Trabectedin in Malignant Pleural Mesothelioma: Results From the Multicentre, Single Arm, Phase II ATREUS Study.

INTRODUCTION: New therapeutic approaches in unresectable malignant pleural mesothelioma (MPM) are eagerly awaited. Trabectedin is an antitumor agent with an effect on cancer cell proliferation and a modulating action on tumor microenvironment. The ATREUS study explored the activity and safety of trabectedin in patients with unresectable MPM. METHODS: Epithelioid patients with MPM received trabectedin as second-line while biphasic/sarcomatoid patients with MPM as first- or second-line therapy. Treatment was given intravenously at an initially planned dose of 1.3 mg/m2 every 3 weeks, until progression or unacceptable toxicity. The primary endpoint was progression-free survival rate at 12 weeks (PFS12wks). RESULTS: Overall, 78 patients (54%) had epithelioid and 67 (46%) nonepithelioid MPM. PFS12wks in 62 evaluable patients with epithelioid MPM was 43.5% (80% confidence interval 34.9%-52.5%); median progression-free and overall survival were 2.4 and 9.0 months, respectively. PFS12wks in 52 evaluable patients with nonepithelioid MPM was 30.8% (90% confidence interval 20.3%-42.9%); median progression-free and overall survival were 1.7 and 5.4 months. Trabectedin starting dose was amended due to excess of liver toxicity. Eighty-four (64%) and 48 (36%) patients received 1.3 mg/m2 and 1.1. mg/m2, respectively. The most common grade 3-4 toxicities were hepatotoxicity, leukopenia/neutropenia, and fatigue. Grade 3-4 hepatotoxicity was reported in 59 (70%) patients treated at 1.3 mg/m2, and in 19 (40%) treated at 1.1 mg/m2. CONCLUSIONS: Trabectedin showed modest clinical activity, at the expense of relevant liver toxicity. Further development of this drug in MPM at full doses is not warranted.

Author Correction: Visual field loss and vision-related quality of life in the Italian Primary Open Angle Glaucoma Study.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Exploiting FAsting-mimicking Diet and MEtformin to Improve the Efficacy of Platinum-pemetrexed Chemotherapy in Advanced LKB1-inactivated Lung Adenocarcinoma: The FAME Trial.

Advanced lung adenocarcinoma with inactive liver kinase B1 (LKB1) tumor suppressor protein is associated with poor response to immune checkpoint inhibitors and molecularly targeted agents, and with dismal patient prognosis. LKB1 is a central orchestrator of cancer cell metabolism, and halts tumor growth/proliferation during metabolic stress. Recent preclinical evidence suggests that LKB1-inactive lung adenocarcinoma is highly sensitive to metformin, a safe and low-cost antidiabetic compound that inhibits mitochondrial oxidative phosphorylation. The effects of metformin can be enhanced by nutrient deprivation (ie, glucose, amino acids), which reduces intracellular levels of ATP and anabolic precursors and can be achieved by the fasting mimicking diet (FMD). Noticeably, metformin also prevents resistance to cisplatin in preclinical in vitro and in vivo models of LKB1-inactive lung adenocarcinoma. Based on such preclinical evidence, the phase II FAME trial was designed to test the hypothesis that the addition of metformin, with or without cyclic FMD, to standard platinum-based chemotherapy improves the progression-free survival of patients with advanced, LKB-1 inactive lung adenocarcinoma. Enrolled patients will be randomized in a 1:1 ratio to receive cisplatin/carboplatin and pemetrexed with the addition of metformin alone (Arm A) or metformin plus FMD (Arm B). The FAME study will use a "pick-the-winner" design with the aim of establishing which of the 2 experimental treatments is superior in terms of antitumor efficacy and safety. The primary assumption of the study is that the combination of the 2 experimental treatments shall improve median progression-free survival from 7.6 months (historical data with chemotherapy alone) to 12 months. Secondary study endpoints are: objective response rate, overall survival, treatment tolerability, and compliance to the experimental treatment.

RELEVENT Trial: Phase II Trial of Ramucirumab, Carboplatin, and Paclitaxel in Previously Untreated Thymic Carcinoma/B3 Thymoma With Area of Carcinoma.

Thymic epithelial tumors are rare malignancies. Thymic carcinoma represents about 20% of all thymic epithelial tumors and has aggressive behavior, with a greater tendency to metastatic spread. Thymic carcinoma is often diagnosed in advanced stages for which systemic treatment is the main therapeutic option. The association of chemotherapy and antiangiogenic agents in the first-line setting has never been investigated in this very rare cancer. However, preclinical and clinical evidence has suggested that inhibition of angiogenesis could be beneficial. The RELEVENT trial is a multicenter, open-label, single-arm, phase II study aimed at investigating the activity and safety of ramucirumab combined with paclitaxel and carboplatin in chemotherapy-naive patients affected by thymic carcinoma or B3 thymoma with area of carcinoma. The primary endpoint of the trial is the overall response rate. Progression-free survival, overall survival, and safety are secondary endpoints. Patient-reported outcomes will be collected at each visit. The mutational status of a subset of genes, polymorphisms, and selected micro-RNA expression will be evaluated.

Visual field loss and vision-related quality of life in the Italian Primary Open Angle Glaucoma Study.

The aim of this study was to examine the relationship between visual field (VF) loss, vision-related quality of life (QoL) and glaucoma-related symptoms in a large cohort of primary open angle glaucoma (POAG) patients. POAG patients with or without VF defects or "glaucoma suspect" patients were considered eligible. QoL was assessed using the validated versions of the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) and glaucoma-related symptoms were assessed using the Glaucoma Symptom Scale (GSS). Patients were classified as having VF damage in one eye (VFD-1), both eyes (VFD-2), or neither eye (VFD-0). 3227 patients were enrolled and 2940 were eligible for the analysis. 13.4% of patients were classified in the VFD-0, 23.7% in the VFD-1, and 62.9% in the VFD-2 group. GSS visual symptoms domain (Func-4) and GSS non-visual symptoms domain (Symp-6) scores were similar for the VFD-0 and VFD-1 groups (p = 0.133 and p = 0.834 for Func-4 and Symp-6, respectively). VFD-0 group had higher scores than VFD-2 both in Func-4 (p < 0.001) and Symp-6 domains (p = 0.035). Regarding the NEI-VFQ-25, our data demonstrated that bilateral VF defects are associated with vision-related QoL deterioration, irrespective of visual acuity.

Latanoprost and Dorzolamide for the Treatment of Pediatric Glaucoma: The Glaucoma Italian Pediatric Study (Gipsy), Design and Baseline Characteristics.

INTRODUCTION: To investigate the efficacy of a treatment strategy with latanoprost and dorzolamide in primary pediatric glaucoma patients partially responsive to surgery. METHODS: Single arm, prospective, interventional multicenter study. Primary pediatric glaucoma patients younger than 13 years after a single surgical procedure with IOP between 22 and 26 mmHg were considered eligible. At baseline, patients were allocated to latanoprost monotherapy once daily. Depending on intraocular pressure (IOP) reduction at first visit, the patients were allocated to one of three groups: continuation of latanoprost monotherapy, addition of dorzolamide twice daily, or switch to dorzolamide three times daily. The same approach for allocation in medication groups was used in all subsequent visits. Patients in the dorzolamide monotherapy group with IOP reduction <20% from baseline were considered non-responders and withdrawn. Study treatment and patient follow-up will continue for 3 years or until treatment failure. The primary endpoint is the percentage of responders. Secondary endpoints are time to treatment failure and frequency of adverse events. RESULTS: A total of 37 patients (69 eyes) were enrolled. The mean age was 4.0 ± 3.8 years, the female/male ratio was 1/1.7, and the majority of patients were Caucasian. Eighty percent of patients had bilateral glaucoma. Goniotomy was the most frequently performed surgery (38.6%), followed by trabeculotomy (22.8%), trabeculectomy (21.1%), and trabeculectomy plus trabeculotomy (17.5%). The baseline IOP was 23.6 ± 1.5 mmHg. CONCLUSION: The study population is representative of patients frequently encountered after the first surgery for primary pediatric glaucoma. The study will produce evidence on the medium-term efficacy of a defined pharmacological approach.

Needle Revision With 5-fluorouracil for the Treatment of Ahmed Glaucoma Valve Filtering Blebs: 5-Fluoruracil Needling Revision can be a Useful and Safe Tool in the Management of Failing Ahmed Glaucoma Valve Filtering Blebs.

PURPOSE: To determine the outcome of needling with adjunctive 5-fluorouracil (5-FU) in patients with a failing Ahmed glaucoma valve (AGV) implant, and to identify predictors of long-term intraocular pressure (IOP) control. METHODS: A prospective observational study was performed on consecutive patients with medically uncontrolled primary open-angle glaucoma (POAG) with AGV encapsulation or fibrosis and inadequate IOP control. Bleb needling with 5-FU injection (0.1 mL of 50 mg/mL) was performed at the slit-lamp. Patients were examined 1 week following the needling, and then at months 1, 3, and 6. Subsequent follow-up visits were scheduled at 6-month intervals for at least 2 years. Needling with 5-FU was repeated no more than twice during the first 3 months of the follow-up. Procedure outcome was determined on the basis of the recorded IOP levels. RESULTS: Thirty-six patients with an encapsulated or fibrotic AGV underwent 67procedures (mean 1.86 ± 0.83). Complete success, defined as IOP ≤ 18 mm Hg without medications, was obtained in 25% at 24 months of observation. The cumulative proportion of cases achieving either qualified (ie, IOP ≤ 18 mm Hg with medications) or complete success at 24 months of observation was 72.2%. In a univariate Cox proportional hazards model, age was the only variable that independently influenced the risk of failing 5-FU needling revision. Fourteen eyes (38.8%) had a documented complication. CONCLUSIONS: Needling over the plate of an AGV supplemented with 5-FU is an effective and safe choice in a significant proportion of POAG patients with elevated IOP due to encapsulation or fibrosis.

Health-related quality of life in patients with primary open-angle glaucoma. An Italian multicentre observational study.

PURPOSE: As a progressive condition, glaucoma may impair health-related quality of life (HRQoL), due to vision loss and other factors. This study evaluated HRQoL in a cohort of patients treated for primary open-angle glaucoma (POAG) and assessed its association with clinical features. METHODS: This was an Italian, multicentre, cross-sectional, observational study with the subgroup of newly diagnosed patients with POAG prospectively followed up for one year. Patients with previous or new diagnosis (or strong clinical suspicion) of POAG aged >18 years were considered eligible. Information was collected on demographic characteristics, medical history, clinical presentation and POAG treatments. HRQoL was measured using the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) and Glaucoma Symptom Scale (GSS). Subscale and total scores were obtained and a Pearson correlation coefficient between instruments' scores calculated. RESULTS: A total of 3227 patients were enrolled from 2012 to 2013 and 3169 were analysed. Mean age was 66.9 years. A total of 93.8% had a previous diagnosis (median duration: 8.0 years). Median values for mean deviation and pattern standard deviation were 3.9 and 3.6 dB, respectively. Mean scores on most subscales of the NEI-VFQ-25 exceeded 75.0 and mean GSS subscale scores ranged between 70.8 and 79.7 (with a total mean score of 74.8). HRQoL scores on both scales were significantly inversely associated with POAG severity. CONCLUSION: In this large sample of Italians treated for POAG, disease severity was limited and HRQoL scores were high. QoL decreased with advancing disease severity. These findings confirm the role of vision loss in impairing QoL in POAG, underlying the importance of timely detection and appropriate treatment.

The ORCHIDEE study: gathering new evidence on the use of everolimus in clinical practice.

Randomized clinical trials are the gold standard to test the efficacy of an intervention within a specified patient population. However, the results of the trials may not be generalizable to routine clinical practice. Observational cohort studies may provide information that complements trial results. Targeted therapies are characterized by tolerability profiles that may differ from those of 'traditional' chemotherapy. Therefore, the post-approval evaluation of these drugs by large, well-designed observational cohort studies in real life populations is warranted. Everolimus is an orally-administered inhibitor of the mammalian target of rapamycin. A number of observational cohort studies have been conducted to characterize the effectiveness and safety of everolimus in clinical practice. In particular, the ORCHIDEE study was designed to identify factors predictive of favorable outcome in patients treated with everolimus such as second-line treatment for metastatic renal cell carcinoma after failure of a first-line treatment with a VEGF TKI. ORCHIDEE is a multicenter, single-arm, phase IV study. The study will enroll approximately 200 metastatic renal cell carcinoma metastatic renal cell carcinoma patients from 20 Italian centers over a 24-month period.

Safe conception for HIV-discordant couples: insemination with processed semen from the HIV-infected partner.

OBJECTIVE: The objective of the study was to evaluate the safety of semen washing with intrauterine insemination (SW-IUI) for achieving pregnancy when the man is human immunodeficiency virus (HIV) infected and the woman is HIV negative. STUDY DESIGN: We conducted a retrospective analysis of 635 HIV-discordant couples enrolled in a SW-IUI program and followed up 367 Italian women. We computed pregnancy, live birth, and multiple delivery rates and assessed the women's postinsemination HIV status. RESULTS: The retrospective analysis included 635 couples (2113 SW-IUI cycles): 41% of the women (95% confidence interval [CI], 37-45%) had a live birth (per-cycle live birth rate 13%; 95% CI, 11-14%). HIV status after SW-IUI was negative when available but unknown for 26% of the women: missing HIV status was not associated with correlates of HIV risk. The follow-up study included 367 couples (1365 cycles): 47% of the women (95% CI, 42-52%) had a live birth (per-cycle rate 14%; 95% CI, 12-16%). Ascertainment of postinsemination HIV status was complete and confirmed no HIV transmission attributable to SW-IUI. The upper 95% confidence limit of the HIV transmission rate was 1.8 per 1000 cycles in the retrospective analysis and 2.7 per 1000 cycles in the follow-up study. CONCLUSION: SW-IUI appears to be a safe and effective method for achieving pregnancy in HIV-discordant couples in which the man is HIV infected.

Infertility treatment for HIV-positive women.

Thanks to antiretroviral combination therapy, HIV-infected individuals live longer, healthier lives and may wish to have children. Women with HIV can attempt to conceive naturally or through simple self-insemination to minimize the risk of horizontal HIV transmission. Assisted reproduction technology is necessary in couples with infertility, which can either be independent of HIV infection and its treatment or be associated with it. This article summarizes the latest evidence regarding the desire for a child in HIV-positive women and how HIV infection and its treatment may impact female fertility. Current data regarding access to and outcomes of assisted conception programs in HIV-positive women wishing to conceive in both high- and low-income countries is also reviewed.

Safe conception for HIV discordant couples through sperm-washing: experience and perceptions of patients in Milan, Italy.

Our research explored the reproductive desires of HIV-negative women and their HIV-positive partners who underwent assisted conception based on sperm-washing and intrauterine insemination in Italy. Twenty-two semi-structured interviews were conducted with former patients (6 women, 5 men and 11 couples). Desire for children, perceived risk from treatment and acceptability of the insemination technique were some of the issues explored. Participants had the treatment for a mean duration of 3.5 years, with a mean number of cycles of 5.3. They were highly motivated to conceive a biological child to bring purpose to their lives, and strongly desired options to conceive safely. Most rejected spontaneous conception. Those who successfully conceived reported a positive impact on their quality of life, fulfilling their desire to be parents and restoring their sense of "normalcy". Participants strongly supported extending assisted conception services to all HIV negative women living with HIV positive partners who wished to become pregnant and felt that withholding such treatment was not ethically justified. They perceived assisted conception services to be a safe and effective alternative to spontaneous conception, and felt that society has a moral obligation to provide such services.

Safety and efficacy of sperm washing in HIV-1-serodiscordant couples where the male is infected: results from the European CREAThE network.

OBJECTIVE: To examine the safety and effectiveness of assisted reproduction using sperm washing for HIV-1-serodiscordant couples wishing to procreate where the male partner is infected. DESIGN AND METHODS: A retrospective multicentre study at eight centres adhering on the European network CREAThE and involving 1036 serodiscordant couples wishing to procreate. Sperm washing was used to obtain motile spermatozoa for 3390 assisted reproduction cycles (2840 intrauterine inseminations, 107 in-vitro fertilizations, 394 intra-cytoplasmic sperm injections and 49 frozen embryo transfers). An HIV test was performed in female partners at least 6 months after assisted reproduction attempt. The outcome measures recorded were number of assisted reproduction cycles, pregnancy outcome and HIV test on women post-treatment. RESULTS: A total of 580 pregnancies were obtained from 3315 cycles. Pregnancy outcome was unknown in 47 cases. The 533 pregnancies resulted in 410 deliveries and 463 live births. The result of female HIV testing after assisted reproduction was known in 967 out of 1036 woman (7.1% lost to follow-up). All tests recorded were negative. The calculated probability of contamination was equal to zero (95% confidence interval, 0-0.09%). CONCLUSION: This first multicentre retrospective study of assisted reproduction following sperm washing demonstrates the method to be effective and to significantly reduce HIV-1 transmission risk to the uninfected female partner. These results support the view that assisted reproduction with sperm washing could not be denied to serodiscordant couples in developed countries and, where possible, could perhaps be integrated into a global public health initiative against HIV in developing countries.

Multicenter quality control of the detection of HIV-1 genome in semen before medically assisted procreation.

Couples in whom the man is HIV-1-positive may use medically assisted procreation in order to conceive a child without contaminating the female partner. But, before medically assisted procreation, the semen has to be processed to exclude HIV and tested for HIV nucleic acid before and after processing. The performance was evaluated of the technical protocols used to detect and quantify HIV-1 in 11 centers providing medically assisted procreation for couples with HIV-1 infected men by testing panels of seminal plasma and cells containing HIV-1 RNA and/or DNA. The performance of these tests varied due to the different assays used. False positive results were obtained in 14-19% of cases. The sensitivity for RNA detection in seminal plasma was 500-1,000 RNA copies/ml, over 500 RNA copies/10(6) cells in semen cells, and for DNA detection in semen cells 50-500 DNA copies/10(6) cells. The use of silica-based extraction seemed to increase the assay performance, whereas the use of internal controls to detect PCR inhibitor did not. This first quality control highlights the need for technical improvements of the assays to detect and quantify HIV in semen fractions and for regular evaluation of their performance.

Sperm washing, use of HAART and role of elective Caesarean section.

PURPOSE OF REVIEW: Today, 50% of people living with HIV are women and most have been sexually infected. Highly active antiretroviral therapy (HAART) reduces the rates of both sexual and vertical infection, but maximum protection is achieved with sperm washing and elective Caesarean section. RECENT FINDINGS: Men taking HAART have lower seminal concentration of HIV, and sexual transmission may be reduced. However, a certain percentage of aviraemic men retain viral presence in semen, and unprotected intercourse to achieve fertilization must be discouraged as it carries the risk of sexual transmission of the virus. HIV-discordant couples should be informed that sperm washing can remove HIV from semen, allowing conception without the risk of infection for the seronegative female and eventually the child. In HIV-positive women, perinatal transmission of HIV can be curtailed to less than 2% by using HAART to decrease maternal viral load and offering prenatal preexposure prophylaxis of the fetus, and elective Caesarean section. Each intervention carries specific risks and benefits. The contribution of each preventive arm in achieving fetal protection can only be crudely measured and optimal obstetric management must involve discussion with the pregnant woman of the pros and cons of each strategy. SUMMARY: In HIV-positive men taking HAART, seminal viral load is decreased but not eliminated and fertilization should be achieved through sperm washing to offer maximum protection for the uninfected female. Pregnant HIV-positive women on antiretroviral medication have a reduced risk of transmitting the virus, but should still be counselled about the possibility to further limit the chances of infecting their infant through elective Caesarean section.