Epithelial cell proliferation and gene mutation in the mucosa of gallbladder with pancreaticobiliary malunion and cancer

The significant association between pancreaticobiliary malunion (PBM), especially undilated-type PBM, and a high risk of gallbladder cancer is known. Reflux and stasis of pancreatic juice induce various epithelial changes in the gallbladder. Recently, epithelial hyperplasia of the gallbladder was shown to be significantly and frequently associated with undilated-type PBM, and it is suggested that the majority of epithelial hyperplasia may exist at birth or be acquired in early childhood, and thereafter present throughout the lives of PBM patients. Cell kinetic studies demonstrated a significant stepwise increase in cellular proliferative activity from normal gallbladder mucosa, through epithelial hyperplasia to cancer. Epithelial hyperplasia with increased proliferative activity may predispose the mucosa to mutational events, thereby increasing cancer risk in PBM patients. K-ras mutations were frequently detected in gallbladder cancer in PBM patients and in epithelial hyperplasia as well. Epithelial hyperplasia is demonstrated to be an important premalignant lesion of gallbladder cancer. A multistep process of carcinogenesis as a consequence of multiple genetic alterations of oncogenes and tumor suppressor genes has been demonstrated in various organs; however, there is limited information on the molecular mechanism in gallbladder carcinogenesis with PBM. Recent findings support the idea that epithelial hyperplasia plays an important role in gallbladder carcinogenesis with PBM and also support the concept that neoplastic development in gallbladder with PBM also evolves through a multistep process associated with hyperproliferation and genetic alterations. Received for publication on Jan. 31, 1999; accepted on March 29, 1999     

Detection of human papillomavirus DNA and p53 gene mutations in human prostate cancer

The relationship between integration with human papillomavirus (HPV) and p53 gene mutations in tissues of prostate cancer was examined. Tissue samples analyzed were obtained by total prostatectomy (29 stage B cancer cases) and from autopsy (22 endocrine therapy-resistant metastatic disease cases). HPV DNA was detected in 8 of 51 (16%, 5 in stage B and 3 in autopsy cases) by polymerase chain reaction (PCR) using consensus primers on L1 region. Genotypes of HPV were entirely type 16. Structural abnormalities of p53 gene were detected in 7 of the 22 autopsy cases (32%) by PCR-single-strand conformation polymorphism analysis and direct sequencing. No p53 gene mutation was found in stage B cancer cases. Analysis of mutation spectra revealed clear differences between Japanese and Westerners. There was a significant difference in the mutation frequency between stage B and autopsy cases (P < 0.01, Fisher's exact test). One case showed both integration of HPV and p53 gene mutation in different cancer foci. However, the other cases revealed an inverse correlation between the presence of HPV DNA and p53 gene mutations. These data show that p53 genetic alteration is correlated with the progression of prostate cancer, in contrast to the integration of HPV that may occur in a relatively early stage. In conclusion, this study may indicate that either p53 gene mutation or the presence of HPV's oncogenic protein E6 is involved in the development of prostate cancer. © 1996 Wiley-Liss, Inc.     

Comparative studies of prostate cancer in Japan versus the United States. A review

This article reviews the available data on prostate cancer in Japan compared with that in the United States, with emphasis on epidemiologic, pathologic, and molecular aspects. Previous studies have demonstrated ethnic/racial differences in the incidence of prostate cancer between the two countries. Recent investigations indicate that different genetic alterations or polymorphisms are related to carcinogenesis in the prostate. Comparative geographic-pathologic autopsy studies suggest that different promoting factors including genetic, epigenetic, and environmental influences may be responsible for ethnic variations in the postinduction progression of prostate cancer.     

Fluorescence in situ hybridization analysis of c-myc amplification in stage T3N0M0 prostate cancer in Japanese patients

OBJECTIVE: Genetic aberration such as the amplification of c-myc has been commonly found in advanced prostate cancer. The aim of this study was to elucidate chromosome 8 alteration, including a gain and amplification of 8q24 (c-myc gene), related to the progression and survival in advanced (Stage C) prostate cancer. MATERIALS AND METHODS: We used dual-probe fluorescence in situ hybridization with a centromere-specific probe for chromosome 8 (8cen), and with a region-specific probe for c-myc (8q24) to evaluate genetic changes in tumor samples from 50 patients who had undergone radical retropubic prostatectomy from 1986 to 2001. RESULTS: We classified the 8cen and c-myc copy numbers as normal, gain and amplification. The carcinoma foci with extra copies of c-myc, which was defined in 35 cases (70%), were divided into two groups: (a) a simple gain of the whole chromosome 8 (no increase in the c-myc copy number relative to the chromosome 8 centromere), which was identified in 15 cases (30%); and (b) a substantial amplification of c-myc (additional increases [AI] in the c-myc copy number relative to the chromosome 8 centromere), which was detected in 20 cases (40%). AI-c-myc was strongly associated with higher histopathological grades and Gleason's scores (P = 0.0330, 0.0190, respectively). Patients with the AI-c-myc had earlier disease progression (P = 0.0029) and earlier cancer death (P = 0.0087) than did patients with normal patterns. CONCLUSION: Identification of an AI-c-myc may serve as a potential marker of prostate cancer progression.     

肿瘤患者化疗相关性味觉改变调查分析

目的描述肿瘤患者化疗相关性味觉改变状况,并分析相关因素。方法采取便利抽样的方法选择北京市某肿瘤专科医院门诊化疗患者169例,采用化疗相关味觉改变量表中文版测评患者味觉改变状况,采用肿瘤患者生活质量量表测评患者生活质量状况,同时收集患者一般资料以及疾病相关资料。结果 169例中,125例患者出现味觉改变,发生率为73.96%,多为轻中度改变,其化疗相关味觉改变量表总分为7.27±2.37。条目"觉得任何东西都不好吃"得分最高、"分辨不出苦味"得分最低;味觉改变的类型和程度与患者化疗前口腔干燥、患病前嗅觉改变、是否合并高血压、化疗方案有关;患者味觉改变总分与其总体健康状况、功能维度得分呈负相关(均P0.01),与其症状维度得分呈正相关(P0.05,P0.01)。结论肿瘤患者化疗相关性味觉改变发生率高,受多重因素影响,味觉改变影响患者生活质量,需引起医护人员的重视。     

Single-cell Sequencing Reveals Variants in ARID1A,GPRC5A and MLL2 Driving Self-renewal of Human Bladder Cancer Stem Cells

Cancer stem cells are considered responsible for many important aspects of tumors such as their self-renewal, tumor-initiating, drug-resistance and metastasis. However, the genetic basis and origination of human bladder cancer stem cells (BCSCs) remains unknown. Here, we conducted single-cell sequencing on 59 cells including BCSCs, bladder cancer non-stem cells (BCNSCs), bladder epithelial stem cells (BESCs) and bladder epithelial non-stem cells (BENSCs) from three bladder cancer (BC) specimens. Specifically, BCSCs demonstrate clonal homogeneity and suggest their origin from BESCs or BCNSCs through phylogenetic analysis. Moreover, 21 key altered genes were identified in BCSCs including six genes not previously described in BC (ETS1, GPRC5A, MKL1, PAWR, PITX2 and RGS9BP). Co-mutations of ARID1A, GPRC5A and MLL2 introduced by CRISPR/Cas9 significantly enhance the capabilities of self-renewal and tumor-initiating of BCNSCs. To our knowledge, our study first provides an overview of the genetic basis of human BCSCs with single-cell sequencing and demonstrates the biclonal origin of human BCSCs via evolution analysis.

饮食指导对肺癌患者化疗相关性味觉改变的影响

目的探讨饮食指导对肺癌患者化疗相关性味觉改变的干预效果。方法按住院时间将肺癌化疗患者分为对照组38例和干预组36例。对照组给予常规护理,干预组在此基础上实施饮食指导,共持续2个化疗周期。干预前及干预后3周每周采用化疗相关性味觉改变量表评估味觉改变情况。结果干预后两组味觉改变量表总分、进食困扰和整体味觉改变维度得分差异有统计学意义(P0.05,P0.01)。结论饮食指导能够降低肺癌患者化疗相关性味觉改变的严重程度。     

COMBINED INTRAARTERIAL CISPLATIN INFUSION AND RADIATION THERAPY FOR INVASIVE BLADDER CANCER

Combined intraarterial cisplatin infusion and radiation therapy were performed as the initial treatment for 23 patients (mean age: 70 years) with invasive bladder cancers (T2 in 17, T3 in 6) who were suitable for total cystectomy. Of these patients, five who had multiple invasive cancers without laterality had their intrapelvic hemodynamics altered by embolizing a contralateral internal iliac artery. Cisplatin (50 mg) was infused into the internal iliac artery through a subcutaneous reservoir twice a week over three weeks while concurrent radiation therapy with 30 Gy, delivered in 15 fractions, was performed. Additional cisplatin infusions were given in six patients. After this combined therapy, total cystectomy and ileal conduit was performed in six patients and transurethral resection of bladder tumor (TURBT) in 17. Two of the patients who underwent total cystectomy were found to exhibit a complete response. Therefore, the overall response rate was 87%, including 13 complete responses and seven partial responses. The complete response rates in patients with clinical stage T2 and T3 disease were 53 and 67%, respectively. The complete response rate was slightly higher in patients with a non-papillary cancer than in those with a papillary one. Toxic reactions included a decrease in bladder capacity in two patients and severe diarrhea due to methicillin-resistant Staphylococcus aureus colitis in one. Other forms of toxicity, including nausea, vomiting, neurotoxicity in the gluteal region, nephrotoxicity and myelosuppression, were tolerable. All but one of the patients are alive. This patient died of distant metastasis and seven other patients had a local recurrence of bladder cancer. One patient who developed invasive bladder cancer reaching the prostatic urethra underwent total cystectomy and ileal conduit. One who had a recurrence at the same site as the previous tumor underwent partial cystectomy. Five patients who had superficial bladder cancer were easily controlled by TURBT. Finally, bladder function was preserved in 65% of all patients in this study at a mean follow-up time of 29 months. We conclude that combined intraarterial cisplatin infusion and radiation therapy is useful for the initial treatment of invasive bladder cancer because this combined therapy provides a favorable quality of life with the preservation of bladder function. Further detailed follow-up is necessary to determine whether this therapy also has a prophylactic effect on the recurrence of bladder cancer.     

CO2气腹对腹膜超微结构的影响

目的：探讨二氧化碳（CO2）气腹腹腔镜手术对人体腹膜形态学的影响。方法：对80例胆囊炎患者随机分别进行腹腔镜手术和传统开腹手术，于手术前及气腹后30min分别采集壁层腹膜，对其进行扫描电镜（SEM）检测观察腹膜间皮细胞形态学变化。结果：传统手术组开腹后间皮细胞未见明显变化，细胞形态正常，基底膜完整，关腹前腹膜结构仍然未出现明显形态学改变。腹腔镜手术组CO2低压充气30min后可见出现腹膜间皮细胞肿胀，高压充气30min可见腹膜间皮细胞间连接断裂基底膜裸露，细胞间隙可见，少量淋巴细胞和巨噬细胞。结论：CO2气腹腹腔镜手术可使腹膜形态学发生明显变化，可能是腹腔镜手术时造成肿瘤细胞发生腹膜转移的原因。     

Advances in Molecular Biological and Translational Studies in World Health Organization Grades 2 and 3 Meningiomas: A Literature Review

The treatment of World Health Organization (WHO) grades 2 and 3 meningiomas remains difficult and controversial. The pathogenesis of high-grade meningiomas was expected to be elucidated to improve treatment strategies. The molecular biology of meningiomas has been clarified in recent years. High-grade meningiomas have been linked to NF2 mutations and 22q deletion. CDKN2A/B homozygous deletion and TERT promoter mutations are independent prognostic factors for WHO grade 3 meningiomas. In addition to 22q loss, 1p, 14p, and 9q loss have been linked to high-grade meningiomas. Meningiomas enriched in copy number alterations may be biologically invasive. Furthermore, several new comprehensive classifications of meningiomas have been proposed based on these molecular biological features, including DNA methylation status. The new classifications may have implications for treatment strategies for refractory aggressive meningiomas because they provide a more accurate prognosis compared to the conventional WHO classification. Although several systemic therapies, including molecular targeted therapies, may be effective in treating refractory aggressive meningiomas, these drugs are being tested. Systemic drug therapy for meningioma is expected to be developed in the future. Thus, this review aims to discuss the distinct genomic alterations observed in WHO grade 2 and 3 meningiomas, as well as their diagnostic and therapeutic implications and systemic drug therapies for high-grade meningiomas.     

胆管癌分子机制的研究进展

胆管癌发病率逐年上升,由于缺乏有效的治疗措施,胆管癌的预后极差,这使得临床上对该疾病越来越重视.加深对胆管癌发生及生长机制的理解,有助于我们找到针对这种致死性肿瘤的治疗靶点.本文将近年来对胆管癌发病及生长调节机制方面的研究做一回顾.通过对胆管癌分子机制更好的认识,以找到诊断、治疗及预防这种致死性肿瘤的特异性的策略,进而取得满意的治疗效果.     

尿脱落细胞微卫星改变分析在膀胱肿瘤诊断中的应用

目的 选择6个微卫星位点，了解其在膀胱肿瘤诊断中的敏感性和特异性。方法 以外周血白细胞作为自身正常对照，检测31例膀胱肿瘤患肿瘤组织、尿脱落细胞以及10例正常人尿脱落细胞中的微卫星改变情况。结果 应用所选6个位点，诊断膀胱肿瘤具有90．3％的敏感性和100％的特异性，显高于尿细胞学检查的敏感性(10．3％)。结论 尿脱落细胞微卫星改变分析是一种无创、敏感、特异的诊断膀胱肿瘤的分子学方法。     

Hormonal replacement therapy and aging： Asian practical recommendations on testosterone supplementation

Profound and diffuse alterations in the production of gonadal and adrenal androgens as well as growth hormone are associated with aging. To convey this concept more appropriately, partial endocrine deficiency in the aging male (PEDAM) was introduced as a term for the phenomenon of hormonal alterations in the aging male.Hormones responsible for some of the manifestations associated with male aging are testosterone, growth hormone,dehydroepiansdrosterone (DHEA), melatonin, thyroid hormones and leptin. Of these, testosterone has been widely investigated and its beneficial and adverse effects on male bodily systems are relatively well established. However, a serious body of confusion and misunderstandings surrounding the diagnosis, treatment and monitoring of men suspected of having androgen deficiency has been raised. Therefore, it is timely to provide practical criteria for diagnosis and treatment to avoid misconception about the use of testosterone in the aging male. To provide an understanding and information of the issues, the following headings are summarized: (1) Important clinical consideration on testosterone supplementation in the aging male; (2) Asian practical recommendations on testosterone supplementation in the aging male.     

Alteration of split skin graft contraction with a synthetic dressing

Summary In a rat model, covering a split skin graft with a synthetic dressing for only one week alters the subsequent contraction characteristics of the underlying wound so that the graft increases in size in a manner similar to a full thickness skin graft.     

Does Subarachnoid Blood Extravasation per se Induce Long-Term Neuropsychological and Cognitive Alterations?

Summary  Although recent advances in medical and management strategies have reduced the mortality and morbidity rates related to subarachnoid haemorrhage (SAH), patients who survive a SAH may remain nevertheless affected by persistent cognitive and neuropsychological disturbances. The presence of these deficits has been attributed to the neurotoxic effects of the widespread subarachnoid blood. To assess the long-term neuropsychological and cognitive outcome related to subarachnoid blood extravasation per se we evaluated 20 patients affected by an unknown origin subarachnoid haemorrhage, and having SAH characteristics generally considered predictive of a favourable outcome. Patients were enrolled after a one-year interval from the initial insult, and were selected accordingly to a pre-designed protocol. We employed a complete battery of tests, assessing general cognitive and language functions, memory and construction ability, attention and vigilance, anxiety and depression. The results were compared with normal reference values and with performances of a socio-demographically homogenous sample of control volunteers. This study did not evidence any significant long-term cognitive and neuropsychological alteration after subarachnoid blood extravasation. These results indicate that the presence of subarachnoid blood initiate a number of secondary mechanisms of pathology.     

Onion and garlic extracts as potential antidotes for cadmium‐induced biochemical alterations in prostate glands of rats

Cadmium (Cd) has been implicated in increased prostate gland malignancy risk in both wildlife and humans. This study examines the chemoprotective roles of onion and garlic extracts on Cd‐induced biochemical alterations in the prostate glands of rats. Adult male Wistar rats were randomly divided into nine groups: control group received double distilled water; Cd group received Cd alone (1.5 mg/100 g bwt per day); extract‐treated groups were pre‐treated with varied doses of onion and/or garlic extract (0.5 ml and 1.0 ml/100 g bwt per day) for 1 week and then co‐treated with Cd (1.5 mg/100 g bwt per day) for additional 3 weeks. Oxidant/antioxidant status and acid phosphatase (ACP_total and ACP_prostatic) activity were examined in prostate glands. Cd intoxication caused a marked (P < 0.001) increase in lipid peroxidation (LPO) and glutathione S‐transferase (GST) levels, whereas glutathione (GSH), superoxide dismutase and catalase levels were markedly (P < 0.001) decreased. We also observed significant (P < 0.001) decrease in ACP_total and ACP_prostatic activities in prostate glands and a concomitant significant (P < 0.001) increase in the plasma. However, treatment of Cd‐intoxicated rats with onion and/or garlic extract significantly minimised these alterations. The onion extract offered a dose‐dependent protection. Our findings suggest a chemoprotective capability for onion and garlic extracts against Cd‐induced biochemical alteration in the prostate glands.     

Biological variables and prognosis of DCIS

Based on current knowledge, biological factors that have been investigated in ductal carcinoma in situ (DCIS) include histology of these lesions, the impact of margin status on local recurrence, and several genetic alterations. Optimal integration of these factors in guiding optimal therapy is of great importance, since the incidence of DCIS is rising as a result of population-based mammographic screening. Mastectomy will almost always cure patients with DCIS but represents overtreatment for many. Less extensive treatment options should combine an optimal cosmetic result with the same safety for outcome of disease as mastectomy. To guide such optimal treatment, histological classification is not sufficient and additional biological factors are being investigated for their ability to predict outcome for individual patients with DCIS. In this review, the histological classification of DCIS is described and in addition the emerging knowledge on genetic alterations is summarised. For clinical management of DCIS patients, genetic or other biological factors should be identified that can predict the risk of progression of DCIS to invasive breast cancer and distant metastases. At present, insufficient knowledge on prognostic and predictive factors in DCIS is available. Research in this area is hampered by the difficulties in obtaining DCIS tumour tissue, as the tumour cells grow in the lumen of pre-existing ducts and lobules. As the recurrence rates are relatively low and the most relevant clinical endpoint, distant metastases, is indeed very rare, large numbers of patients (hundreds to a few thousand) need to be studied. Integration of translational studies into clinical trials aimed at optimising the treatment of DCIS are required to achieve this goal.