Alternative academic approaches for testing homologous recombination deficiency in ovarian cancer in the MITO16A/MaNGO-OV2 trial.

BACKGROUND: The detection of homologous recombination deficiency (HRD) can identify patients who are more responsive to platinum and poly ADP ribose polymerase inhibitors (PARPi). MyChoice CDx (Myriad) is the most used HRD test in ovarian cancer (OC). However, some limitations of commercial tests exist, because of the high rate of inconclusive results, costs, and the impossibility of evaluating functional resistance mechanisms. PATIENTS AND METHODS: Two academic genomic tests and a functional assay, the RAD51 foci, were evaluated to detect HRD. One hundred patients with high-grade OC enrolled in the MITO16A/MaNGO-OV2 trial and treated with first-line therapy with carboplatin, paclitaxel, and bevacizumab were analyzed. RESULTS: The failure rate of the two genomic assays was 2%. The sensitivity in detecting HRD when compared with Myriad was 98.1% and 90.6%, respectively. The agreement rate with Myriad was 0.92 and 0.87, with a Cohen's κ coefficient corresponding to 0.84 and 0.74, respectively. For the RAD51 foci assay, the failure rate was 30%. When the test was successful, discordant results for deficient and proficient tumors were observed, and additional HRD patients were identified compared to Myriad; sensitivity was 82.9%, agreement rate was 0.65, and Cohen's κ coefficient was 0.18. The HRD detected by genomic assays and residual tumor at primary surgery and stage was correlated with progression-free survival at multivariate analysis. CONCLUSIONS: Results suggest the feasibility of academic tests for assessing HRD status that show robust concordance with Myriad and correlation with clinical outcome. The contribution of the functional information related to the RAD51 foci test to the genomic data needs further investigation.

Development and preliminary evaluation of a communication skills training programme for hospital physicians by a specialized palliative care service: the 'Teach to Talk' programme.

BACKGROUND: There is widespread agreement about the importance of communication skills training (CST) for healthcare professionals caring for cancer patients. Communication can be effectively learned and improved through specific CST. Existing CSTs have some limitations with regard to transferring the learning to the workplace. The aim of the study is developing, piloting, and preliminarily assessing a CST programme for hospital physicians caring for advanced cancer patients to improve communication competences. METHODS: This is a Phase 0-I study that follows the Medical Research Council framework; this paper describes the following sections: a literature review on CST, the development of the Teach to Talk training programme (TtT), the development of a procedure for assessing the quality of the implementation process and assessing the feasibility of the implementation process, and the pilot programme. The study was performed at a 900-bed public hospital. The programme was implemented by the Specialized Palliative Care Service. The programme was proposed to 19 physicians from 2 departments. RESULTS: The different components of the training course were identified, and a set of quality indicators was developed. The TtT programme was implemented; all the physicians attended the lesson, videos, and role-playing sessions. Only 25% of the physicians participated in the bedside training. It was more challenging to involve Haematology physicians in the programme. CONCLUSIONS: The programme was completed as established for one of the two departments in which it was piloted. Thus, in spite of the good feedback from the trainees, a re-piloting of a different training program will be developed, considering in particular the bed side component. The program should be tailored on specific communication attitude and believes, probably different between different specialties.

A meta-synthesis study of the key elements involved in childhood vaccine hesitancy.

OBJECTIVES: Immunization is one of the most successful and cost-effective interventions to improve health outcomes. However, internationally, the phenomenon of parental vaccine hesitancy is increasing and presents a growing challenge for health professionals. This article summarizes the evidence surrounding childhood vaccine hesitancy from the perspective of parents. STUDY DESIGN: We conducted a systematic review and meta-synthesis of qualitative studies. METHODS: We searched for qualitative research articles in electronic databases from inception to March 2018. In addition, a manual search of the retrieved articles and their references was conducted to identify other potential articles. We used the Critical Appraisal Skills Programme to examine study validity, adequacy and potential applicability of the results. No articles were excluded for reasons of quality. By performing a meta-synthesis, we identified descriptive themes and, subsequently, the conceptual elements of vaccine hesitancy. RESULTS: The review included 27 studies involving a total of 1557 parents who were hesitant about vaccinating their child. Five overarching categories were identified: (1) risk conceptualization; (2) mistrust towards vaccine-related institutions, pharmaceutical companies, researchers, health professionals and the information from media; (3) parental alternative health beliefs about childhood immunity, vaccine scheduling and the perceived toxicity of vaccinations; (4) philosophical views on parental responsibility; and (5) parents' information levels about vaccination. CONCLUSIONS: Healthcare providers need to approach this difficult situation considering that parents desire to do what they feel right for the child. Understanding the core elements of hesitancy will allow health professionals to adopt effective communication and behavioural strategies.

A Comparative Study of Hummingbirds and Chickens Provides Mechanistic Insight on the Histidine Containing Dipeptide Role in Skeletal Muscle Metabolism.

Histidine containing dipeptides (HCDs) have numerous ergogenic and therapeutic properties, but their primary role in skeletal muscle remains unclear. Potential functions include pH regulation, protection against reactive oxygen/nitrogen species, or Ca2+ regulation. In recognition of the challenge of isolating physiological processes in-vivo, we employed a comparative physiology approach to investigate the primary mechanism of HCD action in skeletal muscle. We selected two avian species (i.e., hummingbirds and chickens), who represented the extremes of the physiological processes in which HCDs are likely to function. Our findings indicate that HCDs are non-essential to the development of highly oxidative and contractile muscle, given their very low content in hummingbird skeletal tissue. In contrast, their abundance in the glycolytic chicken muscle, indicate that they are important in anaerobic bioenergetics as pH regulators. This evidence provides new insights on the HCD role in skeletal muscle, which could inform widespread interventions, from health to elite performance.

Placebo in sports nutrition: a proof-of-principle study involving caffeine supplementation.

We investigated the effects of supplement identification on exercise performance with caffeine supplementation. Forty-two trained cyclists (age 37 ± 8 years, body mass [BM] 74.3 ± 8.4 kg, height 1.76 ± 0.06 m, maximum oxygen uptake 50.0 ± 6.8 mL/kg/min) performed a ~30 min cycling time-trial 1 h following either 6 mg/kgBM caffeine (CAF) or placebo (PLA) supplementation and one control (CON) session without supplementation. Participants identified which supplement they believed they had ingested ("caffeine", "placebo", "don't know") pre- and post-exercise. Subsequently, participants were allocated to subgroups for analysis according to their identifications. Overall and subgroup analyses were performed using mixed-model and magnitude-based inference analyses. Caffeine improved performance vs PLA and CON (P ≤ 0.001). Correct pre- and post-exercise identification of caffeine in CAF improved exercise performance (+4.8 and +6.5%) vs CON, with slightly greater relative increases than the overall effect of caffeine (+4.1%). Performance was not different between PLA and CON within subgroups (all P > 0.05), although there was a tendency toward improved performance when participants believed they had ingested caffeine post-exercise (P = 0.06; 87% likely beneficial). Participants who correctly identified placebo in PLA showed possible harmful effects on performance compared to CON. Supplement identification appeared to influence exercise outcome and may be a source of bias in sports nutrition.

Chronic lactate supplementation does not improve blood buffering capacity and repeated high-intensity exercise.

Since there is conflicting data on the buffering and ergogenic properties of calcium lactate (CL), we investigated the effect of chronic CL supplementation on blood pH, bicarbonate, and high-intensity intermittent exercise performance. Sodium bicarbonate (SB) was used as a positive control. Eighteen athletes participated in this double-blind, placebo-controlled, crossover, fully counterbalanced study. All participants underwent three different treatments: placebo (PL), CL, and SB. The dose was identical in all conditions: 500 mg/kg BM divided into four daily individual doses of 125 mg/kg BM, for five consecutive days, followed by a 2-7-day washout period. On the fifth day of supplementation, individuals undertook four 30-s Wingate bouts for upper body with 3-min recovery between bouts. Total mechanical work (TMW) for the overall protocol and for the initial (1st+2nd) and final (3rd+4th) bouts was determined at each session. Blood pH, bicarbonate, and lactate levels were determined at rest, immediately and 5 min after exercise. CL supplementation did not affect performance (P > 0.05 for the overall TMW as well for initial and final bouts), nor did it affect blood bicarbonate and pH prior to exercise. SB supplementation improved performance by 2.9% for overall TMW (P = 0.02) and 5.9% in the 3rd+4th bouts (P = 0001). Compared to the control session, SB also promoted higher increases in blood bicarbonate than CL and PL (+0.03 ± 0.04 vs +0.009 ± 0.02 and +0.01 ± 0.03, respectively). CL supplementation was not capable of enhancing high-intensity intermittent performance or changing extracellular buffering capacity challenging the notion that this dietary supplement is an effective buffering agent.

Prospective phase II trial of trabectedin in BRCA-mutated and/or BRCAness phenotype recurrent ovarian cancer patients: the MITO 15 trial.

BACKGROUND: Current evidence suggest that trabectedin is particularly effective in cells lacking functional homologous recombination repair mechanisms. A prospective phase II trial was designed to evaluate the activity of trabectedin in the treatment of recurrent ovarian cancer patients presenting BRCA mutation and/or BRCAness phenotype. PATIENTS AND METHODS: A total of 100 patients with recurrent BRCA-mutated ovarian cancer and/or BRCAness phenotype (≥2 previous responses to platinum) were treated with trabectedin 1.3 mg/mq i.v. q 3 weeks. The activity of the drug with respect to BRCA mutational status and to a series of polymorphisms [single-nucleotide polymorphisms (SNPs)] involved in DNA gene repair was analyzed. RESULTS: Ninety-four were evaluable for response; in the whole population, 4 complete and 33 partial responses were registered for an overall response rate (ORR) of 39.4. In the platinum-resistant (PR) and -sensitive (PS) population, an ORR of 31.2% and 47.8%, and an overall clinical benefit of 54.2% and 73.9%, respectively, were registered. In the whole series, the median progression-free survival (PFS) was 18 weeks and the median overall survival (OS) was 72 weeks; PS patients showed a more favorable PFS and OS compared with PR patients. BRCA gene mutational status was available in 69 patients. There was no difference in ORR, PFS and OS according to BRCA 1-2 status nor any association between SNPs of genes involved in DNA repair and NER machinery and response to trabectedin was reported. CONCLUSIONS: Our data prospectively confirmed that the signature of 'repeated platinum sensitivity' identifies patients highly responsive to trabectedin. In this setting, the activity of trabectedin seems comparable to what could be obtained using platinum compounds and the drug may represent a valuable alternative option in patients who present contraindication to receive platinum. EUDRACT NUMBER: 2011-001298-17.

Vibrational spectrum of solid picene (C22H14).

Recently, Mitsuhashi et al observed superconductivity with a transition temperature up to 18 K in potassium doped picene (C(22)H(14)), a polycyclic aromatic hydrocarbon compound (Mitsuhashi et al 2010 Nature 464 76). Theoretical analysis indicates the importance of electron-phonon coupling in the superconducting mechanisms of these systems, with different emphasis on inter- and intra-molecular vibrations, depending on the approximations used. Here we present a combined experimental and ab initio study of the Raman and infrared spectrum of undoped solid picene, which allows us to unambiguously assign the vibrational modes. This combined study enables the identification of the modes which couple strongly to electrons and hence can play an important role in the superconducting properties of the doped samples.

Laparoscopic total fallopian tube removal at the time of bilateral salpingo-oophorectomy in BRCA2 positive women.

About 10% of all serous ovarian cancer has BRCA1 and/or BRCA2 mutations. Recent data showed that following the SEE FIM protocol it is possible to evidence more fimbriae cancers. Due to those studies, fallopian tube cancer in recent years has become the predominant site of cancer in BRCA1 and/or 2 mutation carriers. The pathological study of the fallopian tube is not complete during salpingo-oophorectomy because a small part (intramural site) is situated inside the uterus. In this case report we demonstrate how it is possible to remove the tubes entirely for pathological analysis without hysterectomy by laparoscopic surgery.

X-ray diffraction microtomography (XRD-CT), a novel tool for non-invasive mapping of phase development in cement materials.

A recently developed synchrotron-based imaging technique, X-ray diffraction microtomography (XRD-CT), has been applied here for the first time to a complex system, the hydrating Portland cement paste, in order to monitor the evolution of microstructure and phase formation with a 3D non-invasive imaging approach. The ettringite-XRD-peak-based image reconstructions, combined with transmission microtomography (X-microCT) images, allowed to assess the ubiquitous distribution of this phase, which appears early in the hydration process and showed its preferential concentration in the relatively less compact regions of the paste. The comparison of greyscale histograms for cement pastes after 9 and 58 h from hydration showed an increase of ettringite content with age, in agreement with the quantitative Rietveld analysis of the sum patterns. By renormalizing the greyscale histograms to the relative weight fraction, as obtained from Rietveld refinements, a new technique which allows estimation of phase contents with spatial resolution has been developed. The results achievable by combining XRD-CT, X-microCT and Rietveld appear very promising to provide experimental snapshots of the cement hydration process to be compared with results obtained from computer simulations.

Overall survival in BRCA-associated ovarian cancer: case-control study of an Italian series.

About 10% of all ovarian cancers are due to BRCA 1 and/or BRCA 2 mutations. Some studies have shown that patients belonging to this group have a better survival compared to sporadic groups but data are still inconclusive. The aim of this study was to investigate overall survival in patients with ovarian cancer and germ-line mutations in the BRCA1/2 genes in comparison to high-risk patients, defined as patients with ovarian cancer and a strong family history of breast and ovarian cancer, but who tested negative for the BRCA mutation. We collected all the clinical features and did follow-up. The two groups showed similar characteristics concerning age at diagnosis, histological type and stage. Grade 3 was more frequent in the BRCA group. Survival data did not show any advantage for the BRCA mutated group.

Development, validity and reliability of a questionnaire designed to evaluate rapid weight loss patterns in judo players.

The aim of this study was to develop a questionnaire to evaluate rapid weight loss patterns of competitive judo players and to assess its validity and reliability. We evaluated the reliability (n=94), content validity (evaluation by 10 experts), discriminant validity (differences in scores between athletes with body weight below and above their weight class; n=100) and convergent validity (correlation with Restraint Scale; n=60). No item was considered unclear or ambiguous by more than 20% of the experts. The intraclass Coefficient Correlation was above 0.90 for all questions whose answers were parametric (P<0.001; n=94) and no significant differences were found between test and retest scores (n=94--Wilcoxon's signed rank test). Cronbach's alpha was 0.98 for scores obtained between test and retest. Non-numerical questions showed proportions of agreement >80%; Spearman's Correlation between the Restraint Scale and the Rapid Weight Loss Questionnaire was 0.62 (P<0.001; n=60). Athletes below their weight class (n=50) had a significantly lower score compared with athletes above the weight class (n=50; P<0.001--Mann-Whitney U test). In conclusion, the questionnaire showed good validity and reliability and could be used accurately to assess weight loss patterns of judo players.

Rare presentation of endometrial carcinoma with singular bone metastasis.

The major symptom at diagnosis of endometrial cancer is post-menopausal bleeding; it is present in around 90% of cases. Singular bone metastasis is described as an uncommon site for endometrial cancer at diagnosis, showing in just 5-6% of cases. In this report we describe a rare presentation of a singular bone metastasis because of endometrial cancer of a woman with previous diagnosis of early breast cancer. A review of literature uncovered some cases of bone metastasis at presentation of endometrial cancer and that it can occur as first symptom of cancer before vaginal bleeding. This rare presentation of uterine cancer needs to be studied and described because it may be seen and needs a homogeneous treatment to improve survival.

Exercise training attenuates lipectomy-induced impaired glucose tolerance in rats.

OBJECTIVE: Since visceral adipose tissue (VAT) may account for impaired peripheral and hepatic insulin sensitivity (IS), it has been hypothesized that the partial removal of VAT could result in improved insulin action, while the re-growth of the excised tissue and/or compensatory growth of non-excised depots seems to occur. Thus, it was aimed to investigate whether or not VAT removal and exercise affect IS. METHODS: Male Wistar rats were fed a high-fat diet and subsequently assigned randomly to one of four groups: 1. exercised plus lipectomized (EL), 2. exercised plus sham-lipectomized (ES), 3. sedentary plus lipectomized (CL), 4. sedentary plus sham-lipectomized (CS). After lipectomy, EL and ES animals underwent a 7-consecutive-day training period. Body weight, food intake, basal metabolic rate, fasting glucose, and glucose tolerance were assessed before and after the interventions. Fasting insulin and the HOMA index, body fat mass, and the expression of pro-inflammatory genes were assessed after the interventions. RESULTS: EL group showed greater insulin sensitivity compared to all other groups. EL and ES groups showed lower fasting insulin levels when compared to CL and CS groups, respectively. The EL group showed improved IS when compared to the remaining groups. The CL group showed impaired glucose tolerance and increased TNF-alpha gene expression. Body weight and fat mass did not differ among the groups. PPAR gamma gene expression was increased in the EL and ES groups. CONCLUSIONS: These results showed that short-term swimming training improved insulin sensitivity, but failed to prevent fat regain in lipectomized animals. Lipectomy induced impaired glucose tolerance, which is probably related to increased TNF-alpha gene expression. It is possible that a high-fat diet might be implicated in faster regain of adipose tissue after lipectomy. Our results also show that short-term exercise associated with lipectomy could improve insulin sensitivity.

Effects of creatine supplementation on glucose tolerance and insulin sensitivity in sedentary healthy males undergoing aerobic training.

Recent findings have indicated that creatine supplementation may affect glucose metabolism. This study aimed to examine the effects of creatine supplementation, combined with aerobic training, on glucose tolerance in sedentary healthy male. Subjects (n = 22) were randomly divided in two groups and were allocated to receive treatment with either creatine (CT) ( approximately 10 g . day over three months) or placebo (PT) (dextrose). Administration of treatments was double blind. Both groups underwent moderate aerobic training. An oral glucose tolerance test (OGTT) was performed and both fasting plasma insulin and the homeostasis model assessment (HOMA) index were assessed at the start, and after four, eight and twelve weeks. CT demonstrated significant decrease in OGTT area under the curve compared to PT (P = 0.034). There were no differences between groups or over time in fasting insulin or HOMA. The results suggest that creatine supplementation, combined with aerobic training, can improve glucose tolerance but does not affect insulin sensitivity, and may warrant further investigation with diabetic subjects.

Clinical impact of false-negative sentinel lymph nodes in breast cancer.

AIMS: To evaluate the incidence of false-negative (FN) sentinel lymph node (SLN) cases, their correlation with a series of clinico-pathologic parameters and their impact on adjuvant treatment indications and on clinical axillary relapse in the setting of a multicentric clinical trial comparing SLN biopsy with axillary lymph node dissection (ALND). METHODS: A series of 697 patients with primary breast cancer < or = 3 cm were randomized to SLN biopsy associated with ALND (ALND arm) or to SLN biopsy followed by ALND only if the SLN was metastatic (SLN arm). The FN SLN rate was assessed in the ALND arm. A series of 11 clinico-pathological parameters were tested for a possible association with FN results. The indications for adjuvant treatments were evaluated by considering both the FN nodal stages, as indicated by the SLN, and the true positive axillary status, as indicated by completion ALND. The occurrence of clinically evident axillary recurrences was evaluated in the two arms. RESULTS: The FN rate was 16.7%. Of the clinico-pathologic parameters tested, only a tumour size < or = 2 cm and the presence of a single metastatic axillary node was significantly associated with a risk of FN (p = 0.033 and p = 0.018, respectively). The FN SLN would have led to different adjuvant therapy indications in 12/18 cases. At 56 months, no clinically evident axillary nodal recurrences were present in the ALND arm patients, whereas one case of axillary recurrence was detected in the SLN arm patients. CONCLUSIONS: FN SLN biopsy is not uncommon, especially in the presence of a small primary tumour with a single nodal metastasis. An FN finding can lead to less than optimal adjuvant treatment. However, the clinical impact of FN in terms of axillary recurrence at 56 months was minimal.

Long-term survival in a randomized study of nonplatinum therapy versus platinum in advanced epithelial ovarian cancer.

The purpose of this study was to compare long-term survival in first-line chemotherapy with and without platinum in advanced-stage ovarian cancer. From July 1987 to November 1992, 161 untreated patients with FIGO stage III-IV epithelial ovarian cancer were randomized: 81 patients received no platinum and 80 received platinum combination. Residual disease after surgery was <2 cm in 61 patients without platinum, 59 with platinum. Median age was 58 years in nonplatinum arm and 55 years in platinum arm (range: 15-73). Complete and partial responses were 51% and 10% for nonplatinum arm and 51% and 8% for platinum arm, respectively (P= 0.7960). Stable disease was observed in 18% of patients in nonplatinum arm and 15% of patients in platinum arm and progression in 20% of nonplatinum- and 21% of platinum-treated cases. Ten-year disease-free survival was 37% for therapy without platinum and 31% for platinum combination (P= 0.5679); 10-year overall survival was 23% without platinum and 31% with platinum combination (P= 0.2545). Fifteen-year overall survival showed a trend of short duration in favor of platinum (P= 0.0678). Relapses occurred after 60 months in ten patients (seven with and three without platinum). The overall and disease-free survivals at 5, 10, and 15 years show no statistically significant long-term advantage from the addition of cisplatin; however, there is a slight trend in its favor.

Gemcitabine and liposomal doxorubicin in biliary and hepatic carcinoma (HCC) chemotherapy: preliminary results and review of the literature.

BACKGROUND: Advanced biliary tract cancers have a poor prognosis. Gemcitabine (G) as a single agent or in combination represents an active treatment option. Systemic chemotherapy in hepatocellular carcinoma represents a palliative treatment. Gemcitabine in combination with Liposomal Doxorubicin (LD) may represent an active treatment option. PATIENTS AND METHODS: Clinical trials for biliary and hepatic carcinoma have been reviewed. RESULTS: We obtained RC (1 pt), RP (4 pts), SD (8 pts) and seven pts had PD (RR 25% and SD 40%). Our chemotherapy regimen was Gemcitabine 1000 mg/m(2) d 1 and 8, Liposomal Doxorubicin 30 mg d 1, q 28. Patients were 21 (17 M), aged 44 to 78 (median 63 yrs). Only in 8 pts we observed G 3-4 haematological toxicity, thrombocytopenia and neutropenia (7 G3, 1 G4).