Objective The objective of the study was to investigate the efficacy and safety of hexaminolevulinate (HAL) photodynamic therapy (PDT), a novel therapy for women with cervical intraepithelial ...neoplasia (CIN)1/2, to define the appropriate population and endpoints for a phase 3 program. Study Design This was a double-blind, randomized, placebo-controlled, dose-finding study that included a total of 262 women with biopsy-confirmed CIN 1/2 based on local pathology. Patients received 1 or 2 topical treatments of HAL hydrochloride 0.2%, 1%, 5%, and placebo ointment and were evaluated for response after 3-6 months based on biopsy, Papanicolaou test, and oncogenic human papillomavirus (HPV) test. All efficacy analyses were performed on blinded central histology review to avoid interreader variability. Adverse events, blood biochemistry, and vital signs were assessed after 3 months. Results There were no statistically significant differences between placebo and either the CIN 1 or combined CIN 1/2 populations. A clear dose effect with a statistically significant response in the HAL 5% group of 95% (18/19 patients) compared to 57% (12/21 patients) in the placebo group ( P < .001) was observed at 3 months in women with CIN 2, including an encouraging 83% (5/6 patients) clearance of HPV 16/18 compared to 33% (2/6 patients) in the placebo group at 6 months. The treatment was easy to use and well accepted by patients and gynecologists. Only local self-limiting adverse reactions including discharge, discomfort, and spotting were reported. Conclusion HAL PDT is a novel therapy that shows promise in the treatment of CIN 2 including clearance of oncogenic HPV, but not of CIN 1. The positive risk/benefit balance makes HAL PDT a tissue-preserving alternative in women of childbearing age who wish to preserve the cervix. Confirmatory studies are planned.
IntroductionHigh-risk human papilloma virus (HPV)-associated cervical cancer is the fourth most common cancer in women worldwide. Current treatments of high-grade squamous intraepithelial lesion ...(HSIL) of the cervix are based on invasive surgical interventions, compromising cervical competence and functionality. APRICITY is a multicentre, prospective, double-blind, randomised controlled phase 3 study further evaluating the efficacy and safety of Cevira, an integrated drug-delivery and light-delivery device for hexaminolevulinate photodynamic therapy, which shows promise as a novel, non-invasive outpatient therapy for women with HSIL.Methods and analysisPatients with biopsy-confirmed HSIL histology are invited to participate in the study planned to be conducted at 47 sites in China and 25 sites in Ukraine, Russia and the European Union. The aim is to include at least 384 patients, which will be randomised to either Cevira or placebo group (2:1). All patients will be assessed 3 months after first treatment and a second treatment will be administered in patients who are HPV positive or have at least low-grade squamous intraepithelial lesion. Primary endpoint is the proportion of the responders 6 months after first treatment. Secondary efficacy and safety endpoints will be assessed at 6 months, and data for secondary performance endpoints of the Cevira device will be collected at 3 months and 6 months, in case second treatment was administered. All patients in the Cevira group will be enrolled in an open, long-term extension study for 6 months to collect additional efficacy and safety data (study extension endpoints).Ethics and disseminationThe study was approved by the ethics committee of the Peking Union Medical College Hospital and Hannover Medical University, Germany. Findings will be disseminated through peer review publications and conference presentations.Trial registration numberNCT04484415; clinicaltrials.gov.
Objectives
Triple‐negative breast cancer (TNBC) is known to have unique molecular, clinical, and pathologic characteristics. The growth pattern of this cancer may also affect its appearance on ...sonography. Our study evaluated the sonographic features of TNBC according to the American College of Radiology Breast Imaging Reporting and Data System sonographic classification system and compared these features with those of non‐TNBC.
Methods
Data from 315 consecutive breast cancer cases were collected. The images were reevaluated by an examiner blinded to the patients' characteristics and histologic results according to the Breast Imaging Reporting and Data System. The sonographic features of TNBC (n = 33) and non‐TNBC (n = 282) were compared.
Results
Triple‐negative breast cancer was significantly correlated with a younger patient age (P = .002) and was associated with higher tumor grades (P < .001), more lymph node involvement (P = .014), and a trend toward a larger tumor size. With regard to sonographic features, the margin of TNBC was more frequently described as lobulated or microlobulated (75.8% versus 49.5% in non‐TNBC; P = .005). The echoic halo was observed significantly less often in TNBC than in non‐TNBC(39.4% versus 62.8%; P = .014). Cooper ligaments were displaced rather than disrupted in TNBC compared to non‐TNBC (P = .003). Regarding the posterior acoustic features, enhancement was observed significantly more often in TNBC (36.4% versus 13.0% in non‐TNBC; P = .031).
Conclusions
Triple‐negative breast cancer and non‐TNBC have different sonographic features. This finding can be explained by the pathologic profile of this breast cancer subtype. Some of the distinct sonographic criteria for TNBC are more likely to be associated with benign masses. Knowledge of the distinct sonographic features of TNBC would help the examiner avoid false‐negative classification of this tumor type.
Triple-negative breast cancer (TNBC) is an aggressive form of breast carcinoma with a poor prognosis. Recent evidence suggests that some patients with TNBC harbour germ-line mutations in DNA repair ...genes which may render their tumours susceptible to novel therapies such as treatment with PARP inhibitors. In the present study, we have investigated a hospital-based series of 40 German patients with TNBC for the presence of germ-line mutations in BRCA1, BRCA2, PALB2, and BRD7 genes. Microfluidic array PCR and next-generation sequencing was used for BRCA1 and BRCA2 analysis while conventional high-resolution melting and Sanger sequencing was applied to study the coding regions of PALB2 and BRD7, respectively. Truncating mutations in BRCA1 were found in six patients, and truncating mutations in BRCA2 and PALB2 were detected in one patient each, whereas no truncating mutation was identified in BRD7. One patient was a double heterozygote for the PALB2 mutation, c.758insT, and a BRCA1 mutation, c.927delA. Our results confirm in a hospital-based setting that a substantial proportion of German TNBC patients (17.5%) harbour germ-line mutations in genes involved in homology-directed DNA repair, with a preponderance of BRCA1 mutations. Triple-negative breast cancer should be considered as an additional criterion for future genetic counselling and diagnostic sequencing.
To determine the general appearance of normal axillary lymph nodes (LNs) in real-time tissue sonoelastography and to explore the method's potential value in the prediction of LN metastases.
Axillary ...LNs in healthy probands (n=165) and metastatic LNs in breast cancer patients (n=15) were examined with palpation, B-mode ultrasound, Doppler and sonoelastography (assessment of the elasticity of the cortex and the medulla). The elasticity distributions were compared and sensitivity (SE) and specificity (SP) were calculated. In an exploratory analysis, positive and negative predictive values (PPV, NPV) were calculated based upon the estimated prevalence of LN metastases in different risk groups.
In the elastogram, the LN cortex was significantly harder than the medulla in both healthy (p=0.004) and metastatic LNs (p=0.005). Comparing healthy and metastatic LNs, there was no difference in the elasticity distribution of the medulla (p=0.281), but we found a significantly harder cortex in metastatic LNs (p=0.006). The SE of clinical examination, B-mode ultrasound, Doppler ultrasound and sonoelastography was revealed to be 13.3%, 40.0%, 14.3% and 60.0%, respectively, and SP was 88.4%, 96.8%, 95.6% and 79.6%, respectively. The highest SE was achieved by the disjunctive combination of B-mode and elastographic features (cortex >3mm in B-mode or blue cortex in the elastogram, SE=73.3%). The highest SP was achieved by the conjunctive combination of B-mode ultrasound and elastography (cortex >3mm in B-mode and blue cortex in the elastogram, SP=99.3%).
Sonoelastography is a feasible method to visualize the elasticity distribution of LNs. Moreover, sonoelastography is capable of detecting elasticity differences between the cortex and medulla, and between metastatic and healthy LNs. Therefore, sonoelastography yields additional information about axillary LN status and can improve the PPV, although this method is still experimental.
Ovarian cancer is the most common cause of gynecological cancer-related death in the developed world. Disease recurrence and chemoresistance are major causes of poor survival rates in ovarian cancer ...patients. Ovarian cancer stem cells (CSCs) were shown to represent a source of tumor recurrence owing to the high resistance to chemotherapy and enhanced tumorigenicity. Chimeric antigen receptor (CAR)-based adoptive immunotherapy represents a promising strategy to reduce the risk for recurrent disease. In this study, we developed a codon-optimized third-generation CAR to specifically target CD44, a marker widely expressed on ovarian cancer cells and associated with CSC-like properties and intraperitoneal tumor spread. We equipped NK-92 cells with the anti-CD44 CAR (CD44NK) and an anti-CD19 control CAR (CD19NK) using lentiviral SIN vectors. Compared to CD19NK and untransduced NK-92 cells, CD44NK showed potent and specific cytotoxic activity against CD44-positive ovarian cancer cell lines (SKOV3 and OVCAR3) and primary ovarian cancer cells harvested from ascites. In contrast, CD44NK had less cytotoxic activity against CD44-negative A2780 cells. Specific activation of engineered NK cells was also demonstrated by interferon-γ (IFNγ) secretion assays. Furthermore, CD44NK cells still demonstrated cytotoxic activity under cisplatin treatment. Most importantly, the simultaneous treatment with CD44NK and cisplatin showed higher anti-tumor activity than sequential treatment.
Abstract
Background
Endometriosis can be associated with considerable pain and sterility. After surgical excision of moderate or severe endometriosis lesions, the rate of recurrence reaches up to ...67%. The objective of this retrospective study was to establish the recurrence and pregnancy rates following surgical resection of stage III/IV endometriosis lesions. Indications for operation were endometriosis symptoms, sonographic findings and/or infertility.
Methods
A total of 456 patients who underwent stage III/IV endometriosis surgery between 2004 and 2014 were sent a questionnaire relating to their postoperative medical treatment, pregnancies, relief of symptoms and recurrence. Responses of 206 patients (45.2%) and their clinical data were analysed for this study.
Results
A total of 66.5% (
N
= 137) of patients had stage III disease, and 33.5% (
N
= 69) had stage IV disease. The average age was 37 years (17–59). A total of 63.1% (
N
= 130) of surgeries were performed by laparoscopy, 21.8% (
N
= 45) were performed by laparotomy and 15% (
N
= 31) were performed by conversion. Complete resection of endometriosis lesions was achieved in 90.8% of patients (
N
= 187). After surgery, 48.5% (
N
= 100) of the women did not receive hormonal treatment; the main reason was the desire for children in 53%.
Complete or partial relief in complaints was achieved in 93.2% (
N
= 192). The rate of recurrence was 21.8% (
N
= 45). The statistically significant factors that was associated with a higher risk to develop recurrence was an age < 35 (
p
< 0.005).
After surgery, 65.8% (79/120) of patients who wished to have children became pregnant. There was a statistically significant association among a higher postoperative pregnancy rate and age < 35 (
p
< 0.003) in multivariate logistic regression analysis and laparoscopic surgical access in univariate logistic regression analysis (
p
< 0.01).
Conclusion
We assessed the high percentage of complete or partial relief of symptoms of 93.2%, the high postoperative pregnancy rate of 65.8% and the low rate of recurrence of 21.8% compared to international literature to be very encouraging for women suffering from moderate and severe endometriosis. Though laparoscopy is considered the ‘gold standard’of endometriosis surgery, laparotomy still may be indicated in patients with extensive endometriosis especially to preserve reproductive function.
Abstract
Maternal overweight and obesity are prenatal risk factors for obstetrical complications, preterm birth, neonatal morbidity as well as cognitive and behavioural developmental disorders in ...children. Paediatric morbidity and mortality as well as child development disorders are significantly associated with maternal obesity. Particularly in the neurodevelopmental and psychiatric area, it is becoming increasingly clear that, in children of mothers with an increased body mass index (BMI), there is a high correlation with childhood cognitive disabilities, attention disorders, and diseases on the autistic spectrum. The ELGAN (Extremely Low Gestational Age Newborn) study is a multicentre study which has been supported since 2000 by the National Institutes of Health (NIH) and whose objective is to research predictors for neonatal brain damage and neurological-cognitive sequelae in premature infants. The areas of focus are the connection between maternal overweight and obesity and pregnancy complications, APGAR scores and systemic inflammatory markers. In this overview, our aim is to summarise the work in this area and discuss it critically on the basis of current literature. We will examine the hypothesis whether maternal overweight and obesity in terms of a chronic inflammatory state is associated with neonatal inflammation which in turn is associated with an unfavourable development prognosis.
Zusammenfassung
Mütterliches Übergewicht und Adipositas sind pränatale Risikofaktoren für geburtshilfliche Komplikationen, Frühgeburt, neonatale Morbidität sowie kognitive und verhaltensauffällige Entwicklungsstörungen bei Kindern. Die kindliche Morbidität und Mortalität sowie Störungen der Kindesentwicklung sind signifikant mit maternaler Adipositas assoziiert. Besonders im entwicklungsneurologischen und -psychiatrischen Bereich wird zunehmend klar, dass es bei Kindern von Müttern mit erhöhtem Body-Mass-Index eine hohe Korrelation zu kindlichen kognitiven Einschränkungen, Aufmerksamkeitsstörungen und Erkrankungen aus dem autistischen Spektrum gibt. Die ELGAN-(Extremely Low Gestational Age Newborn-)Studie ist eine seit 2000 von den National Institutes of Health (NIH) geförderte multizentrische Studie, deren Ziel es ist, Prädiktoren für neonatale Hirnschäden und neurologisch-kognitive Folgen bei Frühgeborenen zu erforschen. Schwerpunkte sind der Zusammenhang zwischen mütterlichem Übergewicht und Adipositas und Schwangerschaftskomplikationen, Apgar-Werten und systemischen Inflammationsmarkern. In dieser Übersichtsarbeit verfolgen wir das Ziel, die Arbeiten in diesem Bereich zusammenzufassen und auf Basis der aktuellen Literatur kritisch zu diskutieren. Geprüft wird die Hypothese, ob mütterliches Übergewicht und Adipositas im Sinne eines chronischen Inflammationsstatus mit einer neonatalen Inflammationssituation zusammenhängen, die wiederum mit einer ungünstigen Entwicklungsprognose assoziiert ist.
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