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.

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.

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.

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.

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.

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.

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.

Lactobezoar formation in two premature infants receiving medium-chain triglyceride formula.

We describe two cases of premature infants who developed clinical and radiologic evidence of gastric lactobezoars within the same month in our neonatal intensive care unit while both were receiving medium-chain triglyceride-rich formula as part of the management of chylothoraces.

Placental pathologic changes of maternal vascular underperfusion in bronchopulmonary dysplasia and pulmonary hypertension.

INTRODUCTION: Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease of infancy, and BPD-associated pulmonary hypertension (PH) is a serious complication that can negatively impact later childhood health. There is growing evidence that lung injury leading to BPD and PH is due to chronic fetal hypoxia-ischemia. The purpose of this study was to investigate whether placental pathologic changes of maternal vascular underperfusion (MVU) are associated with BPD, and further increased with PH. METHODS: We conducted a 5-year retrospective cohort study of premature infants born ≤28 weeks. BPD was defined as persistent oxygen requirement at 36 weeks corrected gestational age. PH was identified using a standardized algorithm of echocardiogram review. Archived placental slides underwent standardized masked histopathologic review. Logistic regression modeling was performed, taking into account important maternal and infant covariates. RESULTS: Among 283 births, 121 had MVU, of which 67 (55%) developed BPD, and 24 (20%) had PH. Among the common neonatal complications of extreme prematurity, BPD was the only outcome that was increased with MVU (P < 0.001). After adjustment for birth weight, fetal growth restriction, preeclampsia and other factors, infants with MVU were more likely to develop BPD (adjusted odds ratio = 2.6; 95% confidence interval = 1.4, 4.8). Certain MVU sublesions (fibrinoid necrosis/acute atherosis and distal villous hypoplasia/small terminal villi) were increased with PH (P < 0.001). DISCUSSION: Placental MVU may identify BPD infants who were exposed to intrauterine hypoxia-ischemia, which increases their risk for development of PH disease. CONCLUSIONS: Our findings have important implications for providing earlier and more effective therapies for BPD.

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.

Fetal growth restriction and pulmonary hypertension in premature infants with bronchopulmonary dysplasia.

OBJECTIVE: To identify the association between birth weight (BW)-for-gestational age (GA) and pulmonary hypertension (PHTN) at 36 weeks in infants with moderate-severe bronchopulmonary dysplasia (BPD). STUDY DESIGN: In this retrospective cohort study, we followed 138 premature infants (≤ 28 weeks) with moderate and severe BPD (National Institutes of Health consensus definition) born at Prentice Women's Hospital between 2005 and 2009. BW percentiles were calculated using the Fenton growth curve for premature infants. PHTN was determined using a standardized algorithm of echocardiogram review at 36 weeks. Logistic regression was used to evaluate the associations between BW percentile subgroups and PHTN, taking into account antenatal and neonatal factors that were related to PHTN. RESULT: PHTN was associated with small BW-for-GA, ranging from thresholds of <10th to <25th percentile (P<0.001). These associations remained significant when comparing BW <25th percentile to the reference group (50 to 89 th percentile); after adjustment for GA, gender, multiple gestation, race/ethnicity (odds ratio (OR)=4.2; 95% confidence interval (CI)=1.5, 12.1); and after further adjustment for maternal vascular disease, intrauterine infection, oligohydramnios and relevant postnatal factors (OR=5.7; 95% CI=1.5, 21.2). Longitudinal follow-up of this cohort showed a trend toward higher morbidity and death among PHTN infants with BW <25th percentile. CONCLUSION: BW-for-GA is an important predictor of PHTN in premature infants with moderate-severe BPD. Our findings contribute to the growing evidence supporting fetal mechanisms of later onset pulmonary vascular disease.

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.

[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.

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.

Cord blood immune biomarkers in small for gestational age births.

Fetal growth restriction is a risk factor for development of adulthood diseases, but the biological mechanism of this association remains unknown. Limited biomarkers have been studied in settings of preterm birth and maternal inflammation, but the relationship between a wide range of immune biomarkers and fetal growth has not been studied. The hypothesis of this study was that fetal growth restriction is associated with altered immune biomarker levels. We examined the relationship between small for gestational age (SGA) status and 27 umbilical cord blood immune biomarkers. This study was part of a large-scale cohort study of preterm birth and low birth weight conducted at Boston Medical Center, an inner city, predominantly minority patient population. Growth status was determined based on birth weight standardized to an internal reference. There were 74 SGA births and 319 appropriate for age (AGA) births with complete clinical and biomarker data. Adjusting for covariates and using AGA as reference, SGA births had lower levels of log IL-1ß (ng/l; ß -0.38, 95% CI -0.57, -0.19, P < 0.01), log BDNF (ß -0.29, 95% CI -0.55, -0.03, P < 0.05) and log NT-3 (ß -0.46, 95% CI -0.77, -0.15, P < 0.01). No associations were found between other biomarkers and SGA. In conclusion, three biomarkers were selectively associated with SGA status. Our results provide information that could be used to guide additional studied aimed at determining mechanisms that contribute to fetal growth.