Retroperitoneal lymph node recurrence of epithelial ovarian cancer: Prognostic factors and treatment outcome.

OBJECTIVE: To evaluate the treatment outcome and survival of patients with epithelial ovarian cancer recurrence isolated to the retroperitoneal lymph nodes compared to intraperitoneal spread. METHODS: A retrospective cohort study including women with recurrence of epithelial ovarian, cancer, who were treated at a single medical center, between 2000 and 2015. Patients were classified into three groups according to the site of recurrence: intraperitoneal only, retroperitoneal lymph nodes only, and both. Response to treatment was assessed by the RECIST criteria. RESULTS: Out of 135 patients in our cohort, 66 were diagnosed with intraperitoneal recurrence, 30 with retroperitoneal lymph node recurrence and 39 with combined site recurrence. The clinical, pathological and surgical characteristics were similar among all groups, besides CA-125 which was significantly lower in the retroperitoneal recurrence group at diagnosis, end of treatment and recurrence. The median follow-up period was 45.8 months. Overall survival (OS) and post relapse survival (PRS) were significantly higher in the retroperitoneal recurrence group vs. the intraperitoneal and combined site recurrence groups. (OS - 93.07, 47.9 and 41.7 months, respectively, p < .001, PRS - 68.57, 29.67 and 19.7 months, respectively, p < .001). On cox's regression analysis, retroperitoneal recurrence was found to be an independent prognostic factor for survival. CONCLUSIONS: The site of recurrence has significant prognostic value regarding PRS and OS. Patients with recurrence limited to the retroperitoneal lymph nodes have a favourable prognosis with median survival longer than 5 years.

Long-term safety in patients with recurrent ovarian cancer treated with niraparib versus placebo: Results from the phase III ENGOT-OV16/NOVA trial.

OBJECTIVE: Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor approved for use in heavily pretreated patients and as maintenance treatment in patients with newly-diagnosed or recurrent ovarian cancer following a response to platinum-based chemotherapy. We present long-term safety data for niraparib from the ENGOT-OV16/NOVA trial. METHODS: This multicenter, double-blind, randomized, controlled phase III trial evaluated the efficacy and safety of niraparib for the treatment of recurrent ovarian cancer. Patients were randomly assigned 2:1 to receive either once-daily niraparib 300 mg or placebo. Two independent cohorts were enrolled based on germline BRCA mutation status. The primary endpoint was progression-free survival, reported previously. Long-term safety data were from the most recent data cutoff (September 2017). RESULTS: Overall, 367 patients received niraparib 300 mg once daily. Dose reductions due to TEAEs were highest in month 1 (34%) and declined every month thereafter. Incidence of any-grade and grade ≥ 3 hematologic and symptomatic TEAEs was also highest in month 1 and subsequently declined. Incidence of grade ≥ 3 thrombocytopenia decreased from 28% (month 1) to 9% and 5% (months 2 and 3, respectively), with protocol-directed dose interruptions and/or reductions. Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) were reported in 2 and 6 niraparib-treated patients, respectively, and in 1 placebo patient each. Treatment discontinuations due to TEAEs were <5% in each month and time interval measured. CONCLUSION: These data demonstrate the importance of appropriate dose reduction according to toxicity criteria and support the safe long-term use of niraparib for maintenance treatment in patients with recurrent ovarian cancer. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01847274.

Batzelladine D and norbatzelladine L purified from marine sponge Monanchora arbuscula induce the reversal of fluconazole.

ATP-Binding Cassette (ABC) transporters are the main class of transmembrane transporters involved in pathogenic fungal resistance against chemotherapeutic agents. Herein we report results which show that batzelladine D (1) and norbatzelladine L (2) reverse the fluconazole resistance phenotype mediated by Pdr5p transporter on Saccharomyces cerevisiae. Both alkaloids were able to chemosensitize the Pdr5p-overexpressing strain by synergistic interaction with fluconazole. Both compounds also showed an inhibitory effect on the catalytic activity and on the intracellular accumulation of rhodamine 6G, and did not show significant in vitro mammalian cells toxicity.

Fifth Ovarian Cancer Consensus Conference: individualized therapy and patient factors.

This manuscript reports the consensus statements regarding the design and conduct of clinical trials in patients with newly diagnosed and recurrent epithelial ovarian cancer (EOC), following deliberation at the Fifth Ovarian Cancer Consensus Conference (OCCC), held in Tokyo in November 2015. Three important questions were identified for discussion prior to the meeting and achieved consensus during the meeting: (i) What are the most important factors to be evaluated prior to initial therapy? (ii) What are the most important factors to be evaluated specifically in recurrent disease? (iii) Are there specific considerations for special patient subpopulations? In addition, we report a list of important unmet needs compiled during the consensus process, which is intended to guide future research initiatives.

Antifungal activities of the essential oil and its fractions rich in sesquiterpenes from leaves of Casearia sylvestris Sw.

Casearia genus (Salicaceae) is found in sub-tropical and tropical regions of the world and comprises about 160-200 species. It is a medicinal plant used in South America, also known as "guaçatonga", "erva-de-tiú", "cafezinho-do-mato". In Brazil, there are about 48 species and 12 are registered in the State of Rio de Janeiro, including Casearia sylvestris Sw. There are many studies related to the chemical profile and cytotoxic activities of extracts from these plants, although few studies about the antifungal potential of the essential oil have been reported. In this work, we have studied the antifungal properties of the essential oil of C. sylvestris leaves, as well as of their fractions, against four yeasts (Saccharomyces cerevisae, Candida albicans, C. glabrata and C. krusei) for the first time. The chemical analysis of the essential oil revealed a very diversified (n = 21 compounds) volatile fraction composed mainly of non-oxygenated sesquiterpenes (72.1%). These sesquiterpenes included α-humulene (17.8%) and α-copaene (8.5%) and the oxygenated sesquiterpene spathulenol (11.8%) were also identified. Monoterpenes were not identified. The fractions are mainly composed of oxygenated sesquiterpenes, and the most active fraction is rich in the sesquiterpene 14-hydroxy -9-epi-ß-caryophyllene. This fraction was the most effective in inhibiting the growth of three yeast strains.

Immunohistochemical c-kit expression in uterine serous carcinoma tissue.

AIM: Uterine serous carcinoma (USC) is an aggressive tumor that represents only 10% of endometrial cancer cases but accounts for a disproportionate number of deaths due to uterine cancer. Advances in the development of specific c-kit receptor-targeted drugs have promoted its potential therapeutic application as a target in tumor-related diseases. The aim of the present study was to evaluate imunohistochemical expression of c-kit in USC tissue in order to assess whether positive cases can be candidates for targeted therapy. MATERIALS AND METHODS: C-kit expression assessment by immunohistochemistry was performed on deparaffinized sections of paraffin-embedded tissue blocks of confirmed consecutive available USC uterine specimens of patients diagnosed from 2000 to 2014. Sections of gastrointestinal stromal tumor (GIST) tissue known to contain c-kit served as positive controls. RESULTS: Immunohisto- chemical c-kit staining was not observed in any of 31 USC tissue samples examined. Intense staining was observed in the sections of GIST tissue. CONCLUSION: The present results may indicate that primary USC is not a candidate for c-kit targeted therapy.

Extensive heterosis in growth of yeast hybrids is explained by a combination of genetic models.

Heterosis, also known as hybrid vigor, is the superior performance of a heterozygous hybrid relative to its homozygous parents. Despite the scientific curiosity of this phenotypic phenomenon and its significance for food production in agriculture, its genetic basis is insufficiently understood. Studying heterosis in yeast can potentially yield insights into its genetic basis, can allow one to test the different hypotheses that have been proposed to explain the phenomenon and allows better understanding of how to take advantage of this phenomenon to enhance food production. We therefore crossed 16 parental yeast strains to form 120 yeast hybrids, and measured their growth rates under five environmental conditions. A considerable amount of dominant genetic variation was found in growth performance, and heterosis was measured in 35% of the hybrid-condition combinations. Despite previous reports of correlations between heterosis and measures of sequence divergence between parents, we detected no such relationship. We used several analyses to examine which genetic model might explain heterosis. We found that dominance complementation of recessive alleles, overdominant interactions within loci and epistatic interactions among loci each contribute to heterosis. We concluded that in yeast heterosis is a complex phenotype created by the combined contribution of different genetic interactions.

The effect of coexisting uterine myomas on clinico-pathological variables of endometrial carcinoma.

PURPOSE: To assess the prevalence of leiomyomas in patients with endometrial carcinoma (EC) and the association of their presence with clinico-pathological variables and with survival. MATERIALS AND METHODS: A retrospective chart review was conducted of all endometrial carcinoma (EC) patients diagnosed and treated in the present institution between 2002 and 2008. Selected clinical data were abstracted from medical records. Pathological data such as the presence of myomas (any size), tumor grade, depth of myometrial invasion presence of lymphovascular space involvement (LVSI), and the presence of metastases, are based on the original pathology report. RESULTS: Coexisting myomas were found in 74 (56.9%) of 130 EC patients diagnosed during the study period. No significant difference with regard to age, histological type, stage, grade, depth of myometrial invasion, LVSI, lymph node involvement, and presence of metastases (other than lymph node involvement) was found between patients without and with myomas. There was also no significant difference in survival of EC patients without and with coexistent myomas. CONCLUSION: The present data seem to indicate that the presence of myomas does not affect clinico-pathological variables of EC patients nor their survival.

Supporting new graduate physiotherapists in their first year of private practice with a structured professional development program; a qualitative study.

BACKGROUND: The transition from physiotherapy student to working in private practice has been identified as challenging. However, very little is known about whether structured professional development programs impact on this transition. OBJECTIVES: To describe new graduates' perceptions of a structured professional development program, termed the Recent Graduate Program (RGP), designed to support their transition into physiotherapy private practice. DESIGN: Qualitative analysis of data from a one-year longitudinal mixed methods study. METHOD: A total of 72 interviews were conducted over a one-year period with 20 new graduates from 19 private practices within one publicly listed allied health organisation. Semi-structured interviews were conducted before commencing work and at three, nine and 12 months. Interviews were recorded and transcribed verbatim prior to a conventional content analysis that aimed to acquire direct information from new graduates without imposing preconceived categories or theoretical perspectives. FINDINGS: New graduates reported that the RGP supported their growth as a practitioner and facilitated their learning, particularly when complemented by the experiential learning from client interactions. The RGP met their expectations with the formal education program and regular mentoring sessions highly valued. Informal support from peers and senior clinicians, while not part of the RGP, was also perceived to facilitate their growth and confidence as a physiotherapist. CONCLUSIONS: This study demonstrates that the provision of a structured transition program by a private practice employer was perceived by new graduates to facilitate their learning, confidence and self-efficacy. The RGP provides a useful model by which other practices may support new graduates.

A proof-of-concept study of growth hormone in children with Phelan-McDermid syndrome.

BACKGROUND: Phelan-McDermid syndrome (PMS) is caused by 22q13 deletions including SHANK3 or pathogenic sequence variants in SHANK3 and is among the more common rare genetic findings in autism spectrum disorder (ASD). SHANK3 is critical for synaptic function, and preclinical and clinical studies suggest that insulin-like growth factor-1 (IGF-1) can reverse a range of deficits in PMS. IGF-1 release is stimulated by growth hormone secretion from the anterior pituitary gland, and this study sought to assess the feasibility of increasing IGF-1 levels through recombinant human growth hormone (rhGH) treatment, in addition to establishing safety and exploring efficacy of rhGH in children with PMS. METHODS: rhGH was administered once daily for 12 weeks to six children with PMS using an open-label design. IGF-1 levels, safety, and efficacy assessments were measured every 4 weeks throughout the study. RESULTS: rhGH administration increased levels of IGF-1 by at least 2 standard deviations and was well tolerated without serious adverse events. rhGH treatment was also associated with clinical improvement in social withdrawal, hyperactivity, and sensory symptoms. LIMITATIONS: Results should be interpreted with caution given the small sample size and lack of a placebo control. CONCLUSIONS: Overall, findings are promising and indicate the need for larger studies with rhGH in PMS. Trial registration NCT04003207. Registered July 1, 2019, https://clinicaltrials.gov/ct2/show/NCT04003207 .

A feasibility study of weekly docetaxel with capecitabine in ovarian cancer: a promising combination of two active drugs with a potential for synergism.

OBJECTIVES: To evaluate the safety and efficacy of weekly docetaxel with capecitabine in patients with recurrent/persistent epithelial ovarian cancer (EOC). PATIENTS AND METHODS: Women treated for recurrent/persistent EOC in our department (January 2004 through December 2005) were recruited into this feasibility study. They received 35 mg/m(2) docetaxel on days 1 and 8 and 1,000 mg/m(2) capecitabine twice daily on days 1-14 in a 21-day cycle. RESULTS: Nine patients were enrolled. The median age was 64 years (37-80). Time to progression ranged from 1.67 to 11.27 months: 1 had complete response, 3 had partial responses, 4 had stable disease and 1 had disease progression. There was no grade 3 or 4 bone marrow toxicity. Nonhematological toxicity included partial hair loss (n = 4), fatigue (n = 7), hand and foot syndrome (n = 2), diarrhea (n = 5) and fluid retention syndrome (n = 1). CONCLUSION: There was good antitumor activity but frequent moderate-to-severe nonhematological toxicities when weekly docetaxel and capecitabine were used as second-line therapy for recurrent EOC. Further investigation of this combination is warranted.

Cox-2 immunohistochemical expression in epithelial ovarian carcinoma and platin sensitivity.

PURPOSE: The aim of the study was to assess whether COX-2 expression in epithelial ovarian carcinoma (EOC) tissue can distinguish between platin-sensitive and platin-resistant tumors. METHODS: Clinical and histological data were obtained from medical records of EOC patients diagnosed between the years 1995 and 2005. Patients in complete clinical remission for > 6 months after discontinuation of first-line chemotherapy were considered to be platin-sensitive. Survival of < or = 2 and > 5 years after diagnosis was considered as short- and long-term survival, respectively. Immunohistochemistry staining was performed on deparaffinized sections of tissue blocks obtained at first surgery. The intensity of staining and the percentage of stained cells was assessed by two pathologists blinded to clinical data and a scoring index was calculated. RESULTS: Among 79 patients a positive stain (> 10% of cells stained) was observed in 61 (77.2%). No statistically significant association between distribution of platin sensitivity and immunohistochemical COX-2 staining parameters was observed, although the rate of long-term survival was significantly higher among platin-sensitive then among platin-resistant/unresponsive patients. CONCLUSIONS: Immunohistochemically determined COX-2 expression in EOC is not associated with platin sensitivity and survival.

Platin sensitivity and long-term survival in Stage III epithelial ovarian cancer patients.

PURPOSE: The aim of the present study was to assess the effect of platin sensitivity on long-term survival of Stage III epithelial ovarian cancer (EOC) patients. METHODS: The records of all histologically confirmed Stage III EOC and PPC patients diagnosed during 1995-2006 were reviewed. A comparison of selected characteristics was made between long-term (> 5 years) and short-term (< 3 years) survivors. RESULTS: Among 58 Stage III patients, 20 had long-term and 18 short-term survival. The rate of platin sensitive patients in long-term survivors was significantly higher than in short-term survivors (95.0% vs 27.8%, p < 0.001). The sensitivity and specificity of platin sensitivity for long-term survival was 95% and 72.2%, respectively, and the positive and negative predictive value was 79.2% and 92.8%, respectively. No statistically significant difference between the groups was found with regard to other selected characteristics. CONCLUSION: The rate of platin sensitive patients was significantly higher among long-term survivors than among short-term survivors but the specificity and positive predictive value of platin sensitivity for long-term survival prediction were relatively low precluding its practical clinical use.

Lymphvascular space involvement compromises the survival of patients with stage I endometrial cancer: results of a multicenter study.

AIMS: To quantify the relative risk associated with lymphvascular space involvement (LVSI) on outcome measures in patients with apparent stage I endometrial cancer. METHODS: Six hundred and ninety nine consecutive patients with endometrial carcinoma apparent stage I, who underwent surgery in one of four gynecological oncology centers in Israel, comprised the study population. Forty cases with and 659 without LVSI were followed for a median time of 39 months. Recurrence free, disease specific and overall survival was compared between the two groups. The effect of LVSI, adjusted for other clinical and histo-pathological prognostic factors, was assessed by multivariate analysis. RESULTS: The univariate Kaplan-Meier procedure for survival analysis showed that patients with LVSI had lower recurrence free survival (p=0.0003), worse disease specific (p=0.0007) and overall survival (p<0.0001). Cox proportional hazards model demonstrated a trend toward shorter recurrence free survival (HR=2.0, 95% CI 0.9, 4.5; p=0.08), a worse disease specific survival (HR=2.8, 95% CI 1.1, 7.4; p=0.04) and decreased overall survival (HR=2.0, 95% CI 1.1, 3.8; p=0.03) in cases with LVSI. CONCLUSIONS: In patients with apparent stage I endometrial cancer the presence of LVSI, an independent poor prognostic factor, is associated with a two fold increased risk of death. The presence of LVSI warrants consideration when deciding upon post operative management.

Identification and Characterization of an Insulin-Like Receptor Involved in Crustacean Reproduction.

Sexual differentiation and maintenance of masculinity in crustaceans has been suggested as being regulated by a single androgenic gland (AG) insulin-like peptide (IAG). However, downstream elements involved in the signaling cascade remain unknown. Here we identified and characterized a gene encoding an insulin-like receptor in the prawn Macrobrachium rosenbergii (Mr-IR), the first such gene detected in a decapod crustacean. In mining for IRs and other insulin signaling-related genes, we constructed a comprehensive M. rosenbergii transcriptomic library from multiple sources. In parallel we sequenced the complete Mr-IR cDNA, confirmed in the wide transcriptomic library. Mr-IR expression was detected in most tissues in both males and females, including the AG and gonads. To study Mr-IR function, we performed long-term RNA interference (RNAi) silencing in young male prawns. Although having no effect on growth, Mr-IR silencing advanced the appearance of a male-specific secondary trait. The most noted effects of Mr-IR silencing were hypertrophy of the AG and the associated increased production of Mr-IAG, with an unusual abundance of immature sperm cells being seen in the distal sperm duct. A ligand blot assay using de novo recombinant Mr-IAG confirmed the existence of a ligand-receptor interaction. Whereas these results suggest a role for Mr-IR in the regulation of the AG, we did not see any sexual shift after silencing of Mr-IR, as occurred when the ligand-encoding Mr-IAG gene was silenced. This suggests that sexual differentiation in crustaceans involve more than a single Mr-IAG receptor, emphasizing the complexity of sexual differentiation and maintenance.

Randomized controlled study investigating the effect of biatrial pacing in prevention of atrial fibrillation after coronary artery bypass grafting.

BACKGROUND: Atrial fibrillation (AF) is a common problem after CABG. Prevention with prophylactic drug therapy has had limited success, therefore alternative approaches are required. This study investigated the role of biatrial pacing compared with no pacing on AF incidence after isolated first-time CABG. METHODS AND RESULTS: During surgery, temporary pacing leads were placed in the lateral wall of the right atrium and at the roof of the left atrium in Bachmann's bundle to allow bipolar pacing and sensing at each site. After surgery, all patients were connected to an external pacemaker (Chorum ELA) that also acted as a Holter monitor. Patients were consecutively randomized to either 4 days of biatrial pacing at a base rate of 80 bpm or to no pacing (control group, base rate 30 bpm). End points included an episode of AF lasting >1 hour on pacemaker Holter, clinically detected AF, intensive care unit (ICU) and hospital stay, and postoperative complications. One hundred thirty patients were randomized. Biatrial pacing significantly reduced both monitored (13.8% versus 38.5%, P:=0.001) and clinical (10.8% versus 33.8%, P:=0.002) episodes of AF. Median ICU (19 versus 24 hours, P:=NS) and mean hospital stay (7.7+/-6.9 versus 9.7+/-10, P:=NS) did not significantly change. The number of postoperative complications was lower in the biatrial group (13 versus 35, P:=0. 001). CONCLUSIONS: Biatrial pacing after CABG significantly decreases the incidence of AF. This is associated with reduced postoperative complications and a trend toward reduced ICU and hospital stay.

Phase II study of irinotecan in prior chemotherapy-treated squamous cell carcinoma of the cervix.

PURPOSE: A phase II study was performed to evaluate the antitumor activity and toxicity of irinotecan (CPT-11), a water-soluble derivative of camptothecin, in patients with prior chemotherapy-treated squamous cell cancer of the cervix. PATIENTS AND METHODS: Forty-two patients were included in the study. The median age was 44 years (range, 24 to 59 years). The median Zubrod performance status was 1. All patients were refractory to first-line chemotherapy and 88% had received prior radiotherapy. The initial dose of CPT-11 was 125 mg/m2 given as a weekly 90-minute intravenous infusion for 4 weeks, every 6 weeks. Subsequent doses were unchanged, reduced, or omitted according to toxicity grade. RESULTS: Forty-two patients were assessable for response. The overall response rate was 21%. The median time to response was 6 weeks and the median duration of response was 12 weeks. The overall median duration of survival was 6.4 months. A statistically significant survival advantage (median of 12.6 v 5.1 months) was found in patients whose disease responded to the treatment (P < .015). The major dose-limiting toxic effects (grade > or = 3) were nausea and vomiting (45%), diarrhea (24%), and granulocytopenia (36%). Grade > or = 3 anemia was encountered in 62% of patients and the incidence of thrombocytopenia was negligible. Less severe side effects were alopecia (48%), drug fever (43%), anorexia (33%), fatigue (33%), skin rash (21%), stomatitis (14%), and allergic reaction (9%). The gastrointestinal intolerance was dose-related. The incidence of bone marrow depression did not decrease with dose reduction, possibly because of a cumulative effect or hematologic intolerance by a subset of patients. CONCLUSIONS: CPT-11 has significant activity in refractory cervical carcinoma. Gastrointestinal intolerance and hematologic toxicity must be monitored carefully. Further studies of alternative schedules may improve the tolerance and response rate.