Loss-of-function mutations in ATP6AP1 and ATP6AP2 in granular cell tumors.

Granular cell tumors (GCTs) are rare tumors that can arise in multiple anatomical locations, and are characterized by abundant intracytoplasmic granules. The genetic drivers of GCTs are currently unknown. Here, we apply whole-exome sequencing and targeted sequencing analysis to reveal mutually exclusive, clonal, inactivating somatic mutations in the endosomal pH regulators ATP6AP1 or ATP6AP2 in 72% of GCTs. Silencing of these genes in vitro results in impaired vesicle acidification, redistribution of endosomal compartments, and accumulation of intracytoplasmic granules, recapitulating the cardinal phenotypic characteristics of GCTs and providing a novel genotypic-phenotypic correlation. In addition, depletion of ATP6AP1 or ATP6AP2 results in the acquisition of oncogenic properties. Our results demonstrate that inactivating mutations of ATP6AP1 and ATP6AP2 are likely oncogenic drivers of GCTs and underpin the genesis of the intracytoplasmic granules that characterize them, providing a genetic link between endosomal pH regulation and tumorigenesis.

Adjuvant platinum-based chemotherapy for early stage cervical cancer.

BACKGROUND: This is the second updated version of the original Cochrane review published in the Cochrane Library 2009, Issue 3. Most women with early cervical cancer (stages I to IIA) are cured with surgery or radiotherapy, or both. We performed this review originally because it was unclear whether cisplatin-based chemotherapy after surgery, radiotherapy or both, in women with early stage disease with risk factors for recurrence, was associated with additional survival benefits or risks. OBJECTIVES: To evaluate the effectiveness and safety of adjuvant platinum-based chemotherapy after radical hysterectomy, radiotherapy, or both in the treatment of early stage cervical cancer. SEARCH METHODS: For the original 2009 review, we searched the Cochrane Gynaecological Cancer Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library 2009, Issue 1), MEDLINE, Embase, LILACS, BIOLOGICAL ABSTRACTS and CancerLit, the National Research Register and Clinical Trials register, with no language restriction. We handsearched abstracts of scientific meetings and other relevant publications. We extended the database searches to November 2011 for the first update and to September 2016 for the second update. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing adjuvant cisplatin-based chemotherapy (after radical surgery, radiotherapy or both) with no adjuvant chemotherapy, in women with early stage cervical cancer (stage IA2-IIA) with at least one risk factor for recurrence. DATA COLLECTION AND ANALYSIS: Two review authors extracted data independently. Meta-analysis was performed using a random-effects model, with death and disease progression as outcomes. MAIN RESULTS: For this second updated version we identified only one small trial reporting grade 4 toxicity results, without disease-free or overall survival data with a median follow-up of 16 months.From the first updated version, we identified three trials that were ongoing, and remain so in 2016.Four trials including 401 women with evaluable results with early cervical cancer were included in the meta-analyses. The median follow-up period in these trials ranged from 29 to 42 months. All women had undergone surgery first. Three trials compared chemotherapy combined with radiotherapy versus radiotherapy alone; and one trial compared chemotherapy followed by radiotherapy versus radiotherapy alone. It was not possible to perform subgroup analyses by stage or tumour size.Compared with adjuvant radiotherapy, chemotherapy combined with radiotherapy significantly reduced the risk of death (two trials, 297 women; hazard ratio (HR) = 0.56, 95% confidence interval (CI): 0.36 to 0.87) and disease progression (two trials, 297 women; HR = 0.47, 95% CI 0.30 to 0.74), with no heterogeneity between trials (I² = 0% for both meta-analyses). Acute grade 4 toxicity occurred significantly more frequently in the chemotherapy plus radiotherapy group than in the radiotherapy group (three trials, 321 women; risk ratio (RR) 6.26, 95% CI 2.50 to 15.67). We considered the evidence for all three outcomes to be of a moderate quality, using the GRADE approach due to small numbers and limited follow-up in the included studies. In addition, it was not possible to separate data for bulky early stage disease.In the one small trial that compared adjuvant chemotherapy followed by radiotherapy with adjuvant radiotherapy alone there was no difference in disease recurrence between the groups (one trial, 71 women; HR = 1.34; 95% CI 0.24 to 7.66) and overall survival was not reported. We considered this evidence to be of a low quality.No trials compared adjuvant platinum-based chemotherapy with no adjuvant chemotherapy after surgery for early cervical cancer with risk factors for recurrence. AUTHORS' CONCLUSIONS: The addition of platinum-based chemotherapy to adjuvant radiotherapy (chemoradiation) may improve survival in women with early stage cervical cancer (IA2-IIA) and risk factors for recurrence. Adjuvant chemoradiation is associated with an increased risk of severe acute toxicity, although it is not clear whether this toxicity is significant in the long term due to a lack of long-term data. This evidence is limited by the small numbers and low to moderate methodological quality of the included studies. We await the results of three ongoing trials, which are likely to have an important impact on our confidence in this evidence.

Laparoscopy versus laparotomy for FIGO stage I ovarian cancer.

BACKGROUND: This is an updated version of the original review that was first published in the Cochrane Database of Systematic Reviews 2008, Issue 4. Laparoscopy has become an increasingly common approach to surgical staging of apparent early-stage ovarian tumours. This review was undertaken to assess the available evidence on the benefits and risks of laparoscopy compared with laparotomy for the management of International Federation of Gynaecology and Obstetrics (FIGO) stage I ovarian cancer. OBJECTIVES: To evaluate the benefits and harms of laparoscopy in the surgical treatment of FIGO stage I ovarian cancer (stages Ia, Ib and Ic) when compared with laparotomy. SEARCH METHODS: For the original review, we searched the Cochrane Gynaecological Cancer Group Trials (CGCRG) Register, Cochrane Central Register of Controlled Trials (CENTRAL 2007, Issue 2), MEDLINE, Embase, LILACS, Biological Abstracts and CancerLit from 1 January 1990 to 30 November 2007. We also handsearched relevant journals, reference lists of identified studies and conference abstracts. For the first updated review, the search was extended to the CGCRG Specialised Register, CENTRAL, MEDLINE, Embase and LILACS to 6 December 2011. For this update we searched CENTRAL, MEDLINE, and Embase from November 2011 to September 2016. SELECTION CRITERIA: Randomised controlled trials (RCTs), quasi-RCTs and prospective cohort studies comparing laparoscopic staging with open surgery (laparotomy) in women with stage I ovarian cancer according to FIGO. DATA COLLECTION AND ANALYSIS: There were no studies to include, therefore we tabulated data from non-randomised studies (NRS) for discussion as well as important data from other meta-analyses. MAIN RESULTS: We performed no meta-analyses. AUTHORS' CONCLUSIONS: This review has found no good-quality evidence to help quantify the risks and benefits of laparoscopy for the management of early-stage ovarian cancer as routine clinical practice.

rs1888747 polymorphism in the FRMD3 gene, gene and protein expression: role in diabetic kidney disease.

BACKGROUND: We carried out a case-control study in patients with type 2 diabetes mellitus (T2DM) to evaluate the association between seven single nucleotide polymorphisms (SNPs) previously described to be linked to diabetic kidney disease (DKD) in type 1 diabetes mellitus (T1DM). Additionally, we evaluated gene and protein expression related to the polymorphism associated with DKD. METHODS: The association study included 1098 T2DM patients (718 with DKD and 380 without DKD). Out of the 13 polymorphisms associated with DKD in a previous study with T1DM, seven were chosen for evaluation in this sample: rs1888747, rs9521445, rs39075, rs451041, rs1041466, rs1411766 and rs6492208. The expression study included 91 patients who underwent nephrectomy. Gene expression was assessed by RT-qPCR and protein expression in kidney samples was quantified by western blot and it localization by immunohistochemistry. RESULTS: The C/C genotype of rs1888747 SNP was associated with protection for DKD (OR = 0.6, 95 % CI 0.3-0.9; P = 0.022). None of the other SNPs were associated with DKD. rs1888747 is located near FRMD3 gene. Therefore, FRMD3 gene and protein expression were evaluated in human kidney tissue according to rs1888747 genotypes. Gene and protein expression were similar in subjects homozygous for the C allele and in those carrying the G allele. CONCLUSIONS: Replication of the association between rs1888747 SNP and DKD in a different population suggests that this link is not the result of chance. rs1888747 SNP is located at the FRMD3 gene, which is expressed in human kidney. Therefore, this gene is a candidate gene for DKD. However, in this study, no rs1888747 genotype or specific allele effect on gene and/or protein expression of the FRMD3 gene was demonstrated.

H4K12 and H3K18 Acetylation Associates With Poor Prognosis in Pancreatic Cancer.

BACKGROUND/OBJECTIVES: Epigenetic deregulation may be involved in tumor cell biology, including differentiation, tumor progression, and cell death, and histone acetylation is a major regulatory mechanism of gene transcription. Patterns of global histone modifications have been recently suggested as outcome predictors in cancer patients, but few studies have been conducted on pancreatic ductal adenocarcinomas (PDACs). This study was designed to investigate the predictive value of histone acetylation modifications on PDAC. MATERIALS AND METHODS: A retrospective clinicopathologic analysis was undertaken in 119 patients diagnosed with PDAC between 2005 and 2011, and immunohistochemistry performed with polyclonal antibodies against H4K12ac, H3K9ac, and H3K18ac. Positive nuclear staining for each histone was measured as the intensity and expression, being classified into low-staining or high-staining groups. Results were analyzed in relation to patients' clinicopathologic parameters. RESULTS: There was a positive relationship between tumor differentiation and H4K12ac high scores (P<0.05) and staining with the 3 markers correlated positively with tumor stage (P<0.01). Univariate analysis showed worse survival in patients with high detection levels of H4K12ac (P=0.038) and H3K18Ac (P=0.033). A backwards Cox proportional hazards model analysis revealed the independent prognostic effect of high H4K12ac and H3K18ac levels (hazard ratios of 1.6 and 1.7, respectively, P<0.05), especially for patients at early stages of disease. CONCLUSIONS: We propose that acetylation of H4K12 and H3K18 may be considered valuable prognostic factors for pancreatic cancer, although the mechanism involved needs further investigation. Increasing insights into histone acetylation modifications can ultimately generate new ideas for rational and molecularly based diagnostic and therapeutic approaches.

High phosphate serum levels correlate with the severity of experimental severe acute pancreatitis: insight into the purinergic system.

OBJECTIVES: Extracellular purines are a component of the systemic inflammatory response, and their levels are modulated by ectonucleotidases. In addition, nucleotide hydrolysis releases phosphate. We studied serum phosphate levels as a predictor of severity in acute pancreatitis (AP) and their correlation with extracellular purinergic metabolism. METHODS: Acute pancreatitis was induced by the retrograde injection of sodium taurocholate. The AP group was compared with animals submitted to a model of sepsis by cecal ligation and puncture. The sham group was submitted to laparotomy and closure. We measured the phosphate and purine levels in serum and the expression of 5'-nucleotidase (CD73) and the adenosine A2a receptor in pancreatic tissue by quantitative real-time polymerase chain reaction. RESULTS: Serum phosphate levels were higher in severe AP and correlated with severity. Severe AP led to increased serum levels of adenosine diphosphate, adenosine monophosphate, and adenosine. In addition, adenosine monophosphate conversion to adenosine in serum was accelerated in the AP groups. We found a positive correlation between serum adenosine and phosphate in the AP groups. The expression levels of CD73 and the adenosine A2a receptor in the pancreas were not altered. CONCLUSIONS: Our study suggests that serum phosphate correlates with severity in AP and implicates extracellular purines in the systemic response to severe AP.

Chorioamnionitis and subsequent lung function in preterm infants.

OBJECTIVE: To explore the relationship between prematurity, gender and chorioamnionitis as determinants of early life lung function in premature infants. METHODS: Placenta and membranes were collected from preterm deliveries (<37 weeks gestational age) and evaluated for histological chorioamnionitis (HCA). Patients were followed and lung function was performed in the first year of life by Raised Volume-Rapid Thoracic Compression Technique. RESULTS: Ninety-five infants (43 males) born prematurely (median gestational age 34.2 weeks) were recruited. HCA was detected in 66 (69%) of the placentas, and of these 55(58%) were scored HCA Grade 1, and 11(12%) HCA Grade 2. Infants exposed to HCA Grade 1 and Grade 2, when compared to those not exposed, presented significantly lower gestational ages, higher prevalence of RDS, clinical early-onset sepsis, and the use of supplemental oxygen more than 28 days. Infants exposed to HCA also had significantly lower maximal flows. There was a significant negative trend for z-scores of lung function in relation to levels of HCA; infants had lower maximal expiratory flows with increasing level of HCA. (p = 0.012 for FEF50, p = 0.014 for FEF25-75 and p = 0.32 for FEV0.5). Two-way ANOVA adjusted for length and gestational age indicated a significant interaction between sex and HCA in determining expiratory flows (p<0.01 for FEF50, FEF25-75 and p<0.05 for FEV0.5). Post-hoc comparisons revealed that female preterm infants exposed to HCA Grade 1 and Grade 2 had significant lower lung function than those not exposed, and this effect was not observed among males. CONCLUSIONS: Our findings show a sex-specific negative effect of prenatal inflammation on lung function of female preterm infants. This study confirms and expands knowledge upon the known association between chorioamnionitis and early life chronic lung disease.

Resveratrol-loaded lipid-core nanocapsules treatment reduces in vitro and in vivo glioma growth.

The development of novel therapeutic strategies to treat gliomas remains critical as a result of the poor prognoses, inef-. ficient therapies and recurrence associated with these tumors. In this context, biodegradable nanoparticles are emerging as efficient drug delivery systems for the treatment of difficult-to-treat diseases such as brain tumors. In the current study, we evaluated the antiglioma effect of trans-resveratrol-loaded lipid-core nanocapsules (RSV-LNC) based on in vitro (C6 glioma cell line) and in vivo (brain-implanted C6 cells) models of the disease. In vitro, RSV-LNC decreased the viability of C6 glioma cells to a higher extent than resveratrol in solution. Interestingly, RSV-LNC treatment was not cytotoxic to hippocampal organotypic cultures, a model of healthy neural cells, suggesting selectivity for cancer cells. RSV-LNC induced losses in glioma cell viability through induction of apoptotic cell death, as assessed by Annexin-FITC/PI assay, which was preceded by an early arrest in the S and G1 phases of the cell cycle. In brain-implanted C6 tumors, treatment with RSV-LNC (5 mg/kg/day, i.p.) for 10 days promoted a marked decrease in tumor size and also reduced the incidence of some malignant tumor-associated characteristics, such as intratumoral hemorrhaging, intratumoral edema and pseudopalisading, compared to resveratrol in solution. Taken together, the results presented herein suggest that nanoencapsulation of resveratrol improves its antiglioma activity, thus providing a provocative foundation for testing the clinical usefulness of nanoformulations of this natural compound as a new chemotherapeutic strategy for the treatment of gliomas.

Laparoscopy versus laparotomy for FIGO stage I ovarian cancer.

BACKGROUND: This is an updated version of the original review that was first published in the Cochrane Database of Systematic Reviews 2008, Issue 4. Laparoscopy has become an increasingly common approach to surgical staging of apparent early-stage ovarian tumours. This review was undertaken to assess the available evidence on the benefits and risks of laparoscopy compared with laparotomy for the management of International Federation of Gynaecology and Obstetrics (FIGO) stage I ovarian cancer. OBJECTIVES: To evaluate the benefits and risks of laparoscopy compared with laparotomy for the surgical treatment of FIGO stage I ovarian cancer (stages Ia, Ib and Ic). SEARCH METHODS: For the original review, we searched the Cochrane Gynaecological Cancer Group Trials (CGCRG) Register, Cochrane Central Register of Controlled Trials (CENTRAL 2007, Issue 2), MEDLINE, EMBASE, LILACS, Biological Abstracts and CancerLit from 1 January 1990 to 30 November 2007. We also handsearched relevant journals, reference lists of identified studies and conference abstracts. For this updated review, we extended the CGCRG Specialised Register, CENTRAL, MEDLINE, EMBASE and LILACS searches to 6 December 2011. SELECTION CRITERIA: Randomised controlled trials (RCTs), quasi-RCTs and prospective case-control studies comparing laparoscopic staging with open surgery (laparotomy) in women with stage I ovarian cancer according to FIGO. DATA COLLECTION AND ANALYSIS: There were no studies to include, therefore we tabulated data from non-randomised studies (NRS) for discussion. MAIN RESULTS: We performed no meta-analyses. AUTHORS' CONCLUSIONS: This review has found no good-quality evidence to help quantify the risks and benefits of laparoscopy for the management of early-stage ovarian cancer as routine clinical practice.

Adjuvant platinum-based chemotherapy for early stage cervical cancer.

BACKGROUND: This is an updated version of the original Cochrane review published in The Cochrane Library 2009, Issue 3. Most women with early cervical cancer (stages I to IIA) are cured with surgery or radiotherapy, or both. We performed this review originally because it was unclear whether cisplatin-based chemotherapy after surgery, radiotherapy or both, in women with early stage disease with risk factors for recurrence, was associated with additional survival benefits or risks. OBJECTIVES: To evaluate the effectiveness and safety of platinum-based chemotherapy after radical hysterectomy, radiotherapy, or both in the treatment of early stage cervical cancer. SEARCH METHODS: For the original 2009 review, we searched the Cochrane Gynaecological Cancer Group Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library 2009, Issue 1), MEDLINE, EMBASE, LILACS, BIOLOGICAL ABSTRACTS and CancerLit, the National Research Register and Clinical Trials register, with no language restriction. We handsearched abstracts of scientific meetings and other relevant publications. We extended the database searches to November 2011 for this update. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing adjuvant cisplatin-based chemotherapy (after radical surgery, radiotherapy or both) with no adjuvant chemotherapy, in women with early stage cervical cancer (stage IA2-IIA) with at least one risk factor for recurrence. DATA COLLECTION AND ANALYSIS: Two review authors extracted data independently. Meta-analysis was performed using a random-effects model, with death and disease progression as outcomes. MAIN RESULTS: For this updated version, we identified three additional ongoing trials but no new studies for inclusion. Three trials including 368 evaluable women with early cervical cancer were included in the meta-analyses. The median follow-up period in these trials ranged from 29 to 42 months. All women had undergone surgery first. Two trials compared chemotherapy combined with radiotherapy to radiotherapy alone; and one trial compared chemotherapy followed by radiotherapy to radiotherapy alone. It was not possible to perform subgroup analyses by stage or tumour size.Compared with adjuvant radiotherapy, chemotherapy combined with radiotherapy significantly reduced the risk of death (two trials, 297 women; hazard ratio (HR) = 0.56, 95% confidence interval (CI): 0.36 to 0.87) and disease progression (two trials, 297 women; HR = 0.47, 95% CI 0.30 to 0.74), with no heterogeneity between trials (I² = 0% for both meta-analyses). Acute grade 4 toxicity occurred significantly more frequently in the chemotherapy plus radiotherapy group than in the radiotherapy group (risk ratio (RR) 5.66, 95% CI 2.14 to 14.98). We considered this evidence to be of a moderate quality due to small numbers and limited follow-up in the included studies. In addition, it was not possible to separate data for bulky early stage disease.In the one small trial that compared adjuvant chemotherapy followed by radiotherapy with adjuvant radiotherapy alone there was no significant difference in disease recurrence between the groups (HR = 1.34; 95% CI 0.24 to 7.66) and OS was not reported. We considered this evidence to be of a low quality.No trials compared adjuvant platinum-based chemotherapy with no adjuvant chemotherapy after surgery for early cervical cancer with risk factors for recurrence. AUTHORS' CONCLUSIONS: The addition of platinum-based chemotherapy to adjuvant radiotherapy (chemoradiation) may improve survival in women with early stage cervical cancer (IA2-IIA) and risk factors for recurrence. Adjuvant chemoradiation is associated with an increased risk of severe acute toxicity, although it is not clear whether this toxicity is significant in the long-term due to a lack of long-term data. This evidence is limited by the small numbers and poor methodological quality of included studies. We await the results of three ongoing trials, that are likely to have an important impact on our confidence in this evidence.

Accuracy of telomerase in estimating breast cancer risk: a systematic review and meta-analysis.

OBJECTIVE: To determine the accuracy of telomerase activity in predicting a higher risk for breast cancer. STUDY DESIGN: A quantitative systematic review was performed. Studies that detected telomerase activities in breast tissue were included. RESULTS: Twenty-five primary studies were analyzed, which included 2395 breast lesions. The proportion of breast cancer was 60.8%. Eighty-two percent (1193/1455) of breast cancer cases and 18% (169/940) of benign lesions cases were positive for telomerase activity. For breast cancer vs benign or normal breast tissue, the pooled likelihood ratio for the presence of telomerase activity was 4.5 (95% confidence interval [CI], 3.1-6.5) and the post-test probability was 88% (95% CI, 83-91). For breast cancer vs benign or normal tissue, the area under the summary receiver operating characteristic (SROC) curve was 0.89 with the Q* point value of 0.82. CONCLUSION: Our systematic review showed that telomerase activity was significantly present in breast cancer when compared with normal breast tissue or benign breast lesions.

Effects of the hydroalcoholic extract of Phyllanthus niruri and its isolated compounds on cyclophosphamide-induced hemorrhagic cystitis in mouse.

The effects of Phyllanthus niruri hydroalcoholic extract and the isolated compounds quercetin, rutin, and gallic acid were examined in the mouse model of cyclophosphamide (CYP)-induced hemorrhagic cystitis (HC). HC was induced by a single CYP injection (300 mg/kg, IP), and the animals were evaluated 4 and 6 h after. Some animals were orally treated with the reference compound 2-mercaptoethane sodium sulfonate (Mesna) 80 mg/kg (30 min before CYP) and 160 mg/kg (2 h after CYP). Other groups were treated with P. niruri extract (30 and 50 mg/kg), or quercetin, rutin, and gallic acid (10 and 20 mg/kg), given orally, at the same intervals described for Mesna. P. niruri extract and its active components produced a significant attenuation of the nociception, edema, and hemorrhage evoked by CYP, which was similar to that seen for Mesna. Gallic acid and rutin displayed greater anti-inflammatory effects, whereas quercetin presented superior antinociceptive activities. Noteworthy is that P. niruri extract and compounds significantly reduced CYP-induced liver lipid peroxidation. Our results shed new light on the beneficial effects of P. niruri extract and its active compounds in attenuating the collateral effects elicited by the chemotherapeutic agent CYP.

Accuracy of magnetic resonance imaging in ovarian tumor: a systematic quantitative review.

OBJECTIVE: To estimate the diagnostic accuracy of magnetic resonance in ovarian tumors. STUDY DESIGN: A quantitative systematic review was performed. Studies that compared magnetic resonance and paraffin sections within subjects for diagnosis of ovarian tumors were included. RESULTS: Fifteen primary studies were analyzed, which included 1267 ovarian masses. For borderline or malignant ovarian cancer vs benign ovarian lesions, the pooled likelihood ratio for the occurrence of a positive magnetic resonance result was 6.6 (95% confidence interval, 4.7-9.2) and the posttest probability for borderline or malignant diagnosis was 77% (95% confidence interval, 70-82). Because specificity and likelihood ratio positive were heterogeneous, a random effect model was used and a summary receiver operating characteristic curve was generated. For borderline or malignant ovarian cancer vs benign ovarian lesions, the area under curve was 0.9526. CONCLUSION: Magnetic resonance seems to be a useful preoperative test for predicting the diagnosis of pelvic masses.

Effects of the compounds MV8608 and MV8612 obtained from Mandevilla velutina in the model of hemorrhagic cystitis induced by cyclophosphamide in rats.

Hemorrhagic cystitis (HC) is a common side effect observed in patients under chemotherapy with cyclophosphamide (CYP). The urotoxic side effects of CYP are attributed to the metabolic compound acrolein, and can be partially prevented by the uroprotector agent 2-mercaptoethene sulfate (Mesna). The present study analyzed the anti-inflammatory and the antinociceptive effects of compounds MV8608 and MV8612 obtained from Mandevilla velutina in the rat model of CYP-induced HC. Male Wistar rats were used (six to eight per group, 220-250 g). HC was induced by a single administration of CYP (100 mg/kg, ip). Three behavioral parameters--breathing rate, closing of the eyes, and specific posture--were used as nociception indexes, and scored at different time intervals (15-180 min) after cystitis induction. As inflammatory parameters, hemorrhage presence, edema formation, and bladder weight were determined at 24 h after CYP administration. The neutrophil migration was assessed by means of myeloperoxidase (MPO activity), 4 h after cystitis induction. As expected, Mesna treatment was able to reduce in a significant manner all the inflammatory and the nociceptive parameters induced by CYP. Of note, the administration of MV8608 significantly inhibited the hemorrhage formation and the neutrophil recruitment, while the MV8612 treatment markedly reduced the bladder weight, without interfering with neutrophil influx. Interestingly, the treatment with either MV8608 or MV8612 markedly reduced the nociceptive responses. The present results clearly indicate that MV8608 and MV8612 might represent important alternatives to prevent side effects, especially the nociception, following chemotherapy with CYP.

Adjuvant platinum-based chemotherapy for early stage cervical cancer.

BACKGROUND: Patients with early stage cervical cancer (stages IA2, IB1 or IIA) with risk factors such as lymph node metastasis, lympho vascular space invasion, depth invasion of more than 10mm, microscopic parametrial invasion, non-squamous histology and positive surgical margins have a high risk of recurrence when compared to patients with early stage cervical cancer with no risk factors for recurrence. OBJECTIVES: To evaluate the effectiveness and safety of platinum-based adjuvant chemotherapy after radical hysterectomy, radiotherapy, or both in the treatment of early stage cervical cancer (stages IA2, IB1 or IIA). SEARCH STRATEGY: We searched the Cochrane Gynaecological Cancer Group Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library Issue 1, 2009), MEDLINE, EMBASE, LILACS, BIOLOGICAL ABSTRACTS and Cancerlit, the National Research Register and Clinical Trials register, with no language restriction. Abstracts of scientific meetings and the citation lists of included studies and other relevant publications were checked through hand searching and experts in the field were contacted to identify further reports of trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing adjuvant radiotherapy with adjuvant radiotherapy and cisplatin-chemotherapy after radical surgery for early stage cervix cancer were included. DATA COLLECTION AND ANALYSIS: Two review authors extracted data independently to assess whether the studies met the specified inclusion criteria. Any discrepancies were solved by a third and a forth review author. Meta-analysis was performed using a random effects model, with death and disease progression as outcomes. MAIN RESULTS: Three trials were included. Two trials enrolling 325 participants, of whom 297 (91%) were assessed and compared radiotherapy and chemotherapy with radiotherapy alone found that adjuvant chemotherapy significantly reduced the risk of death (hazard ratio (HR) = 0.56, 95% confidence interval (CI): 0.36 to 0.87) and disease progression (HR = 0.47, 95%CI: 0.30 to 0.74), with no heterogeneity between trials (I(2) = 0% for both meta-analyses). One trial assessing 71 participants compared chemotherapy followed by radiotherapy with radiotherapy alone and found no significant difference between the two groups (HR = 1.34; 95%CI: 0.24 to 7.66). The median follow up of patients varied from 29 to 42 months. AUTHORS' CONCLUSIONS: The addition of platinum-based chemotherapy to radiotherapy may offer clinical benefit in the adjuvant treatment of early stage cervical cancer with risk factors for recurrence. However, the evidence is limited because the selected studies were quantitatively and qualitatively limited, with small number of patients and limited period of follow-up.

Antibody anti-p16(INK4a) in cervical cytology.

OBJECTIVE: To evaluate sensitivity, specificity and positive and negative predictive values (PPV, NPV) of anti-p16(INK4a) in cervical cytology. STUDY DESIGN: A case-control study was conducted in a reference center for cervical pathology. Cytology slides were collected in a standard way with Ayre spatula and Cytobrush. The slides were interpreted by 2 independent pathologists (P1, P2). The cases (n = 61) represented all cervical examinations that had resulted in a biopsy with the diagnosis of CIN 1, 2 or 3 or squamous cell carcinoma. Controls (n = 87) included all examinations with negative cytology (Papanicolaou) and negative colposcopy. RESULTS: The sensitivity for the histologic diagnosis of CIN 2, 3 (n = 23) was 100% and 95.7% (P1, P2), respectively. The NPV for CIN 2 or worse was 100% (P1) and 98.9% (P2). The sensitivity for the diagnosis of CIN 1 was 77.8% (P1) and 58.3% (P2). The NPV for CIN 1 or worse was 90.6% (P1) and 82% (P2). The K index between the 2 pathologists was 0.74. CONCLUSIONS: Our results suggest that the antibody anti-p16(INK4a) could contribute as an adjuvant tool in the follow-up of cervical intraepithelial lesions when the cytology sample is collected in the standard way.

Laparoscopy versus laparotomy for FIGO Stage I ovarian cancer.

BACKGROUND: Over the past ten years laparoscopy has become an increasingly common approach for the surgical removal of early stage ovarian tumours. There remains uncertainty about the value of this intervention. This review has been undertaken to assess the available evidence of the benefits and harms of laparoscopic surgery for the management of early stage ovarian cancer compared to laparotomy. OBJECTIVES: To evaluate the benefits and harms of laparoscopy in the surgical treatment of FIGO stage I ovarian cancer (stages Ia, Ib and Ic) when compared with laparotomy. SEARCH STRATEGY: Trials were identified by searching the Cochrane Gynaecological Cancer Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane Library Issue 2, 2007, MEDLINE (January 1990 to November 2007), EMBASE (1990 to November 2007), LILACS (1990 to November 2007), BIOLOGICAL ABSTRACTS (1990 to November 2007) and Cancerlit (1990 to November 2007). We also searched our own publication archives, based on prospective handsearching of relevant journals from November 2007. Reference lists of identified studies, gynaecological cancer handbooks and conference abstract were also scanned. SELECTION CRITERIA: Studies including patients with histologically proven stage I ovarian cancer according to the International Federation of Gynaecology and Obstetrics (FIGO).Studies comparing laparoscopic surgery with laparotomy for early stage ovarian cancer were only available from 1990. It was anticipated that a very small number of randomised controlled trials (RCTs) were conducted studying the management of early stage ovarian cancer. Therefore, non-randomised comparative studies, cohort studies and case-controls studies, but not studies with historical controls, were also considered. DATA COLLECTION AND ANALYSIS: Data extraction was performed independently by five review authors (LRM, DDR, MIR, MCB and MIE) who assessed study quality and quality of extracted data. Extracted data included trial characteristics, characteristics of the study participants, interventions and outcomes. The quality of non RCTs was assessed using appropriate quality evaluations tools from the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) and from the Newcastle-Ottawa tool for observational studies (NOS). MAIN RESULTS: No RCTs were identified. Three observational studies were identified. AUTHORS' CONCLUSIONS: This review has found no evidence to help quantify the value of laparoscopy for the management of early stage ovarian cancer as routine clinical practice.

P53 and BCL-2 as prognostic markers in endometrial carcinoma.

The objective of this study was to verify the frequency of p53 and BCL-2 immunohistochemical expression in patients with endometrial carcinoma and to correlate it with histological factors (histological type, tumor grade, depth of myometrial invasion, lymph node involvement and surgical staging) and survival. Forty-eight patients with endometrial carcinoma who were submitted to primary surgical treatment were assessed. p53 and BCL-2 immunohistochemical expression was determined using paraffin blocks containing the tumor area. p53 and BCL-2 expression was detected in 39.6% and 58.3% of the tumors, respectively. No significant difference was found regarding the frequency of p53 expression when analyzing histological type (33.3% in endometrioid tumors, 58.3% in non-endometrioid tumors; p = 0.176), depth of myometrial invasion (p = 0.632) and surgical staging (I-11.1%, II-66.7%, III-57.1%; p = 0.061). p53 expression was significantly more frequent in undifferentiated tumors (p = 0.007) and in those showing lymph node involvement (p = 0.030). Univariate analysis showed a positive association with death (RR, 3.358; CI, 1.386-8.134; p = 0.005) and short-term survival. The present study did not reveal any correlation between BCL-2 expression and histopathologic markers or survival. In conclusion, this study showed that p53 expression is directly correlated with undifferentiated tumors, lymph-node involvement and risk of death. On the other hand, BCL-2 expression was not correlated with any known histological factors.

Vascular endothelial growth factor gene therapy induces early re-establishment of canine bronchial circulation.

OBJECTIVE: To evaluate the usefulness of gene therapy with human vascular endothelial growth factor 165 (phVEGF(165)) to promote the early re-establishment of systemic arterial perfusion in canine bronchi deprived of bronchial circulation. METHODS: To disrupt bronchial circulation, dogs were submitted to transversal bronchotomy dividing the left mainstem bronchus into a proximal and a distal portion. phVEGF(165) (VEGF group, n=8) or physiologic saline solution (control group, n=8) were then delivered to the left distal bronchus. After that, the airway was reconstituted with interrupted suture. On day 3, nine dogs (four VEGF and five controls) were euthanized and their left distal bronchi were harvested to evaluate VEGF(165) gene expression by reverse transcription-polymerase chain reaction. In the other dogs (four VEGF and three controls), a microvascular dye was injected through the canine aorta to verify the re-establishment of arterial blood supply to the distal bronchus. Additionally, VEGF immunohistochemistry was performed in distal airway specimens. RESULTS: Microvascular dye was observed in 100% of specimens transfected with phVEGF(165) compared to none in controls. VEGF gene expression (p<0.01) and VEGF protein expression (p<0.05) were higher in VEGF(165)-treated bronchi. CONCLUSIONS: Local transfection with phVEGF(165) promoted the early re-establishment of systemic arterial perfusion to bronchi previously deprived of bronchial circulation. Gene therapy with phVEGF(165) may be a useful tool to restore bronchial circulation by promoting early airway angiogenesis.

Pancreatic intraepithelial neoplasia and ductal adenocarcinoma induced by DMBA in mice.

BACKGROUND: Pancreatic ductal adenocarcinoma has a poor long-term prognosis. Experimental models are necessary to understand not only its biologic behavior, but also the early pancreatic lesions known as pancreatic intraepithelial neoplasia (PanIN) and to develop new treatments. The aim of this study was to evaluate pancreatic carcinogenesis induced by 7,12-dimethyl-1,2-benzanthracene (DMBA) implantation in mice according to the PanIN classification system. METHODS: Ninety male, Mus musculus, CF-1 mice underwent a median laparotomy and 1 mg of DMBA was implanted into the proximal pancreas held in place by a purse-string suture. Mice were killed after 30 and 60 days after which the excised pancreata were fixed in formalin, embedded in paraffin, and stained with hematoxylin-eosin for histologic analysis. The specimens were evaluated blind by 2 pathologists for the presence of the following histology: normal ducts, reactive hyperplasia, PanIN-1A, PanIN-1B, PanIN-2, and PanIN-3, and adenocarcinoma. RESULTS: In the 30-day group, pathologic evaluation showed 4 (17%) reactive hyperplasia, 16 (67%) PanIN lesions, and 4 (17%) adenocarcinomas. In the 60-day group, there were 10 (27%) specimens with reactive hyperplasia, 13 (35%) with PanIN lesions, and 14 (38%) with adenocarcinomas. The difference between groups was statistically significant (P<.05). All pancreata with adenocarcinoma had concomitant PanIN lesions. CONCLUSIONS: The DMBA experimental model in mice induces PanIN lesions and ductal adenocarcinoma that have similar histology to that of human pancreatic cancer. This model may be useful for study of pancreatic carcinogenesis, particularly the molecular progression of early pancreatic ductal lesions.