Benefit of robot-assisted laparoscopy in nerve-sparing radical hysterectomy: urinary morbidity in early cervical cancer

Objective

To evaluate the feasibility of nerve-sparing radical hysterectomy in early cervical cancer by robot-assisted laparoscopy and atonic bladder rate.

Methods

This was a retrospective study with consecutive patients in three gynecological oncology departments. Patients with <2 cm cervical cancer had nerve-sparing radical hysterectomy by robot-assisted laparoscopy and pelvic lymphadenectomy. Two days after surgery, we systematically removed the Foley bladder catheter.

Results

The median (range) age and body mass index of the 30 patients were 44 (33–68) years and 23.9 (17.7–39.4) kg/m², respectively. The median (range) tumor diameter at the time of surgery was 13 (4–38) mm. The median (range) operative time, blood loss, and number of pelvic lymph nodes (any common iliac lymph nodes) were 305 (180–405) min, 100 (30–1,500) ml, and 18 (7–28). The overall complication rate was 52.3 %, of which 6.7 % atonic bladder. Twenty-eight patients (93.3 %) were discharged 2 days after surgery with spontaneous voiding and no residual urine >100 ml.

Conclusions

Nerve-sparing radical hysterectomy by robot-assisted laparoscopy is feasible in early cervical cancer (<2 cm). A total of 93.3 % of the patients were discharged 2 days after surgery with spontaneous voiding. The next step would be a prospective study with objective urodynamic investigations.     

The Sentinel Node Technique Detects Unexpected Drainage Pathways and Allows Nodal Ultrastaging in Early Cervical Cancer: Insights from the Multicenter Prospective SENTICOL Study

Background

Sentinel lymph node (SLN) biopsy may improve nodal staging in cervical cancer. The aims of this study are to determine the rate of unusual patterns of cervical lymphatic drainage, to determine the rates of micrometastases and isolated tumor cells (ITCs) in SLNs, and to assess the clinical impact of SLN biopsy.

Methods

Multicenter prospective study conducted between January 2005 and June 2007 in women undergoing laparoscopic surgery for early cervical cancer. Combined technetium/Patent Blue labeling was used. Lymphoscintigraphy was performed before surgery. SLN location was recorded, and factors associated with location were explored. SLNs underwent step sectioning ± immunohistochemistry.

Results

145 patients were enrolled and 139 included in a modified intention-to-diagnose analysis. Although 80.6 % of SLNs were in external iliac and interiliac areas, 38.2 % of patients had at least one SLN in an unexpected area and 5.1 % had SLNs only in unexpected areas. In unexpected areas, the number of SLNs per patient was not significantly different between lymphoscintigraphy and intraoperative detection (0.79 [0.62–1.02] versus 0.50 [0.37–0.68]; P = 0.096). In expected locations, there were significantly more blue and hot SLNs per patient than blue or hot SLNs (1.70 [1.45–1.99], 0.42 [0.30–0.57], 0.52 [0.39–0.69]). Of 28 metastatic SLNs, 17 contained micrometastases or ITCs. SLN involvement was found only by immunohistochemistry in 39.1 % of patients with positive nodes, and involved SLNs were located in unexpected areas in 17 % of those patients.

Conclusions

Sentinel lymph node biopsy detects unusual drainage pathways and micrometastases in a substantial proportion of patients, thus improving nodal staging.     

Central antihypertensive effects of orally active aminopeptidase A inhibitors in spontaneously hypertensive rats

Brain renin-angiotensin system hyperactivity has been implicated in the development and maintenance of hypertension. We reported previously in the brain that aminopeptidase A and aminopeptidase N are involved in the metabolism of angiotensin II and angiotensin III, respectively. By using in vivo specific and selective aminopeptidase A and aminopeptidase N inhibitors, we showed that angiotensin III is one of the main effector peptides of the brain renin-angiotensin system, exerting a tonic stimulatory control more than blood pressure in hypertensive rats. Aminopeptidase A, the enzyme generating brain angiotensin III, thus represents a potential target for the treatment of hypertension. We demonstrated here the antihypertensive effects of RB150, a prodrug of the specific and selective aminopeptidase A inhibitor, EC33, in spontaneously hypertensive rats, a model of human essential hypertension. Oral administration of RB150 in conscious spontaneously hypertensive rats inhibited brain aminopeptidase A activity, demonstrating the central bioavailability of RB150 and its ability to generate EC33 into the brain. Oral RB150 treatment dose-dependently reduced blood pressure in spontaneously hypertensive rats with an ED(50) of 30 mg/kg, lasting for several hours. This decrease in blood pressure is partly attributed to a decrease in sympathetic tone, reducing vascular resistance. This treatment did not modify systemic renin-angiotensin system activity. Concomitant oral administration of RB150 with a systemic renin-angiotensin system blocker, enalapril, potentiated the RB150-induced blood pressure decrease achieved in <2 hours. Thus, RB150 may be the prototype of a new class of centrally active antihypertensive agents that might be used in combination with classic systemic renin-angiotensin system blockers to improve blood pressure control.     

Genetic modifiers of β-thalassemia and clinical severity as assessed by age at first transfusion

Background

The clinical and hematologic features of β-thalassemia are modulated by different factors, resulting in a wide range of clinical severity. The main factors are the type of disease-causing mutation and the ability to produce α-globin and γ-globin chains. In the present study we investigated the respective contributions of known modifiers to the prediction of the clinical severity of β-thalassemia as assessed by the patients’ age at first transfusion.

Design and Methods

We studied the effect of seven loci in a cohort of 316 Sardinian patients with β⁰-thalassemia. In addition to characterizing the β-globin gene mutations, α-globin gene defects and HBG2:g.−158C>T polymorphism, we genotyped two different markers in the BCL11A gene and three in the HBS1L-MYB intergenic region using single nucleotide polymorphism microarrays, imputation and direct genotyping. We performed Cox proportional hazard analysis of the time to first transfusion.

Results

According to the resulting model, we were able to explain phenotypic severity to a large extent (Harrell’s concordance index=0.72; Cox & Snell R²=0.394) and demonstrated that most of the model’s discriminatory ability is attributable to the genetic variants affecting fetal hemoglobin production (HBG2:g.−158C>T, BCL11A and HBS1L-MYB loci: C-index=0.68, R²=0.272), while the remaining is due to α-globin gene defects and gender. Consequently, significantly distinct survival curves can be described in our population.

Conclusions

This detailed analysis clarifies the impact of genetic modifiers on the clinical severity of the disease, measured by time to first transfusion, by determining their relative contributions in a homogeneous cohort of β⁰-thalassemia patients. It may also support clinical decisions regarding the beginning of transfusion therapy in patients with β-thalassemia.     

Consequences of combining siRNA-mediated DNA methyltransferase 1 depletion with 5-aza-2′-deoxycytidine in human leukemic KG1 cells

5-azacytidine and 5-aza-2′-deoxycytidine are clinically used to treat patients with blood neoplasia. Their antileukemic property is mediated by the trapping and the subsequent degradation of a family of proteins, the DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B) leading to DNA demethylation, tumor suppressor gene re-expression and DNA damage. Here we studied the respective role of each DNMT in the human leukemia KG1 cell line using a RNA interference approach. In addition we addressed the role of DNA damage formation in DNA demethylation by 5-aza-2′-deoxycytidine. Our data show that DNMT1 is the main DNMT involved in DNA methylation maintenance in KG1 cells and in mediating DNA damage formation upon exposure to 5-aza-2′-deoxycytidine. Moreover, KG1 cells express the DNMT1 protein at a level above the one required to ensure DNA methylation maintenance, and we identified a threshold for DNMT1 depletion that needs to be exceeded to achieve DNA demethylation. Most interestingly, by combining DNMT1 siRNA and treatment with low dose of 5-aza-2′-deoxycytidine, it is possible to uncouple DNA damage formation from DNA demethylation. This work strongly suggests that a direct pharmacological inhibition of DNMT1, unlike the use of 5-aza-2′-deoxycytidine, should lead to tumor suppressor gene hypomethylation and re-expression without inducing major DNA damage in leukemia.