Expression and prognostic significance of iNOS in uveal melanoma

Uveal melanoma (UM) is the most common primary intraocular tumor in adults. Disease metastasis occurs in half of the patients and is uniformly fatal despite systemic therapy. Inducible nitric oxide synthase (iNOS) is associated with disease progression in various malignancies including cutaneous melanoma. In this retrospective cohort, we examined the prognostic value of iNOS in UM by performing immunohistochemistry on paraffin‐embedded sections of primary tumors (90 patients) and matched primary and metastatic hepatic tumors (19 patients) with complete histopathological and clinical data. We show that iNOS is expressed in UM (57% of the patients) and high iNOS levels significantly (p = 0.04; hazard ratio (HR) = 2.3) predict disease‐specific survival (DSS) as assessed by Kaplan‐Meier analysis and univariate Cox's proportional hazards regression model. Furthermore, high iNOS expression in the UM primary tissue was significantly associated with metastatic disease and vice versa. Expression of iNOS in hepatic metastases significantly (p = 0.02) predicted a shortened survival as assessed by Kaplan‐Meier analysis. However, iNOS did not appear to be a significant (p = 0.16; HR = 1.9) factor in the multivariate Cox's regression analysis performed together with the clinical parameters tumor diameter, tumor cell type, and tumor location in which only tumor diameter predicted DSS. In conclusion, iNOS predicts DSS in UM and may play a role in disease progression but it is not an independent prognostic factor.     

The prognostic significance of histologic regression in cutaneous melanoma.

A retrospective evaluation of 201 stage I cutaneous melanomas was performed to investigate the prognostic significance of histological regression (present in 67 cases). Thin melanomas showed regression more frequently than thick lesions (48% less than or equal to 0.75 mm vs 12% greater than 3 mm). The mean disease-free interval was 33.53 months in regressing tumours and 19.9 in non-regressing tumours (p = 0.07): differences between the survival curves were not significant (p = 0.61). Metastases developed in 13 (19.40%) patients with regressing tumours and by 40 (29.85%) patients with non-regressing tumours. Although we observed a higher frequency of regression in thin melanomas we could not demonstrate an influence of regression on disease-free interval and survival.     

Clinical prognostic significance of tumour angiogenesis

BACKGROUND:: The importance of tumour angiogenesis in the process of tumourgrowth and metastasis has recently gained wide acceptance. Thishas lead to intense investigation into the biology of tumourangiogenesis and its clinical significance. An understandingof angiogenesis may allow therapeutic modulation in order tointerrupt the progression from tumourigenesis to metastaticdisease and control growth of distant metastases. DESIGN:: A review was undertaken of studies relating clinical outcometo the assessment of tumour angiogenesis in patients with cancer. RESULTS:: Studies have been recently reported in a variety of tumours,particularly early breast cancer and melanoma. Quantitativepathology, using microvessel counting, has been the main methodapplied. However assessment of angiogenic growth factors mayprovide an alternative. In early breast cancer many studieshave shown a worse prognosis for those patients with highlyvascular tumours. The prognostic influence of tumour angiogenesisis independent of conventional prognostic indicators. Similar,although more varied results, have been obtained in studiesof melanoma and other tumour types. CONCLUSION:: Tumour angiogenesis, as assessed with quantitative pathology,is an important prognostic indicator in early breast cancerand possibly in other tumour types. Further confirmatory studiesare required before this indicator is routinely used to guidetreatment selection. Assessment of tumour angiogenesis willbe increasingly important in the investigation of new therapiesaimed at inhibiting angiogenesis or targeting tumour vasculature. angiogenesis, prognosis, breast cancer, melanoma, microvessel counts     

YAP表达与肝细胞癌临床特征及预后的关系

目的 检测Yes相关蛋白(YAP)在肝细胞癌(HCC)组织中表达的差异,探讨其与HCC患者临床特征及预后的关系.方法 选取具有完整临床及预后资料的98例肝切除术后HCC患者的石蜡组织标本,采用免疫组化技术检测癌组织与癌旁组织中的YAP表达差异,回顾性分析YAP表达的差异与患者临床特征及预后之间的关系.结果 肝癌组织中YAP阳性表达率为21.4%(21/98),YAP阴性表达率为78.6%(77/98),YAP高表达率为10.2%(10/98);单因素分析显示,本组HCC患者的中位无复发生存期和中位总生存期与术前甲胎蛋白(AFP)水平、大血管侵犯或存在瘤栓、YAP表达状态有关(P﹤0.05);多因素分析结果表明,AFP≥20 ng/ml、YAP表达阳性是影响HCC患者术后生存的独立危险因素;生存分析结果显示,YAP阳性组中位无复发生存率和中位总生存率低于YAP阴性组(P﹤0.05).结论 YAP与HCC的进展及预后有关,YAP可以作为HCC术后预测预后的一个新指标.     

Clinical and prognostic significance of Yes-associated protein in colorectal cancer

The Hippo signaling pathway is a critical regulator of organ size control during development, and its deregulation is associated with cancers. Acting downstream of this pathway, Yes-associated protein (YAP) was implicated in tumorigenesis. The present study aimed to explore the expression patterns and clinical significance of YAP in human colorectal cancer (CRC). In addition, we investigated the relationship between YAP expression and Wnt/β-catenin pathway activation in CRC. A total of 139 cases of CRC tissues were investigated by immunohistochemistry for the expression of YAP, cyclin D1, and β-catenin. The association between YAP expression and clinicopathologic features was analyzed. Our results showed that YAP was overexpressed in 52.5 % (73/139) cases of CRC and predominantly presented in the nucleus. There was an excellent correlation between YAP expression and pTNM stage (p?=?0.0024). YAP expression in CRC was significantly correlated with nodal status (p?=?0.0034), tumor status (p?=?0.0382), and cyclin D1 overexpression (p?<?0.0001). Importantly, YAP expression was associated with short overall survival (p?<?0.001). Furthermore, patients with YAP-positive and nuclear β-catenin-positive profiles had worse overall survival. Univariate and multivariate analyses revealed that YAP expression was an independent prognostic indicator of CRC (p?=?0.0207). Our results indicated that YAP overexpression contributed to the tumorigenesis and played a pivotal role in the progression in CRC, and the interaction of YAP and Wnt/β-catenin pathways needs further exploration.     

Regression in malignant melanoma. A histologic feature without independent prognostic significance

A total of 844 cutaneous malignant melanomas were examined prospectively for the presence or absence of histologic regression within the primary tumor. Cases were then stratified into three groups according to tumor thickness and survival was compared between substrata with and without regression in each group. The distribution of other major prognostic variables within these substrata was assessed and their influence as potential confounding variables considered. No statistically significant effect of regression on survival was found in any of the three thickness strata. These results do not confirm the finding of an earlier study, which suggested that regression may be a poor prognostic sign when found in association with thin malignant melanomas. Regression was almost invariably associated with the radial growth phase of melanomas. Regression was more common in male than in female patients, and was more frequent in association with truncal than extremity or head and neck melanomas.     

Clinical, histological and quantitative prognostic factors in cutaneous malignant melanoma.

A retrospective study including 55 cutaneous melanoma patients with 9.5 years follow-up was carried out to assess the significance of various prognostic factors. The histological samples were evaluated according to Clark's and Breslow's classifications and six nuclear features were measured by interactive morphometry. Mitotic activity was assessed by two different methods: mitotic activity index (MAI) and volume corrected mitotic index (M/V index). The overall disease-related five-year survival of patients was 76.4%. TNM stage (p = 0.0001), sex (p = 0.0024), M/V index (p = 0.003), standard deviation of nuclear form factor (p = 0.023), MAI (p = 0.02), shortest nuclear axis (p = 0.023) and Breslow's classification (p = 0.044) predicted survival in univariate analysis. A multivariate analysis including clinical, histological and morphometric features pointed the Clark's classification as the most important predictor of survival (p = 0.002), while the other variables included had no independent prognostic value. The prognostic importance of mitotic indices and morphometric features is clearly a subject for further studies in superficial melanomas.     

BANS. A cutaneous region with no prognostic significance in patients with melanoma

Data of 769 Stage I melanoma patients treated from 1967 to 1974 by the W.H.O. Melanoma Group centers were analyzed. The mean follow-up period was 10.3 years. Of the 769 patients (239 males, 530 females), 133 had a primary in the BANS region. The observed ten-year actuarial survival was 54.8% for the 133 BANS patients and 54.9% for the remaining 636. Multivariate analysis showed that thickness was the most important prognostic factor (P = 10(-9]; ulceration and sex were also found to be significantly related to survival (P values were 5 X 10(-4) and 10(-5), respectively). The other criteria were no longer significant when adjusted by these three. In particular, the BANS region had a P value of 0.6. To evaluate the effect of BANS in thin melanoma, a subgroup of 152 patients (29 BANS, 123 other) with primary thickness between 0.76 and 1.69 mm was studied. Multivariate analysis showed that no criteria are significantly associated with prognosis of these patients. Observed actuarial survival rate for BANS patients was 69.2% and for the remaining 123, 66.7%. The number of deaths was 8/29 and 27/123. The BANS region does not appear to be of importance in the prognosis of Stage I melanoma patients.     

Clinical significance of sentinel lymph node involvement in malignant melanoma

In the period 1997-2002, sentinel lymph node (SLN) surgery was performed on 179 primary skin melanoma patients, one to two months after the removal of the primary. Staining with patent blue was combined with an isotope technique. Histological evaluation of the sentinel lymph nodes was performed in serial sections. Immunohistochemical detection of S100, HMB-45, or Melan-A was used in the case of suspected micrometastases. Demonstration of positive sentinel lymph node was followed, preferably within 2-3 weeks, by regional block dissection. In these cases interferon-a2 in low doses or BCG immune therapy were applied as adjuvant therapy. Bimonthly follow-up of the patients included physical examination and the use of imaging techniques as specified in the melanoma protocol. Sentinel lymph node surgery was successful in 177/179 cases (98%). Positive sentinel lymph node was identified in 26/177 patients (14.7%). In node positive patients the thickness of the primary tumour was significantly greater than that of node negative ones (p<0.00001). Patients with micrometastases had significantly poorer symptom-free and overall survival by the Mantel-Cox test than those of the other group (p=0.0001 and p=0.0007 respectively). Comparison of the tumor thickness and positive SLN by discriminance analysis, yielded 81.7% and 79.9%, respectively for correct classification rates. Based on our study and data from the literature, we suggest SLN-positivity as equally strong poor prognosis factor for skin melanoma as the tumor thickness.     

Clinical significance of the RT-PCR positive sentinel node in melanoma

BACKGROUND: The clinical relevance of RT-PCR positivity for melanoma markers in the sentinel node remains controversial. Our purpose was to determine whether patients with a histologically negative but RT-PCR positive node were at an increased risk for recurrence than their RT-PCR negative counterparts. METHODS: Thirty-nine adult patients underwent sentinel node biopsies for melanoma between 1998 and 2000. Each sentinel node was bivalved. Half was serially sectioned and examined by routine hematoxylin and eosin (H&E) and immunohistochemistry (IHC; S100, HMB-45, melanA, and tyrosinase). The other half was analyzed by a nested RT-PCR assay for tyrosinase. RESULTS: Patients were followed for recurrence with a mean follow-up of 71.1 months. The odds ratio of recurrence for RT-PCR positive versus RT-PCR negative patients was 1.39 (0.34, 5.62; p = 0.73). Within the histology negative subgroups, the risk of recurrence in the RT-PCR positive group (26.7%) was not significantly different from the risk of recurrence in the RT-PCR negative group (22.2%) (p = 0.33 chi-squared). RT-PCR of the sentinel node was not a predictor for recurrence on multivariate analysis (p = 0.65). CONCLUSION: Sentinel node RT-PCR positivity did not risk stratify histologically negative melanoma patients beyond routine pathologic examination in this series.     

Stage-specific prognostic biomarkers in melanoma

The melanoma staging system proposed by the American Joint Committee on Cancer (AJCC) (which classifies melanoma patients into four clinical stages) is currently the most widely used tool for melanoma prognostication, and clinical management decision making by clinicians. However, multiple studies have shown that melanomas within specific AJCC Stages can exhibit varying progression and clinical outcomes. Thus, additional information, such as that provided by biomarkers is needed to assist in identifying the patients at risk of disease progression.Having previously found six independent prognostic biomarkers in melanoma, including BRAF, MMP2, p27, Dicer, Fbw7 and Tip60, our group has gone on to investigate if these markers are useful in risk stratification of melanoma patients in individual AJCC stages. First, we performed Kaplan-Meier survival and Cox proportional multivariate analyses comparing prognostication power of these markers in 254 melanoma patients for whom the expression levels were known, identifying the best performing markers as candidates for stage-specific melanoma markers. We then verified the results by incorporating an additional independent cohort (87 patients) and in a combined cohort (341 patients).Our data indicate that BRAF and MMP2 are optimal prognostic biomarkers for AJCC Stages I and II, respectively (P = 0.010, 0.000, Log-rank test); whereas p27 emerged as a good marker for AJCC Stages III/IV (0.018, 0.046, respectively, log-rank test). Thus, our study has identified stage-specific biomarkers in melanoma, a finding which may assist clinicians in designing improved personalized therapeutic modalities.     

Alterations and prognostic significance of p16 and p53 protein expression in subgroups of cutaneous melanoma

The role of p16 and p53 alterations in cutaneous melanoma has been recently discussed, but it remains to be clarified. In the present immunohistochemical study, the expression of p16 and p53 proteins and their possible prognostic relevance have been examined in 102 melanomas of the aggressive nodular type. Twelve percent showed a strong expression of p53 protein, and these cases were significantly more frequent in the head/neck area compared with other sites (32% vs. 6%). Expression of p16 protein was negative or weak in 9% of the cases, and this tended to be less frequent in head/neck tumors compared with the others (0% vs. 12%). Whereas p53 staining was not prognostically important, loss of p16 staining was significantly associated with markedly reduced recurrence free and patient survival in univariate analysis (product-limit method). In multivariate analysis, lack of p16 staining was significantly associated with recurrent disease (p = 0.013). Our findings indicate an important role of altered p16 protein expression in a subgroup of melanoma patients. Int. J. Cancer 74:535–539, 1997. © 1997 Wiley-Liss, Inc.     

Clinical significance of CXCR3 and CXCR4 expression in primary melanoma

Tumor cell migration involved in metastases is a tightly regulated, nonrandom process. Chemokines have been identified as critical molecules guiding cell migration. We performed a prospective study to analyze a possible association between the expression of chemokine receptors CXCR3 and CXCR4 by primary melanoma and clinical outcome. Forty primary melanomas were available for analysis; 57% of the tumors expressed CXCR3 and 35% expressed CXCR4 by melanoma cells. At initial diagnosis, 5 patients had subclinical lymph node involvement and after a median follow-up time of 32 months, 2 additional patients developed regional lymph node metastases and 5 patients developed distant metastases. The expression of CXCR4, but not CXCR3, by melanoma cells in primary lesions was significantly associated with the presence of ulceration, increased tumor thickness, a greater risk of developing regional and distant metastases and a higher mortality rate. Our study underscores the value of CXCR4 expression as a useful marker for predicting outcome in patients with localized melanoma. In addition, our findings support that, among chemokine receptors, CXCR4 might be an appropriate therapeutic target for adjuvant therapy in patients at risk for metastatic disease.     

恶性淋巴瘤患者凝血纤溶指标变化的意义

 目的　探讨恶性淋巴瘤患者凝血纤溶指标的变化,提高对恶性淋巴瘤患者合并血栓的认识。方法　应用全自动血凝分析仪对20名健康对照及71例恶性淋巴瘤患者的血浆凝血酶原时间（PT）、活化部分凝血活酶时间（APTT）、纤维蛋白原定量（FIB）及凝血酶时间（TT）进行检测,用免疫散射比浊法测定两组血浆D-二聚体（D-DI）的含量。结果　71例恶性淋巴瘤患者APTT（30.44±1.43）s、FIB（3.28±0.20）g／L、D-DI（297.05±56.59）μg／L均高于健康对照组的（23.72±0.76）s、（2.57±0.22）g／L、（94.50±26.07）μg／L,差异有统计学意义（P＜0.05）。Ⅰ、Ⅱ期淋巴瘤患者各项凝血纤溶指标较健康对照组差异无统计学意义（P＞0.05）。Ⅲ、Ⅳ期淋巴瘤患者APTT延长,FIB增高,与健康对照组及Ⅰ、Ⅱ期组比较差异有统计学意义（P＜0.05）。合并静脉血栓患者7例,该组与Ⅰ、Ⅱ期患者相比FIB及D-DI均高,与Ⅲ、Ⅳ期患者相比D-DI明显升高。结论　恶性淋巴瘤患者存在凝血纤溶指标的异常,需定期动态检测,化疗后易发生静脉血栓,需及早预防,延长患者生存期。     

Differential expression of the retinoblastoma gene family members in choroidal melanoma: prognostic significance.

We evaluated 55 samples of choroidal melanoma managed by enucleation. Knowing that the immunohistochemical expression of the retinoblastoma gene family members Rb/p105, p107, and pRb2/p130 was inversely correlated with the degree of malignancy in at least some histological types, we investigated the expression of these three proteins in choroidal melanoma. We focused on the relationship between patient survival and the immunohistochemical detection of the retinoblastoma proteins. No correlation with clinical outcome was found for Rb/p105 and p107. However, we found pRb2/p130 to be an independent prognostic factor correlating positively or directly with patient survival times and indirectly or inversely with the degree of malignancy. Demonstration of the prognostic value of the immunohistochemical expression of pRb2/p130 is of significance, even if additional studies are required to confirm these data and to compare the prognostic value of pRb2/p130 immunodetection to that of other recently proposed markers, such as p53.