Efficacy and activity of PD-1 blockade in patients with advanced esophageal squamous cell carcinoma: a systematic review and meta-analysis with focus on the value of PD-L1 combined positive score.

BACKGROUND: Recently, several randomized controlled trials (RCTs) investigated immunotherapy-based regimens versus chemotherapy alone in patients with advanced esophageal squamous cell carcinoma (ESCC). Here we conducted a systematic review and meta-analysis on the efficacy and activity of programmed cell death protein 1 blockade in these patients, with focus on the value of programmed death-ligand 1 combined positive score (CPS) for selecting patients who may benefit the most. METHODS: RCTs investigating treatment with or without immune checkpoint inhibitors for advanced ESCC were selected. The hazard ratio (HR) and the odds ratio were used to compare the treatment effect on survival outcomes and tumor response, respectively, for immunotherapy-based regimens compared with standard chemotherapy, overall and according to geographic region or treatment line. We carried out a subgroup analysis comparing patients with CPS ≥10 or <10 and the evidence for treatment effect was evaluated by interaction test. RESULTS: A total of 5257 patients and 10 RCTs were included. Overall, the HR for overall survival benefit with immunotherapy-based regimens was 0.71 [95% confidence interval (CI) 0.66-0.76] compared with chemotherapy alone; such effect was independent from geographical region (Asia versus rest of the world) and treatment line (upfront versus second/further lines). The HR for progression-free survival benefit and the odds ratio for overall response rate increase were 0.78 (95% CI 0.66-0.93) and 1.50 (95% CI 1.22-1.83), respectively. The HR for overall survival benefit with immunotherapy-based treatment was 0.60 (95% CI 0.51-0.70) for CPS ≥10 subgroup versus 0.83 (95% CI 0.69-1.00) for CPS <10 (P for interaction 0.009). CONCLUSIONS: Immune checkpoint inhibitors have a consistent benefit in reducing the risk of death for ESCC patients which is dependent on programmed death-ligand 1 CPS status. Further investigations of biomarkers for immunotherapy in the subgroup of patients with CPS <10 are needed.

Endoscopic management of frontal sinus diseases after frontal craniotomy: a case series and review of the literature.

PURPOSE: To evaluate frontal sinus complications developed after previous external craniotomies requiring frontal sinus reconstruction and their treatment with an endoscopic approach. METHODS: We retrospectively evaluated 22 patients who referred to Sant'Orsola-Malpighi University Hospital and Bellaria Hospital (Bologna, Italy) between 2005 and 2017. All patients presented with frontal sinus disease after frontal craniotomy with sinus reconstruction performed to treat various pathological conditions. We reported our experience in the endoscopic management of such complications and we reviewed the current literature concerning the endoscopic treatment of these conditions. RESULTS: In total, 14 frontal mucoceles, 4 cases of chronic frontal sinusitis, 2 mucopyoceles and 2 fungus ball of the frontal sinus were identified. Endoscopic surgical treatment included 7 DRAF IIa, 1 DRAF IIb, 11 DRAF III and 3 DRAF IIc (modified DRAF III) approaches. The success rate of the surgical procedure was 86% (19/22 patients). Recurrence of the initial pathology occurred in three patients (14%) requiring a conversion of previous frontal sinusotomy into a DRAF III sinusotomy. CONCLUSION: Frontal sinusopathy can be a long-term complication following craniotomies and may lead to potentially severe pathological conditions, such as mucoceles and frontal sinus inflammation. Its management is still debated and requires recovery of the patency of nasal-frontal route. Our study confirms that the endoscopic endonasal approach may offer a valid solution with low morbidity avoiding re-opening of the craniotomic access. For selected cases, endoscopic approach could also be performed simultaneously to craniotomy as a combined surgery to reduce the risk of short- and long-term complications. Long-term follow-up is mandatory in patients with a history of opened and reconstructed frontal sinus and should include imaging and endoscopic outpatient evaluation.

Sentinel node biopsy versus elective neck dissection in early-stage oral cancer: a systematic review.

PURPOSE: To provide a summary of the evidence on the comparative effectiveness of two surgical treatment strategies, sentinel node biopsy (SNB) and elective neck dissection (END), in patients with T1-T2 oral cancer and clinically negative (cN0) neck, in terms of overall survival (OS), disease-free survival (DFS) and neck recurrence rates (NRRs). METHODS: A systematic review was performed by including studies published up to April 2019. Meta-analysis was performed to compare NRRs between SNB and END. A narrative summary of the results was generated for OS, DFS and morbidity outcomes. The certainty of evidence was assessed according to the GRADE methodology. RESULTS: No randomized studies were retrieved. Five observational studies were included in the comparative effectiveness analysis and four observational studies were included in the comparative morbidity analysis. The pooled risk ratio showed no differences in NRRs between SNB and END (10.5% vs 11.6%; pooled RR 1.09; 95% CI 0.67-1.76). No differences in OS or DFS between the two treatments were found. SNB appears to be associated with a lower rate of postoperative complications and lower shoulder dysfunction than END. Conversely, the results of the quality of life (QoL) questionnaires are not sufficient to advocate a particular strategy. CONCLUSION: Our review highlights the lack of well conducted and randomized studies comparing SNB to END, leading to poor clinical evidence. Although our findings suggest no significant differences in OS, DFS and NRR between the two strategies, the certainty of our evidence is too low to make it useful for clinical decision making.

Influence of conjugation and other structural changes on the activity of Cu²âº based PNAzymes.

We have previously shown that PNA-neocuproine conjugates can act as artificial RNA restriction enzymes. In the present study we have additionally conjugated the PNA with different entities, such as oligoethers, peptides etc. and also constructed systems where the PNA is designed to clamp the target RNA forming a triplex. Some conjugations are detrimental for the activity while most are silent which means that conjugation can be done to alter physical properties without losing activity. Conjugation with a single oligoether close to the neocuproine does enhance the rate almost twofold compared to the system without the oligoether. The systems designed to clamp the RNA target by forming a triplex retain the activity if the added oligoT sequence is 5 PNA units or shorter and extends the arsenal of artificial RNA restriction enzymes. Changing the direction of a closing base pair, where the target RNA forms a bulge, from a GC to a CG pair enhances the rate of cleavage somewhat without compromising the selectivity, leading to the so far most efficient artificial nuclease reported.

Aesthetic comparison between synthetic glue and subcuticular sutures in thyroid and parathyroid surgery: a single-blinded randomised clinical trial.

The aim of our study was to compare, in terms of aesthetic results, the use of synthetic glue to intradermal absorbable sutures in postthyroidectomy and parathyroidectomy wound closure in a single blinded, randomised, per protocol equivalence study. From September 2008 to May 2010, patients undergoing thyroid or parathyroid surgery (with an external approach) at the Otolaryngology Department of the University Hospital of Modena were assessed for eligibility. In total, 42 patients who had had synthetic glue application on surgical incisions (A) and 47 patients who had subcuticular sutures on their surgical incisions (B) were enrolled. The mean of the endpoint (based on the Wound Registry Scale) of group A at 10 days was 1.4, while that in group B (based on the Stony Brook Scar Evaluation Scale) was 2.9. Statistically significant (p = 0.002) and clinically significant (difference of the means = 1.5) differences in the aesthetic results were found between groups A and B at 10 days, with better results in group B. On the other hand, at 3 months, the mean of the endpoint in group A was 3.1 while that in group B was 2.8; no statistically significant (p = 0.62) or clinically significant (difference in means = 0.3) differences were found between groups A and B. In conclusion, synthetic glue differs from subcuticular suture in post-thyroidectomy or post-parathyroidectomy incision for early aesthetic results, with better outcomes for subcuticular sutures. At 3 months, there were no differences in aesthetic outcomes between groups. Moreover, sex, incision length, age, cold/hot blade and correspondence of the incision with a wrinkle in the skin did not seem to influence aesthetic outcomes with this type of incision.

Does increasing body mass index affect cerclage efficacy?

OBJECTIVE: To study the relationship between body mass index (BMI) and gestational age (GA) at delivery in patients with cervical insufficiency (CI) undergoing cerclage. STUDY DESIGN: We accessed a database of patients with singleton gestations undergoing cerclage (N=168) for a well-characterized history of CI, shortened cervix <2.5 cm with a history of prior preterm delivery or prolapse of membranes through the external os. Univariate and multivariate logistic regression analysis were performed to compare obstetrical outcomes between obese and normal-weight patients. RESULT: Prior preterm delivery <35 weeks in obese vs normal-weight patients was significantly higher (44% vs 9%), odds ratio=6.9 (95% CI: 2.5, 18.5), with lower mean GA at delivery (32.6±7.0 vs 37.2±3.4 weeks, P<0.001). After controlling for confounders, BMI remained significantly predictive of prematurity (coefficient: -0.12, adjusted R (2)=0.24), such that every additional 1 unit of BMI was associated with a 1-day reduction in GA at delivery (P=0.03). CONCLUSION: An inverse correlation exists between BMI and GA at delivery in patients with CI receiving cerclage. The findings are unexpected given the protective effect of obesity on spontaneous preterm delivery.

Can adverse neonatal outcome be predicted in late preterm or term fetal growth restriction?

OBJECTIVE: To identify independent predictors of adverse neonatal outcome in cases of fetal growth restriction (FGR) at > or = 34 weeks. METHODS: From a cohort of 481 FGR cases delivered at > or = 34 weeks, demographic and obstetric variables, fetal biometry and Doppler indices of the uterine, umbilical and fetal middle cerebral arteries available within 2 weeks of delivery, were related to adverse neonatal outcome, defined as admission to the neonatal intensive care unit for indications other than low birth weight alone. RESULTS: Logistic regression analysis showed that gestational age (GA) at delivery (odds ratio (OR) = 0.59; 95% CI, 0.50-0.70), abdominal circumference (AC) centile (OR = 0.69; 95% CI, 0.59-0.81) and umbilical artery (UA) pulsatility index (PI) centile (OR = 1.02; 95% CI, 1.01-1.04) significantly correlated with adverse neonatal outcome. From this model we calculated a score of adverse neonatal outcome expressed by the formula: (UA-PI centile/3) - (10 x AC centile) + (10 x (40 - GA at delivery in weeks)). Receiver-operating characteristics curve analysis demonstrated that a score of > or = 25 optimally predicted adverse neonatal outcome (sensitivity of 75%, false-positive rate of 18%). Beyond 37.5 weeks, gestational age no longer had an independent impact on outcome. CONCLUSIONS: In late preterm or term FGR, GA at delivery is the most important predictor of adverse neonatal outcome. At > 37.5 weeks, delivery may be the best option to minimize adverse outcome in all FGR cases. At 34-37 weeks, a score based on GA at delivery, UA-PI centile and AC centile optimally predicts adverse neonatal outcome.

Are ultrasonographic myoma characteristics associated with blood loss at delivery?

OBJECTIVES: The presence of myomas in pregnancy is associated with greater blood loss at delivery. The aim of this study was to evaluate whether the sonographic characteristics of myomas can predict blood loss at delivery in women with large myomas. METHODS: Among women who underwent second-trimester ultrasound screening at our department between January 1996 and December 2004, 251 had at least one myoma with a mean diameter > or = 5 cm. Number of myomas (single vs. multiple), maximum diameter of the largest myoma, sum of the maximum diameter of each myoma, change in size of myomas between first and last scan, and location in relation to the placenta and to the presenting part of the fetus (above or below) were analyzed in relation to blood loss at delivery and severe postpartum hemorrhage (> or = 1000 mL). RESULTS: Multivariate analysis showed that the presence of multiple myomas was the only parameter independently associated with amount of blood loss at delivery (P = 0.003). The association between the presence of multiple myomas and severe postpartum hemorrhage was of borderline significance for the statistical power of this study (P = 0.08). CONCLUSIONS: In women with large myomas, the presence of multiple tumors is independently associated with heavier blood loss at delivery but not with postpartum hemorrhage of > or = 1000 mL.

Prenatal sonographic evaluation of male genitalia development.

AIM: The aim of this study was to evaluate the sonographic development of normal fetal male genitalia. METHODS: A longitudinal study was performed on 60 male fetuses. The development of penis, prepuce and presence of testes in scrotum were observed with a high resolution transabdominal ultrasonography between weeks 11 and 40. RESULTS: The overall success of identifying correctly the fetal male gender increased with gestational age from 46% to 80%, and 96% at 12, 13 and 14 week, respectively. The number of the scans performed in relation to the gestational age from week 11 to week 14 improves the ability to assign the male gender and to report the penile length (P<0.05); the earliest observations of descend testis were at 24 weeks. The bilateral observation of testicular descend was at 31 weeks in 98% of fetuses. CONCLUSION: Development of male genitalia is easy evaluated through the pregnancy. This could be useful to early identify male genitalia abnormalities.

Amnioinfusion in preterm PROM: effects on amnion and cord histology.

OBJECTIVE: To investigate the effects of transabdominal amnioinfusion (TA) on the histology of amnion (A) and umbilical cord (UC). STUDY DESIGN: From a cohort of 56 singleton pregnancies with premature rupture of membranes (PROM) at

Prenatal diagnosis of supernumerary ring chromosome 1: case report and review of the literature.

A supernumerary ring chromosome was found on amniocentesis performed for advanced maternal age. A review of the literature found 34 reports of supernumerary ring chromosome I which are compared to our case.

Pentraxin 3 in plasma and vaginal fluid in women with preterm delivery.

OBJECTIVE To investigate the role of pentraxin 3 (PTX3), an acute-phase protein produced by cells of innate immunity in response to inflammatory signals, in spontaneous preterm delivery (PTD). DESIGN Cohort study. SETTING Department of Obstetrics and Gynecology of the University of Milano-Bicocca. POPULATION Forty-six pregnant women with preterm rupture of membranes (n=33) or preterm labour with intact membranes (n=13) delivering at <34 weeks of gestation and 34 women with uncomplicated pregnancies (control group). METHODS We compared plasma and vaginal PTX3 levels between study group and controls, and in women with versus women without clinical or histologic evidence of intrauterine infection using statistical analysis. MAIN OUTCOME MEASURES Peak PTX3 concentration. RESULTS Peak PTX3 concentration in plasma samples of study group was significantly higher than that in controls (1175, 0-9630 versus 650, 0-1450 pg/ml; P=0.0003) but not in vaginal swabs (1660, 0-6604 versus 457, 0-4649 pg/ml; P=0.386). PTX3 levels in plasma were significantly higher in women with placenta vasculopathy compared with that in women with no placental lesions (2910, 0-9630 versus 636, 0-5692 pg/ml; P=0.04). Peak plasma and vaginal PTX3 concentrations were not significantly different in women with versus women without intrauterine infection (1168, 0-7110 versus 845, 0-9630 pg/ml, P=0.34 and 1975, 471-6604 versus 1919, 0-4150 pg/ml, P=0.38, respectively). CONCLUSIONS Spontaneous PTD is associated with a significant increase of maternal plasma concentrations of PTX3. PTX3 seems to be a marker of placenta vasculopathy rather than intrauterine infection.

Endoscopic removal of ethmoido-sphenoidal foreign body with intracranial extension.

We describe the case of a foreign body lodged into ethmoidal labyrinth and sphenoidal sinus with fracture of the clivus and consequent rhinoliquorrhea removed by an endoscopic technique. We performed a skull base plasty to close the rhino-liquoral fistula with resolution of the rhinoliquorrhea. There were no postoperative complications and there was a good therapeutic result at long-term follow-up.

Gender differences in amniotic fluid cytokine levels.

OBJECTIVE: Placental trophoblast invasion and amniotic fluid cytokine receptor levels have been reported to vary with fetal gender. We investigated whether fetal gender affects amniotic fluid levels of the inflammatory cytokines interleukin (IL)-6 and IL-10 and the pro-angiogenesis cytokine angiogenin. METHODS: Specimens from singleton gestations undergoing mid-trimester amniocentesis for genetic indications were used. Inclusion criteria were (1) outcome information available, (2) no structural or chromosomal anomaly and (3) no conditions associated with preterm delivery. Amniotic fluid IL-6, IL-10 and angiogenin levels were measured by immunoassay. Statistical analysis included the Mann-Whitney U test and Fisher's exact test with p < 0.05 indicating significance. RESULTS: A total of 74 samples were analyzed. Angiogenin levels were significantly lower in amniotic fluid samples from pregnancies with a male than with a female fetus (median (range): 22.2 (5.9-66.4) vs. 32.0 (11.4-159.2) ng/ml, p=0.007), in contrast to no differences in amniotic fluid IL-6 and IL-10 levels (p=0.4 and p=0.1, respectively). In pregnancies with male fetuses delivering preterm (< 37 weeks), angiogenin was also detected at lower levels (p=0.02). There were no gender differences with respect to race, nulliparity or maternal age. CONCLUSION: Angiogenin levels, but not IL-6 or IL-10 levels, are significantly lower in second-trimester amniotic fluid of women with male compared with female fetuses, including those women delivering preterm.

Serial assessment of amniotic fluid index in uncomplicated term pregnancies: prognostic value of amniotic fluid reduction.

OBJECTIVE: Assessment of amniotic fluid volume in association with a non-stress test is a commonly used method to monitor fetal well-being in high-risk pregnancies. The aims of our study were to determine whether oligohydramnios and the trend in amniotic fluid volume have prognostic significance in low-risk pregnancies between 40.0 and 41.6 weeks' gestation. METHODS: Between January 1997 and December 2000, all uncomplicated gestations with a singleton non-anomalous fetus reaching 40.0 weeks' gestation underwent semi-weekly monitoring of amniotic fluid index (AFI) until delivery. Oligohydramnios was defined as an AFI of < or = 5 cm. Changes in AFI were expressed as centimeters per day, and were calculated as: [(last AFI before delivery minus first AFI at 40.0 weeks) / interval in days between the two scans]. Adverse outcome was considered the occurrence of 5-min Apgar score < 7; umbilical artery pH < 7.0; Cesarean section for fetal distress; or fetal death. Comparisons between the groups with favorable and adverse outcomes was performed with chi(2) or Fisher's exact test for categorical variables, and Student's t test for continuous variables. A two-tailed p value < 0.05 was considered significant. RESULTS: A total of 3050 women met the study criteria, and underwent a median number of two (range 1-7) sonographic assessments of AFI after 40.0 weeks, with oligohydramnios detected in 341 women. In 1466 women at least two serial AFI determinations were obtained, allowing computation of an AFI trend. Gestations resulting in adverse perinatal outcome (n = 167, 5.5%) had a significantly higher rate of oligohydramnios (33/167, 19.8% vs. 308/2883, 10.7%, p = 0.001), but a similar rate of reduction in AFI ( -0.65 +/- 0.64 vs. - 0.66 +/- 0.66 cm/day; p = 0.85) than those with favorable outcome. The difference in rate of reduction of AFI between the two groups was not significant, even in the subset of gestations that developed oligohydramnios ( -1.08 +/- 0.87 vs. -1.26 +/- 0.89 cm/day; p = 0.27). CONCLUSION: A sonographic diagnosis of oligohydramnios carries an increased risk of adverse perinatal outcome, even in low-risk pregnancies after 40 weeks. The trend in amniotic fluid volume reduction does not seem to have prognostic significance.