[Laparoscopic type C1 hysterectomy based on the anatomic landmark of the uterus deep vein and its branches for cervical cancer].

Objective: To introduce the laparoscopic type C1 hysterectomy based on the anatomic landmark of the uterus deep vein and its branched and to evaluate its feasibility and safety for cervical cancer and its effect to bladder function and to provide some reference to simplify the surgical procedures of laparoscopic type C1 hysterectomy. Methods: The clinicopathologic data of the patients with stage ⅠA2~ⅡB cervical cancer and who underwent the laparoscopic C1 hysterectomy based on anatomic landmark of the uterus deep vein and its branches between March 2010 and December 2015 was retrospectively analysed. Results: A total of 99 patients received laparoscopic type C1 hysterectomy based on the anatomic landmark of the uterus deep vein and its branches, in which 93 patients reserved unilateral or bilateral pelvic autonomic nerve successfully, the other 6 patients were transfered to receive type C2 hysterectomy due to adhesions, bleeding or the low possibility of curative resection. The failure rate of the surgery was 6.1% (6/99). The average age of these 93 patients was 44.4±8.2 years (range 25~61 years) and there was one case of stage ⅠA2, 84 stage ⅠB1, 2 stage ⅠB2, 5 stage ⅡA1 and 1 stage ⅡB. The number of patients with squamous cell carcinoma was 67, adenocarcinoma was 19, adenosquamous carcinoma was 3, small cell neuroendocrine carcinoma was 3 and mixed type was 1. The average operation time was 4.1±0.5 h, the average amount of intraoperative blood loss was 103.8±84.0 ml and the mean number of excisional pelvic lymph nodes was 29.7±8.9. There was no patient with positive parametrial margin, positive vaginal margin or intraoperative ureteral injury. The postoperative catheter extraction time was 20.3±8.4 d. The median follow-up time was 20 months (rang 5~44 months), the long-term bladder dysfunction rate was 8.6% (8/93). The numbers of locally uncontrolled and distantly metastasis case were both one and both patients died. The fatality rate were 2.2% (2/93). The two-year disease-free survival and overall survival rate were 97.6% and 96.2%, respectively. Conclusion: Laparoscopic type C1 hysterectomy based on the anatomic landmark of the uterus deep vein and its branches is a safe and feasible treatment method for cervical cancer and it provides a new approach for simplifying the surgical procedures of laparoscopic type C1 hysterectomy.

[A Resected Case of Adenosquamous Carcinoma of Pancreas That Relapsed in Remnant Pancreas].

A 70's man underwent subtotal stomach preserving pancreatoduodenectomy(SSPPD)for pancreatic head cancer. The pathological diagnosis was adenosquamous carcinoma(ASC)of the pancreas. Two months after surgery, a recurrent tumor in the remnant pancreas was confirmed with a CT scan and suspected to be ASC by endoscopic ultrasound-guided fine needle aspiration(EUS-FNA). As the recurrent lesion was limited in the pancreas, total remnant pancreatectomy(TP)was performed 4 months after SSPPD. The final pathological diagnosis was ASC. Two months after TP, liver and para-aortic lymph node metastases were revealed. The patient has been alive for 14 months after SSPPD with chemotherapy. Because of its rarity, it is difficult to implement treatment plans for recurrent ASC in the remnant pancreas.

Enhancing fraction measured using dynamic contrast-enhanced MRI predicts disease-free survival in patients with carcinoma of the cervix.

BACKGROUND: There is a need for simple imaging parameters capable of predicting therapeutic outcome. METHODS: This retrospective study analysed 50 patients with locally advanced carcinoma of the cervix who underwent dynamic contrast-enhanced MRI before receiving potentially curative radiotherapy. The proportion of enhancing pixels (E(F)) in the whole-tumour volume post-contrast agent injection was calculated and assessed in relation to disease-free survival (DFS). RESULTS: Tumours with high E(F) had a significantly poorer probability of DFS than those with low E(F) (P=0.011). INTERPRETATION: E(F) is a simple imaging biomarker that should be studied further in a multi-centre setting.

hCG beta expression by cervical squamous carcinoma--in vivo histological association with tumour invasion and apoptosis.

AIMS: To investigate the correlation of beta-subunit of human chorionic gonadotrophin (hCG beta) expression by cervical carcinomas with measures of tumour apoptosis. METHODS AND RESULTS: Eighty-nine cervical carcinoma patients' samples were subject to hCG beta immunohistochemistry and scored with respect to intensity of immunopositivity and percentage of positive cells. Apoptosis was evaluated by three independent parameters: morphological characteristics [haematoxylin and eosin (H&E)], terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling (TUNEL) and poly (ADP-ribose) polymerase (PARP) immunopositivity. Of the 12 adenocarcinomas, only one (8%) was hCG beta+. However, 87% (61/70) of the squamous cell and 100% (7/7) of adenosquamous cell carcinomas were hCG beta+. hCG beta reactivity and intensity was predominantly confined to peripheral tumour cells at the stromal-epithelial interface. Correlation analysis showed that H&E and PARP apoptotic immunopositivity negatively correlated with hCG beta expression (P < 0.001 and P = 0.028 respectively), whereas TUNEL did not (P = 0.12). However, immunopositivity for apoptotic cells by TUNEL was significantly less in tumours where hCG beta expression was greater (scoring >or= 6) and vice versa. hCG beta immunopositivity was also observed in newly formed blood vessels, as well as tumour cells within lymphatic vessels. When tumour vascularization was taken into account, samples with noted vascularization positively correlated with hCG beta scoring. CONCLUSIONS: hCG beta expression correlates with reduced tumour cell apoptosis and may be involved in tumour vascularization and dissemination.

Immunoreactivity for thyroid transcription factor-1 in stage I non-small cell carcinomas of the lung.

Thyroid transcription factor-1 (TTF-1) is a nuclear protein regulating the transcriptional activity of lung-specific genes in the normal and neoplastic bronchioloalveolar cells. It has been implicated in the normal growth and development of the lung, and the disruption of the TTF-1 locus leads to neonatal death with pulmonary hypoplasia. We evaluated retrospectively the prevalence and clinical significance of TTF-1 immunoreactivity in 222 patients with stage I non-small cell lung carcinoma (NSCLC) with a follow-up time of at least 5 years, and we investigated its relationship with other markers of tumor growth, namely cell proliferation and angiogenesis. TTF-1 immunoreactivity was documented by using the commercially available monoclonal antibody 8G7G3/1 in 72% of 97 adenocarcinomas, 5% of 119 squamous cell carcinomas, and in the glandular component of two adenosquamous carcinomas. Four large cell carcinomas were completely unreactive. In adenocarcinomas, but not squamous cell carcinomas, TTF-1 immunoreactivity correlated significantly with microvessel density (p = 0.04) and inversely with the tumor proliferation fraction assessed by Ki-67 immunostaining (p = 0.03). Also, TTF-1-immunoreactive adenocarcinomas showed a trend for a size less than 3 cm (p = 0.08). TTF-1 expression was not related to specific growth patterns, tumor grade, or tumor cell typing. TTF-1 immunoreactivity did not significantly affect patient survival, although patients with more than 75% immunoreactive neoplastic cells showed a trend for longer overall and disease-free survival. Our findings suggest that TTF-1 could be involved in the development of small pulmonary adenocarcinomas, but it has not prognostic implications in patients with stage I NSCLC.

Association between host tissue vascularity and the prognostically relevant tumor vascularity in human cervical cancer.

For many human solid tumors including carcinoma of the uterine cervix it has been shown that vascularity is linked to the malignant potential of the neoplasm. However, tumor microvessel density might not just represent the angiogenic potential of the neoplastic cells but could also be influenced by the primary vascularization of the host tissue. Vascular densities were assessed by systematic random sampling of normal cervical stroma and of cervical cancer tissue in surgical specimens of 52 consecutive patients. Spatially defined tumor vascular densities were related to the vascular density of the normal cervix, tumor size and survival probability. Median vascular densities of the normal cervix, tumor periphery and tumor core were 53 (range 16-105), 66 (range 24-181) and 31 (range 3-117) microvessels per mm2, respectively. Vascular densities of the tumor periphery were related to the vascular densities of the normal cervical stroma and did not depend on tumor size, whereas the vascular densities of the tumor core were independent of the vascular densities of the normal cervical stroma and decreased with increasing tumor size. Microvascular 'hot spots' were detected in the tumor periphery in 67% and in the tumor core regions in 33% of the cases. 'Hot spot' vascular densities were independent of tumor size but significantly (p=0.001) correlated with the vascular densities of the normal cervical stroma. Patients with high tumor 'hot spot' vascular densities (> or =40 vessels/counting field) had significantly (p=0.01) poorer survival probability than patients with low tumor 'hot spot' vascular densities (<40 vessels/counting field). Growth of cervical cancer is accompanied by hypervascularity at the periphery and hypovascularity within the tumor core upon comparison with the vascular density of the normal cervical stroma remote from the invasion front. Our study confirms the prognostic relevance of 'hot spot' vascular density in cancer of the uterine cervix. The association between normal cervix microvascular density remote from the tumor and the 'hot spot' vascular density of the tumor suggests an influence of the local host tissue vascularity on the tumor's aggressiveness.

Serum levels of angiogenin (ANG) in invasive cervical cancer and in cervical intraepithelial neoplasia (CIN).

BACKGROUND: The propensity of malignant tumors to increase in size, to invade locally and to metastasize is dependent on angiogenesis, which is induced by a variety of proteins including the family of fibroblast growth factors, vascular endothelial growth factor and angiogenin (ANG). The aim of the present study was to measure the serum levels of ANG in patients with CIN and invasive cervical cancer and to evaluate a possible correlation between ANG and various clinicopathologic parameters. MATERIALS AND METHODS: Blood was collected from 62 patients with invasive cervical cancer and 47 patients with CIN. Serum samples of 30 age-matched healthy women acting as a control group were obtained. Determination of serum levels of ANG was performed using a quantitative human ANG immunoassay. RESULTS: The overall median ANG serum level was 272.0 pg/ml (range 101.6-869.2). The median serum levels of ANG were 248.9 (range 101.6-307.2) for healthy female controls, 246.8 (range 169.7-468.1) for patients with CIN and 308.1 pg/ml (range 180.1-869.2) for patients with invasive cervical cancer. Serum levels of ANG were significantly elevated in patients with invasive cervical cancer compared with patients with CIN (p < 0.05) as well as healthy female controls (p < 0.05). No difference was found between ANG serum levels in women with CIN, and healthy controls (p < 0.05). No correlations were found between serum levels of ANG and clinico-pathologic parameters (p > 0.05). CONCLUSIONS: Our data indicate the important role of ANG in tumor angiogenesis in invasive cervical cancer as ANG serum levels were significantly elevated in these patients. However, elevated ANG serum levels seem to occur only after the transformation from pre-invasive to invasive lesions.

Relationship between inducible nitric oxide synthase expression and angiogenesis in primary gallbladder carcinoma tissue.

AIM: To explore the relationship between angiogenesis and biological behaviors of primary gallbladder carcinoma (PGBC), the relationship between the expression of inducible nitric oxide synthase (iNOS) and biological behaviors of PGBC and its relationship with the expression of iNOS and angiogenesis of PGBC. METHODS: The expression of iNOS and micro-vessel density (MVD) were assessed by immunohistochemical method and image analysis system in 40 specimens of PGBC and in 8 specimens of normal gallbladder. The immunostaining results and related clinicopathologic materials were analyzed by statistical methods. RESULTS: MVD in PGBC was significantly higher than that in normal gallbladder tissue (46+/-14 vs 14+/-6, P<0.05), and was not related with age, gender, tumor size and histological type. MVD of poorly and undifferentiated tumor tissues was higher than that of moderately-differentiated and well-differentiated tumor tissues (52+/-9 vs 43+/-9 vs 33+/-6, P<0.01). MVD of Nevin IV and V stages was higher than that of Nevin I, II and III stages (52+/-8 vs 37+/-13, P<0.01). MVD of cases with lymphatic or liver metastasis was significantly higher than that without liver metastasis (55+/-6 vs 42+/-10, P<0.05)or lymphatic metastasis (53+/-8 vs 38+/-8, P<0.01). The positive level index (PLI) of iNOS in PGBC was 0.435+/-0.134, and was not related with age, gender, tumor size, histological type, differentiation and clinical stage of PGBC. The PLI of iNOS in cases with lymphatic metastasis was higher than that without lymphatic metastasis (0.573+/-0.078 vs 0.367+/-0.064, P<0.01). The PLI of iNOS in cases with liver metastasis was higher than that without liver metastasis (0.533+/-0.067 vs 0.424+/-0.084, P<0.05). There was a significant correlation between PLI of iNOS and MVD in PGBC (P<0.05). CONCLUSION: Angiogenesis of PGBC is significantly related to the biological behaviors of PGBC. The expression of iNOS is related to the biological behaviors of PGBC. The detection of MVD and the expression of iNOS in PGBC can be used as parameters to determine the degree of malignancy and prognosis.

The association between vascular endothelial growth factor, microvessel density and clinicopathological features in invasive cervical cancer.

OBJECTIVE: The aim of this study was to analyse the vascular endothelial growth factor (VEGF) expression in a series of cervical carcinomas and to compare the results with the microvessel density (MVD) and clinicopathological features. STUDY DESIGN: The immunoreactivity for VEGF was studied in 130 invasive cervical carcinomas and in 22 patients with a carcinoma in situ of the cervix. The results were compared with the MVD. RESULTS: Staining for VEGF of less then 50% per slide occurred in 80% of the invasive carcinomas and in 82% of the in situ carcinomas. The median MVD was 261 vv/mm(2) (range: 11-1000) in the invasive group and 146 vv/mm(2) (range: 25-536) in the in situ group. Unlike the microvessel density there was no association between VEGF expression and survival. The MVD was higher in VEGF poorer (<50%) tumours (P=0.055). Beside tumour histology (P=0.012) there were no other significant relationships between the remaining histopathological findings and VEGF expression. CONCLUSION: Tissue VEGF expression has no prognostic value in contrast with the MVD in patients with invasive cervical cancer.

Contrast-enhanced ultrasonograpic studies on pancreatic carcinoma with special reference to staining and muscular arterial vessels.

Comparative study of contrast-enhanced ultrasonography (CE-US) and histopathology of surgically resected specimens in 13 patients with pancreatic carcinoma. A time intensity curve was used to determine the percentage brightness increase in cancerous and normal regions and the patients were divided into two groups, hyperperfusion, with a percentage brightness increase over 80% (n=6) and hypoperfusion, with an increase of less than 80% (n=7) on CE-US. The hyperperfusion group included well-differentiated tubular adenocarcinoma, adenosquamous cell carcinoma and acinar cell carcinoma, while all 7 patients in the hypoperfusion group had moderately differentiated tubular adenocarcinoma. Immunological staining (α-SMA and anti-CD34) of the resected specimens showed significantly higher microartery count (MAC) in the hyperperfusion group (p<0.005) than in the hypoperfusion group or normal pancreas. In the normal pancreas, the mean vessel diameter was significantly higher (over 100 µm) than in the hyperperfusion group (30 µm; p<0.005). It was concluded that a muscular arterial vessel density of less than 30 µm is an important factor in determining staining degree and carcinoma progression by CE-US in pancreatic carcinoma.

miR-205 targets PTEN and PHLPP2 to augment AKT signaling and drive malignant phenotypes in non-small cell lung cancer.

AKT signaling is constitutively activated in various cancers, due in large part to loss-of-function in the PTEN and PHLPP phosphatases that act as tumor suppressor genes. However, AKT signaling is activated widely in non-small cell lung cancers (NSCLC) where genetic alterations in PTEN or PHLPP genes are rare, suggesting an undefined mechanism(s) for their suppression. In this study, we report upregulation of the oncomir microRNA (miR)-205 in multiple subtypes of NSCLC, which directly represses PTEN and PHLPP2 expression and activates both the AKT/FOXO3a and AKT/mTOR signaling pathways. miR-205 overexpression in NSCLC cells accelerated tumor cell proliferation and promoted blood vessel formation in vitro and in vivo. Conversely, RNA interference-mediated silencing of endogenous miR-205 abrogated these effects. The malignant properties induced by miR-205 in NSCLC cells were reversed by AKT inhibitors, FOXO3a overexpression, rapamycin treatment, or restoring PHLPP2 or PTEN expression. Mechanistic investigations revealed that miR-205 overexpression was a result of NF-κB-mediated transactivation of the miR-205 gene. Taken together, our results define a major epigenetic mechanism for suppression of PTEN and PHLPP2 in NSCLC, identifying a pivotal role for miR-205 in development and progression of this widespread disease.

The prognostic value of histopathologic grading parameters and microvessel density in patients with early squamous cell carcinoma of the uterine cervix.

The purpose of this study was to investigate the prognostic importance of clinical and histopathologic factors, including malignancy grading systems (MGS), partial index (PI), invasive front grading (IFG), and microvessel density. A complete geographic series of 172 early stage (FIGO I-II) cervical carcinomas treated by Wertheim-Meigs surgery during the period 1965-1990 was studied. The patients were followed up for at least 10 years. Significant prognostic factors for disease-free survival were lymph node status (P < 0.0000001), radical surgical margins (P = 0.00003), and tumor size (P = 0.008). In a multivariate Cox analysis it was shown that lymph node status was the single most important prognostic factor with regard to disease-free survival. The total MGS and the PI scores were highly significantly (P = 0.0001) associated with pelvic lymph node metastases and disease-free survival rate in squamous cell carcinomas. The MGS and the PI systems were superior to the IFG system in predicting lymph node metastases. The total IFG score was also a statistically highly significant (P = 0.003) prognostic factor with regard to disease-free survival in both univariate and multivariate analyses. Microvessel density was a nonsignificant prognostic factor. There was a highly significant (P = 0.002) association between vascular space invasion of tumor cells and the presence of lymph node metastases. In conclusion, histopathologic malignancy grading systems provide valuable prognostic information in patients with early stage squamous cell carcinomas of the uterine cervix.

Tumor vascularity--a novel prognostic factor in advanced cervical carcinoma.

OBJECTIVE: In the search for the optimal treatment of advanced cervical cancer, the identification of valid prognostic factors obtainable without histopathologic investigation of the entire tumor and the locoregional lymph nodes is of paramount interest. Tumor microvessel density has recently been demonstrated to correlate strongly with disease aggressiveness in breast cancer and other malignancies. METHODS: We established a computerized image analysis system to quantify tumor microvascularity by using the closest-individual method, which determines the distribution of distances from random points within the tumor to the closest microvessel (DTCMV). Tumor microvascularity was assessed in paraffin sections of two cylindrical 2 x 20-mm core biopsies obtained transvaginally from the 12 and 6 o'clock positions of each tumor and then immunohistochemically stained for Factor VIII-related antigen. The oncologic relevance of tumor vascularity is studied in an open prospective trial. RESULTS: Tumor vascularity was quantified in 42 patients with cervical cancers > 3 cm in largest diameter, FIGO stages Ib-IVa. This new parameter representing pathophysiological tumor-host interactions was independent of various other patient and tumor characteristics, including age, FIGO stage, tumor size, differentiation, lymph node metastases and lymphatic space involvement. Thirty-nine patients were treated with curative intent either by primary surgery (n = 22) or radiation (n = 17). After a median observation time of 18 months (range 4-41 months), the patients with higher tumor vascularity (mean DTCMV < 83 microns) had significantly shorter disease-free (P = 0.025) and overall (P = 0.032) survival probabilities than patients with lower tumor vascularity (mean DTCMV > or = 83 microns). Cox regression analysis identified tumor vascularity as the strongest independent prognostic factor in this group of patients. CONCLUSIONS: The assessment of tumor microvascularity by computerized image analysis of defined tumor biopsies could become a novel means of predicting tumor aggressiveness in non-early cervical cancer.

Lymphatic microvessel density as a novel prognostic factor in early-stage invasive cervical cancer.

Few data on the influence of lymphatic microvessel density (MVD) on survival in cancer are available since until recently there was no reliable immunohistological marker for lymphatic endothelium. Using an antibody staining podoplanin, a novel marker for lymphatic endothelium, lymphatic MVD in tissue samples of 85 patients with cervical cancer classification pT1b treated by radical hysterectomy was investigated. Survival was determined using univariate and multivariate analyses. Lymphatic MVD was also compared to MVD assessed by immunostaining against factor VIII-related antigen, which is considered a marker for blood vessels. Patients with >5 lymphatic microvessels/0.25 mm(2) field had significantly better overall survival (mean 91.8 months) than those with < or =5 lymphatic microvessels/field in univariate analysis (mean 113 months) (p = 0.0105, log-rank test). In multivariate analysis, lymphatic node involvement (p =0.0183), vessel infiltration (p =0.0158) and lymphatic MVD (p =0.0269) remained independent prognostic factors. No correlation between lymphatic MVD and various clinical and histopathological parameters was observed. Correlation between lymphatic MVD and MVD assessed by immunostaining against factor VIII was only weak (p = 0.004, r = 0.312, Spearman's coefficient of correlation). Our results suggest that increased lymphatic MVD is associated with favorable prognosis in early-stage cervical cancer.

Different angiogenic pathways in human cervical cancers.

OBJECTIVE: The objective of this study is to clarify the association between the expression of two types angiogenic factors, vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF)/thymidine phosphorylase(dThdPase) and clinicopathological features, including tumor angiogenesis, in cervical cancers. METHODS: The expression of VEGF and PD-ECGF was evaluated by immunohistochemical staining of tumor specimens from 73 patients with stage Ib-IIb cervical cancer (51, squamous cell carcinoma; 19, adenocarcinoma; 3, adenosquamous carcinoma) who underwent radical hysterectomy. The microvessel density was assessed by immunostaining for factor VIII-related antigen in the most neovascularized area. RESULTS: The microvessel density in adenocarcinomas was significantly higher than that in squamous cell carcinomas (P < 0.01). The intensity of VEGF expression in adenocarcinomas was significantly stronger than that in squamous cell carcinomas (P < 0.05). In contrast, the expression of PD-ECGF in squamous cell carcinomas was significantly higher than that in adenocarcinomas (P < 0.0001) and adenosquamous carcinomas (P < 0.01). There was an inverse relationship between VEGF expression and PD-ECGF expression among all patients studied (P < 0.001). The microvessel density was significantly correlated with the intensity of VEGF expression (P < 0.05). In contrast, there was no correlation between the microvessel density and the expression of PD-ECGF. CONCLUSIONS: The expression of VEGF appears to be involved in the promotion of angiogenesis in cervical cancers. Furthermore, we propose that angiogenic pathways may be different in different types of cervical cancers.