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Background This trial investigated the hypothesis that the treatment with trabectedin/PLD (TP) to extend the platinum-free interval (TFIp) can improve overall survival (OS) in patients with recurrent ovarian cancer (OC). Methods Patients with OC (up to two previous platinum-based lines), with a TFIp of 6–12 months, were randomised to receive carboplatin/PLD (CP) or TP followed by platinum therapy at relapse. The primary endpoint was OS (HR: 0.75). Results The study enrolled 617 patients. The median TFIp was 8.3 months and 30.3% of patients had received two previous platinum lines. 74% and 73.9% of patients, respectively, received a subsequent therapy (ST) in the CP and TP arm; in the latter TP arm 87.2% of ST was platinum-based, as per protocol. The median OS was 21.4 for CP and 21.9 months for TP (HR 1.13; 95% CI: 0.94–1.35; p = 0.197). Grade 3–5 adverse reactions occurred in 37.1% of patients in the CP arm and 69.7% of patients in the TP arm, and the most frequent were neutropenia (22.8% CP, 39.5% TP), gastrointestinal (7.1% CP, 17.4% TP), hepatic (0.7% CP, 19.1% TP). Conclusions This study did not meet the primary endpoint. CP combination remains the standard for patients with recurrent OC and a 6–12 months TFIp; TP is an effective treatment in patients suffering from persistent platinum toxicities. Clinical trial registration ClinicalTrials.gov, number NCT01379989.

In this work, we aimed to identify molecular epidermal growth factor receptor (EGFR) tissue biomarkers in patients with ovarian cancer who were treated within the phase III randomized European Organisation for Research and Treatment of Cancer-Gynaecological Cancer Group (EORTC-GCG) 55041 study comparing erlotinib with observation in patients with no evidence of disease progression after first-line platinum-based chemotherapy. Somatic mutations in KRAS, BRAF, NRAS, PIK3CA, EGFR, and PTEN were determined in 318 (38 %) and expression of EGFR, pAkt, pMAPK, E-cadherin and Vimentin, and EGFR and HER2 gene copy numbers in 218 (26 %) of a total of 835 randomized patients. Biomarker data were correlated with progression-free survival (PFS) and overall survival (OS). Only 28 mutations were observed among KRAS, BRAF, NRAS, PIK3CA, EGFR, and PTEN (in 7.5 % of patients), of which the most frequent were in KRAS and PIK3CA. EGFR mutations occurred in only three patients. When all mutations were pooled, patients with at least one mutation in KRAS, NRAS, BRAF, PIK3CA, or EGFR had longer PFS (33.1 versus 12.3 months; HR 0.57; 95 % CI 0.33 to 0.99; P = 0.042) compared to those with wild-type tumors. EGFR overexpression was detected in 93 of 218 patients (42.7 %), and 66 of 180 patients (36.7 %) had EGFR gene amplification or high levels of copy number gain. Fifty-eight of 128 patients had positive pMAPK expression (45.3 %), which was associated with inferior OS (38.9 versus 67.0 months; HR 1.81; 95 % CI 1.11 to 2.97; P = 0.016). Patients with positive EGFR fluorescence in situ hybridization (FISH) status had worse OS (46.1 months) than those with negative status (67.0 months; HR 1.56; 95 % CI 1.01 to 2.40; P = 0.044) and shorter PFS (9.6 versus 16.1 months; HR 1.57; 95 % CI 1.11 to 2.22; P = 0.010). None of the investigated biomarkers correlated with responsiveness to erlotinib. In this phase III study, increased EGFR gene copy number was associated with worse OS and PFS in patients with ovarian cancer. It remains to be determined whether this association is purely prognostic or is also predictive.

A recent study on the use of cancer antigen 125 (CA-125) in follow-up of patients with epithelial ovarian cancer after complete response on primary treatment is critically reviewed. As it has been suggested to refrain from CA-125 altogether, this European Society of Gynaecologic Oncology report has also reviewed possible disadvantages, even possible harm, and potentially missed opportunities when such policy would be implemented. It is concluded that indeed routine use of CA-125 does not provide patient benefit in survival or quality of life. However, there may be other reasons for monitoring CA-125, which are discussed in this review. It is noted that the lack of benefit of CA-125 monitoring has only been proven for a specific subset of ovarian cancer patients with serous histology and frequent follow-up visits including imaging and in a clinical environment where, particularly, surgery for recurrent disease and clinical studies on new second-line agents will not be considered. A special warning is issued not to stop tumor marker follow-up in other than epithelial ovarian cancers and in follow-up of patients who not have been treated with chemotherapy.

The management of pelvic masses represent a rising problem due to the need to obtain an early diagnosis and treatment of ovarian cancers. Materials and Methods: In order to evaluate the clinical and surgical approach to ovarian cysts in Italy, we sent a multiple choice questionnaire to 214 members of the Italian Society of Gynecologic Oncology (SIOG) and to 230 members of the Italian Society of Gynecologic Endoscopy (SEGi). Ninety-six resulted evaluable. Results: Transabdominal and transvaginal ultrasound associated with CA125 determination represent the basis for the diagnosis, even if there is no univocal agreement on the ultrasound aspects that may define an ovarian cyst as doubtful. If an ovarian cyst, classified as suspicious, has been diagnosed in a postmenopausal woman, a wide range of therapeutic options have been reported: laparotomic hysterectomy and bilateral salpingo-oophorectomy represent the treatment of choice for 49% of SIOG members, whereas laparoscopic bilateral (45%) or monolateral (39%) salpingo-oophorectomy represents the standard for SEGi members. Ultrasound criteria to distinguish among benign or probably malignant or doubtful ovarian cysts, the treatment of an ovarian cyst during pregnancy, and the management of an unexpected intraoperative diagnosis of borderline ovarian neoplasia are discussed on the basis of answers received by SIOG and SEGi members.

Purpose of investigation: The objective of this retrospective multicenter study was to assess the clinical outcome of patients with microinvasive squamous cell carcinoma of the uterine cervix. Methods: The hospital records of 166 patients with microinvasive squamous cell carcinoma of the uterine cervix were reviewed. All cases were retrospectively staged according the 1994 International Federation of Gynecology and Obstetrics (FIGO) nomenclature. One hundred and forty-three cases were in Stage Ia1 and 23 in Stage Ia2 disease. Surgery consisted of conization alone in 30 (18.1%) patients, total hysterectomy in 82 (49.4%), and radical hysterectomy in 54 (32.5%). All patients in whom conization was the definite treatment had Stage Ia1 disease and had cone margins negative for intraepithelial or invasive lesions. Results: None of the 67 patients submitted to pelvic lymphadenectomy had histologically proven metastatic lymph nodes. Of the 166 patients, eight (4.8%) had an intraepithelial recurrence and four (2.4%) had an invasive recurrence. With regard to FIGO substage, disease recurred in nine (6.3%) out of 143 patients with Stage Ia1 and three (13.0%) out of 23 with Stage Ia2 cervical cancer. With regard to type of surgery, disease recurred in three (10.0%) out of the patients treated with conization alone, four (4.9%) out those who underwent total hysterectomy, and five (9.3%) out of those who underwent radical hysterectomy. It is worth noting that none of the 30 patients treated with conization alone had recurrent invasive cancer after a median follow-up of 45 months. However three (10%) of these patients developed a cervical intraepithelial neoplasia (CIN) III after 16, 33, and 94 months, respectively, from conization. Conclusions: Conization can represent the definite treatment for patients with Stage Ia1 squamous cell cervical cancer, if cone margins and apex are disease-free. For patients with Stage Ia2 cervical cancer extrafascial hysterectomy with pelvic lymphadenectomy might be an adequate standard therapy, although the need for lymph node dissection is questionable

The present studies assessed the nature of the recognition site for [3H]ceranapril in tissue from rat and human brain. [3H]Ceranapril exhibited high affinity saturable specific (defined by 1 microM captopril) binding to homogenates of tissue from both rat and human brain (mean pKd values between 8.42 and 8.69). High binding densities were observed in rat striatum and homogenates of tissue from human caudate (Bmax values 3317 +/- 192 and 1900 +/- 110 fmol/mg protein respectively), with comparatively low densities in cortical tissues. In kinetic experiments, association of [3H]ceranapril to homogenates of rat and human cortex was found to be rapid and fully reversible (K+1 = 6 x 10(5) M-1 sec-1 and 2.4 x 10(6) M-1 sec-1, K-1 = 7.6 x 10(-3) sec-1 and 4.5 x 10(-3) sec-1 respectively). In competition studies, lisinopril, captopril, unlabelled ceranapril, epicaptopril and fosinopril, all competed to a similar extent and with similar rank order of potency for the binding of [3H]ceranapril to homogenates of both rat and human brain. In in vivo studies, pretreatment of rats with either captopril or lisinopril (15 micrograms/250 g) significantly reduced the content of tritium in brain, as measured 20 min after intravenous administration of [3H]ceranapril. From these experiments [3H]ceranpril appears to selectively label, with high affinity, the inhibitor binding site of angiotensin converting enzyme and this site appears to be similar in both species studied.

The abilities of the ACE inhibitors captopril and SQ29,852 to modify aversive behaviour was compared to the effects of diazepam in the light/dark exploration test in the mouse, the elevated plus maze and social interaction test in the rat, and in anxiety-related behaviours induced by human threat in the marmoset. In the four tests the acute administration of captopril, SQ29,852 and diazepam had the same profiles of action to reduce aversive responding. This was also observed during chronic administration with the three agents in the mouse. However, withdrawal from a chronic treatment with diazepam precipitated a syndrome of increased aversion, whereas withdrawal from treatment with captopril and SQ29,852 was uneventful, values waning to control levels. Withdrawal from treatment with ethanol, nicotine and cocaine also enhanced aversive responding. Treatment with captopril and SQ29,852 antagonised the behavioural consequences of withdrawal from treatment with diazepam and nicotine and SQ29,852 also blocked the consequences of withdrawal from ethanol and cocaine. It is concluded that captopril and SQ29,852 have an anxiolytic profile of action in 3 species, that cessation of treatment is not associated with a withdrawal syndrome, that the ACE inhibitors cross tolerate with diazepam and can antagonise the behavioural consequences of withdrawal from treatment with drugs of abuse.

The angiotensin converting enzyme (ACE) inhibitor [3H]SQ29,852 identified a single high affinity recognition site (defined by 10.0 microM captopril) in the human temporal cortex (pKD 8.62 +/- 0.03; Bmax 248 +/- 24 fmol mg-1 protein, mean +/- S.E.M., n = 4). ACE inhibitors and thiorphan competed to a similar level for the [3H]SQ29,852 binding site in the human temporal cortex with a rank order of affinity (pKi values mean +/- S.E.M., n = 3), lisinopril (9.49 +/- 0.02), captopril (9.16 +/- 0.08), SQ29,852 (8.58 +/- 0.04), epicaptopril (7.09 +/- 0.08), fosinopril (7.08 +/- 0.05) and thiorphan (6.40 +/- 0.04). Since this rank order of affinity is similar to the affinity of these compounds to inhibit brain ACE activity it is concluded that [3H]SQ29,852 selectively labels the inhibitor recognition site of ACE in the human temporal cortex.

Whenever a scientist or group of scientists make a new discovery (in the case of biological research, a new drug, a new formulation, a new process or new use for an old drug, etc.), they owe it to themselves and their sponsoring institution to protect a proprietary ownership of that invention. If these scientists work in government, the public that supports them deserves a return so that they can support future work and, of course, the stockholders of a private or public company also deserve a return for their monetary investment in this research.

In the present studies we have shown that angiotensin II (AT II), in a concentration-dependent manner in rat tissue (10(-9)-10(-5) M) or at a single concentration in human tissue (10(-6) M), can inhibit potassium-stimulated release of [3H]acetylcholine ( [3H]Ach) from slices of rat entorhinal cortex and human temporal cortex preloaded with [3H]choline for the biochemical analyses. The inhibitory effects of AT II (10(-6) M) were antagonised by the specific AT II receptor antagonist [1-sarcosine, 8-threonine]AT II in a concentration-dependent manner in rat tissue (10(-11)-10(-8) M) and at the single concentration employed in the human studies (10(-7) M). Also demonstrated were other components of the angiotensin system in the human temporal cortex; ACE activity was present (1.03 nmol min-1 mg-1 protein), as were AT II recognition sites (Bmax = 8.6 fmol mg-1 protein). It is hypothesised that the potential cognitive enhancing properties of ACE inhibitors may reflect their action to prevent the formation of AT II and so remove an inhibitory modulator of cholinergic function.

Angiotensin II was shown to inhibit potassium-stimulated release of [3H]acetylcholine from slices of fresh human temporal cortex, obtained at surgery, and subsequently loaded with [3H]choline for the biochemical analyses. The inhibitory effect of angiotensin II was antagonised by the specific angiotensin II receptor antagonist [1-sarcosine, 8-threonine]-angiotensin II. High affinity binding sites were identified in the human temporal cortex using [125I]angiotensin II, and may provide the functional site of action of angiotensin II to modify [3H]acetylcholine release.

Indirect systolic blood pressure (SBP) was monitored in 9 groups of 15 male conscious 2-kidney renal hypertensive rats (RHR) for over 6 months. Daily oral dosing with captopril (SQ 14,225, D-3-mercapto-2-methyl-propanoyl-L-proline, 30 mg/kg), an orally active angiotensin I-converting enzyme inhibitor, lowered SBP 30–50 mm Hg during this period. Withdrawal of captopril for 5 days at 1,3 and 6 months resulted in gradual return of SBP to control levels without overshoot. Resumption of dosage with captopril again decreased SBP. Daily oral dosing with hydrochlorothiazide (HCTZ, 6 mg/kg/day) alone for 6 months had little or no effect on SBP, but increased the antihypertensive effect of captopril. Daily oral dosing with hydralazine (6 mg/kg) caused an initial marked antihypertensive effect greater than that of captopril but almost complete tolerance developed within 4 weeks of dosing. Highest survival rates occurred in RHR treated with captopril plus HCTZ. In four other similarly treated groups of RHR and normotensive rats (NR), least cardiac hypertrophy and highest plasma renin activity occurred in captopril-treated animals compared with vehicle-treated controls. Plasma renin activity was about 2 to 4 fold higher in the rats dosed with captopril compared with vehicle-treated rats. Heart weight/body weight ratios, initially higher in the two RHR groups compared to NR, decreased only in the captopril treated group to or near those of the NR groups. These results indicate that chronic treatment with captopril decreased SBP and cardiac weights of RHR, and that HCTZ, or possibly other diuretics, can augment the antihypertensive effect of captopril while having little or no effect by themselves.

The effects of daily captopril therapy (30 mg/kg p.o.) given for one year on systolic blood pressure, heart rate and survival of 2-kidney renal hypertensive rats (2K-RHR) were examined. Captopril caused significant and sustained reductions in systolic blood pressure of 2K-RHR throughout the 1-year period with no important changes in heart rate. Simultaneous administration of the diuretic hydrochlorothiazide (HCTZ) enhanced the antihypertensive effect of captopril but did not normalize blood pressure, this despite no effect on blood pressure by HCTZ given alone. On the other hand, co-administration of guanethidine with captopril normalized blood pressure. Survival rates of 2K-RHR were highest in the rats receiving captopril plus HCTZ, next highest in rats receiving captopril alone and lowest in rats receiving water or HCTZ. The results demonstrate the long-term efficacy of captopril and suggest a sympathetic component in the maintenance of chronic 2-kidney renal hypertension.