate tissue specimens were obtained from 50 patients with localized prostate cancer and 10 with invasive bladder cancer. EPCA expression was analyzed with a polyclonal antibody. Anti-P504S/anti-p63/anti-34betaE12 monoclonal antibodies were used for adjunct diagnosis for prostatic intraepithelial neoplasia. A monoclonal antibody, CD45RO, was used to confirm inflammatory infiltrates surrounding focal atrophic glands. RESULTS: EPCA staining was positive in the prostate samples of 94% of patients with prostate cancer but it was completely negative in samples from patients with bladder cancer. There was no correlation of EPCA staining intensity with Gleason grade or pT stage. In noncancerous tissues adjacent to major cancer foci EPCA was positive in 86% of prostate cancers. Most EPCA positive glands adjacent to cancer consisted of prostatic intraepithelial neoplasia and proliferative inflammatory atrophy. CONCLUSIONS: EPCA seems to reflect nuclear matrix alterations that occur in the earlier stage of prostate carcinogenesis. Individuals in whom the prostate is influenced by this field effect may be detected with this new biomarker.

Adenocarcinoma↗

Uroplakin II as a promising marker for molecular diagnosis of nodal metastases from bladder cancer: comparison with cytokeratin 20.

PURPOSE: Current methods used to determine pathological examination of the lymphatics after radical cystectomy are tedious and costly. We performed a systemic study of uroplakin II (UP II) and cytokeratin 20 (CK 20) expression in pelvic lymph nodes on multiple sides in patients with bladder cancer. MATERIALS AND METHODS: A total of 82 pelvic lymph node and 19 bladder tumor samples were obtained from 21 patients with bladder cancer by radical cystectomy with pelvic lymphadenectomy for reverse transcriptase-polymerase chain reaction assay. RESULTS: Of the 19 bladder tumor tissue specimens 19 (100%) and 13 (68.4%) were positive for UP II and CK 20 mRNA expression, respectively. UP II mRNA was detected in 15 of 16 pelvic lymph node samples (93.8%) with pathologically proven metastases, whereas 9 (56.6%) were positive for CK 20 mRNA. The reverse transcriptase-polymerase chain reaction assay for UP II was statistically more sensitive than that for CK 20 in detecting not only primary tumors, but also metastatic pelvic lymph nodes (p = 0.0179 and 0.0373, respectively). Of 66 pelvic lymph node samples without metastasis UP II was detected in 6 (10%), while CK 20 was not. In addition, UP II and CK 20 mRNA could be detected in at least 50 and 500 bladder cancer HT1197 cells, respectively. CONCLUSIONS: These results indicate that UP II might be a more useful marker than CK 20 for detecting micrometastases of bladder cancer in the pelvic lymph nodes, although a greater number of patients and longer followup are needed to come to a definitive conclusion.

Aged↗

Ten cases of congenital urethral stricture in childhood with enuresis.

BACKGROUND: To report short-term clinical outcomes of endoscopic correction of congenital urethral stricture in 10 boys who suffer from enuresis resistant to conservative therapy. METHODS: Fifteen boys ranging between 5 and 15 years old consulted our clinics for nocturnal and diurnal enuresis which had not been improved by medication and behavioral therapy. Among them, voiding cystography revealed bulbar narrowing (Cobb's Collar) in 10 cases and vesico-ureteral reflux was found in four cases (seven ureters). Endoscopically, this lesion was recognized as a ring-form stenosis just distal to the urethral sphincter. It was incised with infantile urethrotome. RESULTS: Vesico-ureteral reflux was resolved in four ureters and improved in one. In all cases, daytime enuresis resolved dramatically and night enuresis became controllable. CONCLUSIONS: Boys who suffer from diurnal enuresis should immediately be explored for the existence of congenital urethral stenosis. Early resolution may bring about better urinary behavior.

Adolescent↗

[The Japanese translation and cultural adaptation of Expanded Prostate Cancer Index Composite (EPIC)].

PURPOSE: To develop a Japanese version of the Expanded Prostate Cancer Index Composite (EPIC): originally designed to measure the Quality of Life of localized prostate cancer patients, after careful assessments of cross-cultural equivalence, face validity and practically. METHODS: We translated the original version that consisted of 50 items into a preliminary Japanese version. This multi-stage procedure included a forward-translation, back-translation and discussion with the original developer. Additionally, we tested the preliminary Japanese version on 11 localized prostate cancer patients and identified problems with its cross-cultural equivalence, practicality. Based on the findings of this pretest, we revised the Japanese version. Consensus by discussion among all researchers was obtained through out this process. RESULTS: The original developer reviewed the back-translation of the preliminary Japanese version: some wording was revised. In the pretest, the average age of patients was 68.8 years old. Four of the sexual subscale showed over 10 percent missing data. In five items, all patients chose identical answers. We conducted an in-depth qualitative investigation of these items. The average response time was 11.7 minutes. We revised the Japanese to reflect patients' opinions as much as possible. Items which were showed problems in terms of cross-cultural adaptation included questions measuring 'bother' and two items of the sexual subscale. The wordings of these items were revised so that Japanese patients could easier understand them. We ensured that the original developer's intentions remained the same. The original developed approved all revisions. CONCLUSION: We translated and adapted the original EPIC to the Japanese culture. The Japanese version of EPIC was found to be functional in the pretest.

Asian People↗

[Quality of life after radical prostatectomy].

Prostate cancer is increasingly detected at early stages and patients can choose various forms of treatment which have favorable survival outcomes. Radical prostatectomy is a major procedure for treating early stage prostate cancer curatively. The instruments of measuring health related QOL (HRQOL) accurately for early prostate cancer treatment were developed. Some of the instruments were useful in Japan after translating into Japanese and pilot testing. Many authors have reported QOL data after radical prostatectomy. These data suggested that general and urinary domains of HRQOL recovered rapidly after radical prostatectomy, but recovery of sexual domains of HRQOL took longer. Recently several authors have reported that HRQOL were affected with ethnic and cultural differences. These results strongly suggested a need for longitudinal surveys in Japanese patients.

Humans↗

[Cancer prevention].

The 12 th Oncology Forum discussed the progress and future strategy of cancer prevention in Japan. The National Cancer Center has established a research center for screening focusing on the most common six cancer, stomach, lung, liver, colon, breast and uterus cancer. The program so far had a cumulative detection rate of 3.3%, which is high,and may reflect the selection of subjects. Screening and chemoprevention is also being investigated in prostate cancer, but the issues centre on how to make this widely available. High risk subjects can also be identified for breast cancer. Obesity and family history are especially important. In colorectal cancer studies are evaluating different diets, but general application is not yet possible and the infrastructure to implement any general screening and prevention does not exist. Development of pharmaceutical treatments for prevention is difficult because of the need for very safe treatments, and also because of the length of time needed to carry out studies. Overall, cancer prevention is still in evolution. New approaches are needed, and new infrastructure will be needed at a government level to implement this.

Breast Neoplasms↗

Induction and function of CYR61 (CCN1) in prostatic stromal and epithelial cells: CYR61 is required for prostatic cell proliferation.

BACKGROUND: CYR61 is an extracellular matrix-associated protein that promotes adhesion, migration, and proliferation of endothelial cells and fibroblasts. Prostate enlargement, which frequently causes the urethral compression, is often histologically observed as stromal and epithelial hyperplasia in an enlarged gland. To determine whether or not CYR61 has relevance to the progression of benign prostatic hyperplasia (BPH), we investigated the induction of CYR61, and also examined its function in both prostatic stromal and epithelial cells. METHODS: Recombinant CYR61 protein was used for the examination of the activity of CYR61 as to cell adhesion and proliferation. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was utilized to screen for inducers of the CYR61 gene in prostatic cells. Finally, the effects of an anti-sense oligonucleotide, which could reduce the production of CYR61, on the morphology and growth of prostatic cells were also examined. RESULTS: Recombinant CYR61 protein promotes prostatic cell adhesion and proliferation. The mRNA for CYR61, a growth factor-inducible immediate early gene, was markedly induced by fetal bovine serum (FBS) within 1 hr, and strongly induced by transforming growth factor-beta1 (TGF-beta) for at least 19 hr following stimulation. The suppression of CYR61 production with an anti-sense oligonucleotide causes obvious morphological changes of prostatic cells. Furthermore, we have shown that CYR61 is necessary, at least in part, for FBS-induced prostatic cell proliferation, because dramatic inhibition of cellular growth was caused by the suppression of CYR61 production with the addition of the anti-sense oligonucleotide before FBS stimulation. CONCLUSIONS: In this study, we demonstrate that serum growth factors induce the CYR61 gene in both stromal and epithelial cells, and that CYR61 plays functional roles in cell adhesion, morphology, and proliferation, supporting its involvement in benign prostatic enlargement. These results strongly suggest that CYR61 is a key molecule, and therefore could be a potential therapeutic target in prostatic hyperplastic growth.

Cell Adhesion↗

Prostatic acid phosphatase degrades lysophosphatidic acid in seminal plasma.

Lysophosphatidic acid (LPA) is a lipid mediator with multiple biological activities and is detected in various biological fluids, including human seminal plasma. Due to its cell proliferation stimulatory and anti-apoptotic activities, LPA has been implicated in the progression of some cancers such as ovarian cancer and prostate cancer. Here, we show that prostatic acid phosphatase, which is a non-specific phosphatase and which has been implicated in the progression of prostate cancer, inactivates LPA in human seminal plasma. Human seminal plasma contains both an LPA-synthetic enzyme, lysoPLD, which converts lysophospholipids to LPA and is responsible for LPA production in serum, and its major substrate, lysophosphatidylcholine. In serum, LPA accumulated during incubation at 37 degrees C. However, in seminal plasma, LPA did not accumulate. This discrepancy is explained by the presence of a strong LPA-degrading activity. Incubation of LPA with seminal plasma resulted in the disappearance of LPA and an accompanying accumulation of monoglyceride showing that LPA is degraded by phosphatase activity present in the seminal plasma. When seminal plasma was incubated in the presence of a phosphatase inhibitor, sodium orthovanadate, LPA accumulated, indicating that LPA is produced and degraded in the fluid. Biochemical characterization of the LPA-phosphatase activity identified two phosphatase activities in human seminal plasma. By Western blotting analysis in combination with several column chromatographies, the major activity was revealed to be identical to prostatic acid phosphatase. The present study demonstrates active LPA metabolism in seminal plasma and indicates the possible role of LPA signaling in male sexual organs including prostate cancer.

Acid Phosphatase↗

Down-regulation of macrophage inhibitory cytokine-1/prostate derived factor in benign prostatic hyperplasia.

BACKGROUND: Macrophage inhibitory cytokine-1 (MIC-1) is a member of transforming growth factor-beta/bone morphogenetic protein (BMP) superfamily. Despite its potential role in prostatic regulation, little is known about its biological activity. METHODS: Expression profiling using 42K Affymetrix HuGeneFL array was conducted to compare symptomatic benign prostatatic hyperplasia (BPH), histological BPH without symptoms, and normal prostate samples from donors. MIC-1 gene expression was analyzed by RT-PCR in pure culture of prostate epithelial and stromal cells, and prostate cancer cells, LNCaP, PC-3, DU-145. Influence of androgens on MIC-1 expression in LNCaP cells was analyzed by Northern blot. Enhancement of promoter activity of MIC-1 by androgens was examined using reporter assays. RESULTS: In contrast to normal prostates, MIC-1 gene was down-regulated in BPH samples with symptoms and histological BPH obtained from cystoprostatectomy specimens (P < 0.005 and P < 0.01, respectively). Expression level of MIC-1 in androgen-sensitive LNCaP cells was high and enhanced by androgens, whereas in the androgen-insensitive PC-3 and DU-145 cells the expression level was low. An 11 kb promoter region of MIC-1 gene was identified to be 6- to 12-fold activated by androgens. CONCLUSIONS: Down-regulation of MIC-1 may play a role in the development of BPH. MIC-1 is positively regulated by androgens, but other regulatory factors remain unclear.

Adult↗

Increased expression of CYR61, an extracellular matrix signaling protein, in human benign prostatic hyperplasia and its regulation by lysophosphatidic acid.

Lysophosphatidic acid (LPA) is an endogenous lipid growth factor that is thought to play important roles in cell proliferation and antiapoptosis and therefore may have roles in the development and progression of benign prostatic hyperplasia (BPH). CYR61 (CCN1), on the other hand, is a growth factor-inducible immediate early gene that functions in cell proliferation, differentiation, and extracellular matrix synthesis. Here we show the close relationship between LPA-induced expression of CYR61 and prostate enlargement. CYR61 mRNA and protein were dramatically up-regulated by 18:1 LPA (oleoyl-LPA) within 1 and 2 h, respectively, in both stromal and epithelial prostatic cells. G protein-coupled receptors, i.e. Edg-2, Edg-4, and Edg-7, for LPA were also expressed in both stromal and epithelial prostatic cells. Furthermore, on DNA microarray analysis for normal and BPH patients, CYR61 was found to be related to the development and progression of BPH, regardless of symptoms. Although CYR61 mRNA was synthesized in hyperplastic epithelial cells, in many cases of BPH, CYR61 protein was detected in both the epithelial and stromal regions of BPH patient tissues. The functional contribution of CYR61 to prostatic cell growth was demonstrated by recombinant CYR61 protein and anti-CYR61 neutralizing antibodies, which inhibited CYR61-dependent cell spreading and significantly diminished cell proliferation, respectively. In conclusion, these data support the hypothesis that LPAs induce the expression of CYR61 by activating G proteincoupled receptors and that CYR61 acts as a secreted autocrine and/or paracrine mediator in stromal and epithelial hyperplasia, demonstrating the potential importance of this signaling mechanism in the disease.

Aged↗

Clinical evaluation of p53 mutations in urothelial carcinoma by IHC and FASAY.

OBJECTIVES: To assess the clinical benefit of the methods of detection of p53 mutations in human urothelial carcinoma. METHODS: A total of 75 surgical specimens of urothelial carcinoma were analyzed using a yeast functional assay (FASAY) and immunohistochemistry (IHC), in combination with sequencing analysis. RESULTS: Of the 75 specimens, 24 (32.0%) were positive (mutant) by FASAY and 23 (30.7%) were positive by IHC. The sequencing analysis confirmed that all 24 FASAY-positive tumors harbored mutations, and no mutations were detected in any FASAY-negative tumors. In contrast, nuclear accumulation of p53 protein was detected in 9 (17.6%) of 51 tumors with no mutation, and 10 (41.7%) of 24 tumors with mutation showed no positive staining on IHC. The mutations detected by FASAY and IHC were both associated with stage and grade, but null mutations of p53 were not associated with stage. Concerning chemosensitivity, 6 (85.7%) of 7 responders harbored p53 missense mutations in at least one allele (P = 0.01), and only 4 (57.1%) were judged positive by IHC (P = 0.13). CONCLUSIONS: FASAY is more accurate than IHC in detecting the various types of p53 mutations, suggesting that a comprehensive approach for the detection of p53 mutations may be essential to elucidate their clinical significance.

Adult↗