A phase I dose-escalation study of enzalutamide in combination with the AKT inhibitor AZD5363 (capivasertib) in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: Activation of the PI3K/AKT/mTOR pathway through loss of phosphatase and tensin homolog (PTEN) occurs in approximately 50% of patients with metastatic castration-resistant prostate cancer (mCRPC). Recent evidence suggests that combined inhibition of the androgen receptor (AR) and AKT may be beneficial in mCRPC with PTEN loss. PATIENTS AND METHODS: mCRPC patients who previously failed abiraterone and/or enzalutamide, received escalating doses of AZD5363 (capivasertib) starting at 320 mg twice daily (b.i.d.) given 4 days on and 3 days off, in combination with enzalutamide 160 mg daily. The co-primary endpoints were safety/tolerability and determining the maximum tolerated dose and recommended phase II dose; pharmacokinetics, antitumour activity, and exploratory biomarker analysis were also evaluated. RESULTS: Sixteen patients were enrolled, 15 received study treatment and 13 were assessable for dose-limiting toxicities (DLTs). Patients were treated at 320, 400, and 480 mg b.i.d. dose levels of capivasertib. The recommended phase II dose identified for capivasertib was 400 mg b.i.d. with 1/6 patients experiencing a DLT (maculopapular rash) at this level. The most common grade ≥3 adverse events were hyperglycemia (26.7%) and rash (20%). Concomitant administration of enzalutamide significantly decreased plasma exposure of capivasertib, though this did not appear to impact pharmacodynamics. Three patients met the criteria for response (defined as prostate-specific antigen decline ≥50%, circulating tumour cell conversion, and/or radiological response). Responses were seen in patients with PTEN loss or activating mutations in AKT, low or absent AR-V7 expression, as well as those with an increase in phosphorylated extracellular signal-regulated kinase (pERK) in post-exposure samples. CONCLUSIONS: The combination of capivasertib and enzalutamide is tolerable and has antitumour activity, with all responding patients harbouring aberrations in the PI3K/AKT/mTOR pathway. CLINICAL TRIAL NUMBER: NCT02525068.

A case of hidradenitis suppurativa linked to trisomy 1q.

Hidradenitis suppurativa (HS) is a chronic relapsing disorder of the apocrine gland affecting mainly areas subjected to friction (e.g. the axillae, groin, perineum and medial aspects of the thighs). This condition can be linked to different comorbidities: autoimmune and inflammatory disease, hormone-related disorders, obesity and the metabolic syndrome, as well as rare syndromes such as Bazex-Dupré-Christol, Down's, KID, PAPASH, PASS, PASH, and SAPHO syndromes, or Dowling-Degos disease. We report a case of severe HS in a patient with Trisomy 1q;13, a very rare cytogenetic anomaly characterized by severe anomalies including dysmorphisms, multiple congenital malformations, heart defects and intellectual disability.

Evaluation of applying IHC4 as a prognostic model in the translational study of Intergroup Exemestane Study (IES): PathIES.

BACKGROUND: Intergroup Exemestane Study (IES) was a randomised study that showed a survival benefit of switching adjuvant endocrine therapy after 2-3 years from tamoxifen to exemestane. This PathIES aimed to assess the role of immunohistochemical (IHC)4 score in determining the relative sensitivity to either tamoxifen or sequential treatment with tamoxifen and exemestane. PATIENTS AND METHODS: Primary tumour samples were available for 1274 patients (27% of IES population). Only patients for whom the IHC4 score could be calculated (based on oestrogen receptor, progesterone receptor, HER2 and Ki67) were included in this analysis (N = 430 patients). The clinical score (C) was based on age, grade, tumour size and nodal status. The association of clinicopathological parameters, IHC4(+C) scores and treatment effect with time to distant recurrence-free survival (TTDR) was assessed in univariable and multivariable Cox regression analyses. A modified clinical score (PathIEscore) (N = 350) was also estimated. RESULTS: Our results confirm the prognostic importance of the original IHC4, alone and in conjunction with clinical scores, but no significant difference with treatment effects was observed. The combined IHC4 + Clinical PathIES score was prognostic for TTDR (P < 0.001) with a hazard ratio (HR) of 5.54 (95% CI 1.29-23.70) for a change from 1st quartile (Q1) to Q1-Q3 and HR of 15.54 (95% CI 3.70-65.24) for a change from Q1 to Q4. CONCLUSION: In the PathIES population, the IHC4 score is useful in predicting long-term relapse in patients who remain disease-free after 2-3 years. This is a first trial to suggest the extending use of IHC4+C score for prognostic indication for patients who have switched endocrine therapies at 2-3 years and who remain disease-free after 2-3 years.

Primary HPV test screening in cervical cancer: a two-year experience of a single screening center in Latina (Italy).

OBJECTIVE: The aim of this study was to evaluate the effect and performance of the new algorithm in cervical cancer screening program in two years' experience of Latina (Italy). MATERIALS AND MTHODS: The female population was divided into two groups, the first group was referred to PAP test and the second one to hr-HPV test according to national guidelines. RESULTS: In two years the participation mean rate increased among women aged 35-64 compared to women aged 25-34. The primary PAP test positive rate and hr-HPV test positive rate were 4.0% and 5.2%, respectively. The PAP test positive rate among hr-HPV+ women decreased from 2012 to 2013. Women with hr-HPV+/PAP+ were referred immediately to colposcopy and this rate was 1.2%. The predictive positive value for CIN2+ to colposcopy was 10.9% in 2012 and 9.1% in 2013, while the detection rate for CIN2+ was 1.6% in 2012 and 1.4% in 2013. CONCLUSION: The stratification of the female population leads to a decreased inappropriate therapeutic path while the combination of hr-HPV test with PAP test in woman aged 35-64 lets obtain high levels specificity and sensitivity results.

Sterile leukocyturia is associated with interstitial fibrosis and tubular atrophy in kidney allograft protocol biopsies.

Kidney allograft interstitial fibrosis and tubular atrophy (IF/TA) is associated with a poorer renal function and outcome. In the current clinical practice, an early diagnosis can only be provided by invasive tests. We aimed to investigate the association of sterile leukocyturia with Banff criteria histological findings in kidney allograft protocol biopsies. We studied 348 allograft biopsies from two different European countries performed at 8.5 + 3.5 months after transplantation. In these cases, the presence of sterile leukocyturia (Leuc+, n = 70) or no leukocyturia (Leuc-, n = 278) was analyzed and related to Banff elementary lesions. Only IF/TA was significantly different between Leuc+ and Leuc- groups. IF/TA was present in 85.7% of Leuc+ and 27.7% of Leuc- patients (p < 0.001). IF/TA patients had higher serum creatinine and presence of proteinuria (p < 0.05). Independent predictors of IF/TA were donor age, donor male sex, serum creatinine and Leuc+ (hazard ratio 18.2; 95% confidence interval, 8.1-40.7). The positive predictive value of leukocyturia for predicting IF/TA was 85.7% whereas the negative predictive value was 72.3%. These studies suggest that leukocyturia is a noninvasive and low-cost test to identify IF/TA. An early diagnosis may allow timely interventional measures directed to minimize its impact and improve graft outcome.

Carbon, hydrogen and oxygen stable isotope ratios of whole wood, cellulose and lignin methoxyl groups of Picea abies as climate proxies.

RATIONALE: Carbon, hydrogen and oxygen (C, H and O) stable isotope ratios of whole wood and components are commonly used as paleoclimate proxies. In this work we consider eight different proxies in order to discover the most suitable wood component and stable isotope ratio to provide the strongest climate signal in Picea abies in a southeastern Alpine region (Trentino, Italy). METHODS: δ(13)C, δ(18)O and δ(2)H values in whole wood and cellulose, and δ(13)C and δ(2)H values in lignin methoxyl groups were measured. Analysis was performed using an Isotopic Ratio Mass Spectrometer coupled with an Elemental Analyser for measuring (13)C/(12)C and a Pyrolyser for measuring (2)H/(1)H and (18)O/(16)O. The data were evaluated by Principal Component Analysis, and a simple Pearson's correlation between isotope chronologies and climatic features, and multiple linear regression were performed to evaluate the data. RESULTS: Each stable isotope ratio in cellulose and lignin methoxyl differs significantly from the same stable isotope ratio in whole wood, the values begin higher in cellulose and lignin except for the lignin δ(2)H values. Significant correlations were found between the whole wood and the cellulose fractions for each isotope ratio. Overall, the highest correlations with temperature were found with the δ(18)O and δ(2)H values in whole wood, whereas no significant correlations were found between isotope proxies and precipitation. CONCLUSIONS: δ(18)O and δ(2)H values in whole wood provide the best temperature signals in Picea abies in the northern Italian study area. Extraction of cellulose and lignin and analysis of other isotopic ratios do not seem to be necessary.

Correlation of Clinician- and Patient-Reported Outcomes in the BC2001 Trial.

AIMS: To evaluate whether there is sufficient correlation between patient-reported outcomes (PROs) and clinician-reported outcomes (CROs) in bladder cancer follow-up post-radiotherapy to streamline data collection and to reduce trial follow-up burden on patients, clinicians and trial programmes. MATERIALS AND METHODS: PROs data were collected within the BC2001 trial using the Functional Assessment of Cancer Therapy specific to bladder cancer (FACT-BL) questionnaire. CROs data were collected by clinicians using Late Effects in Normal Tissues Subjective, Objective and Management (LENT/SOM). Data were collected at baseline, post-treatment, at 6 and 12 months post-randomisation and then annually to 5 years. The percentage agreement between CROs and PROs measures was evaluated at 2 and 5 years post-randomisation. Concordance was tested using the weighted Kappa statistic with 95% confidence intervals. RESULTS: Correlation was evaluated between six categories of the FACT-BL and LENT/SOM scores. At 2 years the percentage agreement across these domains ranged from 45 to 78%, with the weighted Kappa statistic between 0.07 and 0.35. Results were similar in year 5 with 48-83% agreement and kappa statistics between -0.02 and 0.21. CONCLUSION: The correlation between CROs and PROs in patients treated with radiotherapy for bladder cancer were generally poor. PROs appear to be more sensitive, with higher grade events reported. Further work is needed to evaluate whether PROs alone can be used to evaluate toxicity-related outcomes in randomised controlled trials.

Differences in Quality of Life and Toxicity for Male and Female Patients following Chemo(radiotherapy) for Bladder Cancer.

AIMS: BC2001, a randomised trial of treatment for muscle-invasive bladder cancer, demonstrated no difference in health-related quality of life (HRQoL) or late toxicity between patients receiving radical radiotherapy with and without chemotherapy. This secondary analysis explored sex-based differences in HRQoL and toxicity. MATERIALS AND METHODS: Participants completed the Functional Assessment of Cancer Therapy Bladder (FACT-BL) HRQoL questionnaires at baseline, end of treatment, 6 months and annually until 5 years. Clinicians assessed toxicity with the Radiation Therapy Oncology Group (RTOG) and Late Effects in Normal Tissues Subjective, Objective and Management (LENT/SOM) scoring systems at the same timepoints. The impact of sex on patient-reported HRQoL was evaluated using multivariate analyses of change in FACT-BL subscores from baseline to the timepoints of interest. For clinician-reported toxicity, differences were compared by calculating the proportion of patients with grade 3-4 toxicities occurring over the follow-up period. RESULTS: For both males and females, all FACT-BL subscores had a reduction in HRQoL at the end of treatment. For males, the mean bladder cancer subscale (BLCS) score remained stable through to year 5. For females, there was a decline in BLCS from baseline at years 2 and 3 with a return to baseline at year 5. At year 3, females had a statistically significant and clinically meaningful worsening of mean BLCS score (-5.18; 95% confidence interval -8.37 to -1.99), which was not seen in males (0.24; -0.76 to 1.23). RTOG toxicity was more frequent in females than males (27% versus 16%, P = 0.027). CONCLUSION: Results suggest that female patients treated with radiotherapy ± chemotherapy for localised bladder cancer report worse treatment-related toxicity in post-treatment years 2 and 3 than males.

Long-term results of biopsy-guided selection and allocation of kidneys from older donors in older recipients.

In our old-for-old program, we discard or allocate older extended criteria donor kidneys to single (SKT) or dual kidney transplantation (DKT) depending on histological Remuzzi's score in recipients older than 60 years. Here, we analyze the long-term results of this program and try to identify independent predictors of patient and graft survival. Between December 1996 and January 2008, we performed 115 SKT and 88 DKT. Discard rate was 15%. Acute rejection incidence was higher in SKT than in DKT (22.6% vs. 11.4%, p = 0.04). Renal function was better in DKT than in SKT up to 5 years after transplantation. Surgical complications were frequent in DKT. Ten-year cumulative graft survival was significantly lower in the SKT group (31% vs. 53%, p = 0.03). In SKT, histological score 4 provided similar graft survival than 3 or less, whereas in DKT score 4, 5 or 6 displayed similar outcome. Finally, independent predictors of graft survival were history of major adverse cardiac event and 1-year serum creatinine, rather than SKT or DKT. In conclusion, this biopsy-guided old-for-old strategy resulted in acceptable long-term graft survival. Our results suggest that DKT should be considered for scores of 5 or 6 only.

[Testing of microsatellite primers with different populations of Eurasian spruces Picea abies (L.) Karst. and Picea obovata Ledeb].

From a clone library containing microsatellite DNA fragments of Norwegian spruce, seven pairs of primers were selected. These primers were tested to be the markers in the genetic structure analysis of nine populations of Eurasian spruce species Picea abies (L.) Karst. and Picea obovata Ledeb. Five pairs of these primers identified polymorphic loci with the allele numbers from 6 to 15. In the populations examined, the observed and expected heterozygosity values assessed at five loci varied from 0.1778 to 0.6556 and from 0.7800 to 0.900, respectively. In the populations examined, the values of F(st) index varied from 0.0691 to 0.2551 with the mean value of 0.1318. On the dendrogram based on Nei genetic distances, the populations formed three groups: Pskov-Ciscarpathia, Komi-Tatarstan-Arkhangelsk, Kazakhstan-Karelia(natural)-Karelia(culture)-Krasnoyarsk. Five of the primer pairs tested proved useful for analysis of the population genetic structure in Eurasian spruce species.

A case of proliferative nodule arising within blue nevus.

Abstract: Blue nevi are a heterogeneous group of lesions that can display a variety of different clinicopathological characteristics. Although attempts are made to classify each lesion into defined subtypes, there can be overlap between the subtypes. The clinical , dermoscopic and histolopathologic features of a case of proliferative nodule arising within blue nevus is discussed. Running title: Blue nevi are an heterogeneous group of melanocytic lesions blue tinctorial properties. Proliferative nodules are rare benign lesions often present at birth as a component of a large congenital melanocytic nevi, congenital or acquired nevi. We first report a case of proliferative nodule arising within blue nevus.

[Use of ketogenic diet in children in France from 2001 to 2008]. / Evolution de la prescription du régime cétogène en France chez l'enfant entre 2001 et 2008.

INTRODUCTION: The ketogenic diet is an adequate treatment for drug-resistant epilepsy and certain inborn metabolic disorders. The efficacy of the ketogenic diet for the treatment of epilepsy is now well established. In France, and more widely in Europe, there is currently no consensus concerning appropriate initiation of the ketogenic diet and subsequent patient management. METHODS: Using the same questionnaire in 2005 and 2008, we retrospectively recorded the practices of child neurology departments of the French university hospitals during three study periods (2001-2002, 2002-2003 and 2005-2008). The aim was to evaluate the number of ketogenic diets started and how the ketogenic diet was initiated. RESULTS: The ketogenic diet was widely used by pediatric neurologists. The number of patients on a ketogenic diet increased over time. Diet initiation protocols also changed over time, being modified adequately with advances in knowledge of the ketogenic diet. CONCLUSION: The French pediatric neurologists appear to have a good understanding of the ketogenic diet.

PET-guided Switch from Immunotherapy to Targeted Therapy in a Metastatic Melanoma Patient: a personalized approach.

An early identification of non-responders in oncology is of crucial importance to rapidly switch treatment regimens. Here we report a positron emission tomography, (PET)-guided switch from immunotherapy to targeted therapy in a patient affected by metastatic melanoma. We describe the case of a 78-years-old male patient diagnosed with nodular melanoma, submitted to baseline PET/CT with 18fluorodeoxyglucose (18F-FDG) that showed cutaneous and skeletal metastases (stage IV). The patients started immunotherapy with pembrolizumab. A PET/CT performed 3 months after the start of immunotherapy demonstrated progressive metabolic disease both at skeletal and cutaneous level, confirmed also by the biopsy. As patients resulted positive for BRAF V600k mutation, treatment regimen was rapidly switched to combined anti-BRAF/MEK targeted therapy. The PET/CT performed 3 months later, showed almost complete metabolic response. Ten months after the beginning of targeted therapy, the patient continues to present a durable metabolic response. PET/CT with 18F-FDG may help in monitoring the response to treatment in metastatic melanoma thus defining personalized therapeutic pathways.

Is Cupressus sempervirens native in Italy? An answer from genetic and palaeobotanical data.

This study represents the first large-scale analysis using nuclear molecular markers to assess genetic diversity and structure of Cupressus sempervirens L.. Genetic and fossil data were combined to infer the possible role of human activity and evolutionary history in shaping the diversity of cypress populations. We analysed 30 populations with six polymorphic nuclear microsatellite markers. Dramatic reductions in heterozygosity and allelic richness were observed from east to west across the species range. Structure analysis assigned individuals to two main groups separating central Mediterranean and eastern populations. The two main groups could be further divided into five subgroups which showed the following geographical distributions: Turkey with the Greek islands Rhodes and Samos, Greece (Crete), Southern Italy, Northern Italy, Tunisia with Central Italy. This pattern of genetic structure is also supported by SAMOVA and Barrier analyses. Palaeobotanical data indicated that Cupressus was present in Italy in the Pliocene, Pleistocene and Holocene. Furthermore, our molecular survey showed that Italian cypress populations experienced bottlenecks that resulted in reduced genetic diversity and allelic richness and greater genetic differentiation. Recent colonization or introduction may also have influenced levels of diversity detected in the Italian populations, as most individuals found in this range today have multilocus genotypes that are also present in the eastern range of the species. The data reveal a new interpretation of the history of cypress distribution characterized by ancient eastern populations (Turkey and Greek islands) and a mosaic of recently introduced trees and remnants of ancient, depauperate populations in the central Mediterranean range.

[The ketogenic diet and its variants: state of the art]. / Le régime cétogène et ses variants : certitudes et doutes.

The ketogenic diet is a high-fat, low-protein, low-carbohydrate diet that has been employed as a nonpharmacologic therapy for intractable epilepsy. Several multicenter or randomized studies have demonstrated the anticonvulsive properties of the ketogenic diet. The reports on the clinical efficacy have described a greater than 50% reduction in seizure frequency for about 60% of patients on a ketogenic diet. Efficacy has been reported both for child-teenager and adult patients. Patients who were responders to the ketogenic diet exhibited a decrease in seizure frequency within two months of treatment onset. Underlying mechanisms remain unknown. The current hypotheses are: anticonvulsive properties of ketone bodies, variation in excitatory or inhibitory brain neurotransmissions, modulation of cell excitability or implication of polyunsaturated fatty acids. Ketogenic diet is a fastidious and restrictive therapy. Moreover, side effects have been reported. In order to facilitate patient tolerability and palatability, the diet protocols are gradually modified including changes in ratios of the fat versus non fat components, initiation of the diet with or without fasting, fatty acids composition. A modified Atkins diet seems to be a possible alternative diet with a comparable efficacy on intractable epilepsy. This diet induces ketosis without fluid, calorie or protein restriction, nor the requirement for fasting and food weighing. Furthermore, 10 to 20 grams carbohydrates are allowed per day to increase patient tolerability and palatability. New data suggest that ketogenic diet and its variants should not be considered like a "last chance" treatment.

Inter-center variation in death or tracheostomy placement in infants with severe bronchopulmonary dysplasia.

OBJECTIVE: To estimate the presence and sources of inter-center variation (ICV) in the risk of death or tracheostomy placement (D/T) among infants with severe bronchopulmonary dysplasia (sBPD)Study design:We analyzed the Children's Hospitals Neonatal Database between 2010 and 2013 to identify referred infants born <32 weeks' gestation with sBPD. The association between center and the primary outcome of D/T was analyzed by multivariable modeling. Hypothesized diagnoses/practices were included to determine if these explained any observed ICV in D/T. RESULTS: D/T occurred in 280 (20%) of 1383 eligible infants from 21 centers. ICV was significant for D/T (range 2-46% by center, P<0.001) and tracheostomy placement (n=187, range 2-37%, P<0.001), but not death (n=93, range 0-19%, P=0.08). This association persisted in multivariable analysis (adjusted center-specific odds ratios for D/T varied 5.5-fold, P=0.009). CONCLUSIONS: ICV in D/T is apparent among infants with sBPD. These results highlight that the indications for tracheostomy (and subsequent chronic ventilation) remain uncertain.

Predicting death or extended length of stay in infants with congenital diaphragmatic hernia.

OBJECTIVE: To predict mortality or length of stay (LOS) >109 days (90th percentile) among infants with congenital diaphragmatic hernia (CDH). STUDY DESIGN: We conducted a retrospective analysis using the Children's Hospital Neonatal Database during 2010 to 2014. Infants born >34 weeks gestation with CDH admitted at 22 participating regional neonatal intensive care units were included; patients who were repaired or were at home before admission were excluded. The primary outcome was death before discharge or LOS >109 days. Factors associated with this outcome were used to develop a multivariable equation using 80% of the cohort. Validation was performed in the remaining 20% of infants. RESULTS: The median gestation and age at referral in this cohort (n=677) were 38 weeks and 6 h, respectively. The primary outcome occurred in 242 (35.7%) infants, and was distributed between mortality (n=180, 27%) and LOS >109 days (n=66, 10%). Regression analyses showed that small for gestational age (odds ratio (OR) 2.5, P=0.008), presence of major birth anomalies (OR 5.9, P<0.0001), 5- min Apgar score ⩽3 (OR 7.0, P=0.0002), gradient of acidosis at the time of referral (P<0.001), the receipt of extracorporeal support (OR 8.4, P<0.0001) and bloodstream infections (OR 2.2, P=0.004) were independently associated with death or LOS >109 days. This model performed well in the validation cohort (area under curve (AUC)=0.856, goodness-of-fit (GF) χ(2), P=0.16) and acted similarly even after omitting extracorporeal support (AUC=0.82, GF χ(2), P=0.05). CONCLUSIONS: Six variables predicted death or LOS ⩾109 days in this large, contemporary cohort with CDH. These results can assist in risk adjustment for comparative benchmarking and for counseling affected families.

Reference values for respiratory rate in the first 3 years of life.

BACKGROUND: Raised respiratory rate is a useful sign to diagnose lower respiratory infections in childhood. However, the normal range for respiratory rate has not been defined in a proper, large sample. OBJECTIVE: To assess the respiratory rate in a large number of infants and young children in order to construct percentile curves by age; to determine the repeatability to the assessment using a stethoscope and compare it with observation. METHODS: Respiratory rate was recorded for 1 minute with a stethoscope in 618 infants and children, aged 15 days to 3 years old, without respiratory infections or any other severe disease when awake and calm and when asleep. In 50 subjects we compared respiratory rate taken 30 to 60 minutes apart to assess repeatability, and in 50 others we compared simultaneous counts obtained by stethoscope versus observation. RESULTS: Repeatability was good as the standard deviation of differences was 2.5 breaths/minute in awake and 1.7 breaths/minute in asleep children. Respiratory rate obtained with a stethoscope was systematically higher than that obtained by observation (mean difference 2.6 breaths/minute in awake and 1.8 breaths/minute in asleep children; P = .015 and P < .001, respectively). A decrease in respiratory rate with age was seen for both states, and it was faster in the first few months of life when also a greater dispersion of values was observed. A second degree polynomial curve accurately fitted the data. Reference percentile values were developed from these data. CONCLUSIONS: The repeatability of respiratory rate measured with a stethoscope was good. Percentile curves would be particularly helpful in the first months of life when the decline in respiratory rate is very rapid and prevents to use cut off values for defining "normality."