Growth hormone treatment and adverse events in Prader-Willi syndrome: data from KIGS (the Pfizer International Growth Database)

OBJECTIVE: To evaluate the response to recombinant GH treatment and adverse events in children with Prader-Willi syndrome (PWS) from KIGS, the Pfizer International Growth Database. PATIENTS: A total of 328 children (274 prepubertal, median age 6.0 years; 54 pubertal, median age 12.7 years) were treated for 1 year and 161 children were treated for 2 years with GH. RESULTS: Height standard deviation score (SDS) increased significantly during treatment; the response was greater in prepubertal (-0.7 vs.-1.8 pretreatment) compared with pubertal children (-1.5 vs.-1.8). Predictors of first-year height velocity in multiple regression analysis were GH dose, body weight (positively correlated), height SDS minus mid-parental height SDS and chronological age (negatively correlated), together accounting for 39% of the variation in response to GH. Body mass index (BMI) SDS did not change significantly during 2 years of treatment. Of all the 675 GH-treated PWS patients in KIGS, there were five cases of sudden death (age range 3-15 years). Three were obese (weight for height > 200%) and causes of death included bronchopneumonia, respiratory insufficiency and sleep apnoea. Scoliosis was the most commonly reported adverse event (n = 24), four children developed hyperglycaemia and six had presumptive diabetes (type 2 in five, and one case of type 1). CONCLUSIONS: Short-term growth improved in response to conventional doses of GH in children with PWS. Prior to commencement of GH, examination of the upper airways and sleep studies should be performed in PWS patients. GH should be used with caution in those with extreme obesity or disordered breathing and all patients should be closely monitored for adverse events.     

Phylogenetic analysis of multiple FISH markers in oral tongue squamous cell carcinoma suggests that a diverse distribution of copy number changes is associated with poor prognosis

Oral tongue squamous cell carcinoma (OTSCC) is associated with poor prognosis. To improve prognostication, we analyzed four gene probes (TERC, CCND1, EGFR and TP53) and the centromere probe CEP4 as a marker of chromosomal instability, using fluorescence in situ hybridization (FISH) in single cells from the tumors of sixty‐five OTSCC patients (Stage I, n = 15; Stage II, n = 30; Stage III, n = 7; Stage IV, n = 13). Unsupervised hierarchical clustering of the FISH data distinguished three clusters related to smoking status. Copy number increases of all five markers were found to be correlated to non‐smoking habits, while smokers in this cohort had low‐level copy number gains. Using the phylogenetic modeling software FISHtrees, we constructed models of tumor progression for each patient based on the four gene probes. Then, we derived test statistics on the models that are significant predictors of disease‐free and overall survival, independent of tumor stage and smoking status in multivariate analysis. The patients whose tumors were modeled as progressing by a more diverse distribution of copy number changes across the four genes have poorer prognosis. This is consistent with the view that multiple genetic pathways need to become deregulated in order for cancer to progress.     

NET‐producing CD16high CD62Ldim neutrophils migrate to tumor sites and predict improved survival in patients with HNSCC

The concept of functional neutrophil subsets is new and their clinical significance in malignancies is unknown. Our study investigated the role of CD16^dim CD62L^high, CD16^high CD62L^high and CD16^high CD62L^dim neutrophil subsets in head and neck squamous cell carcinoma (HNSCC) patients. These neutrophil subsets may play different roles in immune‐related activity in cancer, based on their profile, activation state and migration ability within a tumor site, which may be important in predicting cancer prognoses. Tumor biopsies and blood were obtained from newly diagnosed untreated HNSCC patients and healthy controls. Neutrophil subsets and their phenotype were characterized using flow cytometry. Isolated granulocytes were assessed for anti‐tumor immune functions. Compared to controls HNSCC patients exhibited increased CD16^high CD62L^dim neutrophils in blood; this subset displayed a distinct phenotypes with high expression of CD11b and CD18. This subset was prone to migrate into the tumor facilitated by tumor‐derived IL‐8. Furthermore, IL‐8 was also found to activate neutrophils and thereby promoting subset transition. Various assays demonstrated that activated CD16^high CD62L^dim neutrophils inhibited migration, proliferation and induced apoptosis of FaDu cancer cells. Neutrophil elastase detected in activated CD16^high CD62L^dim neutrophils and tumor biopsies suggested that CD16^high CD62L^dim neutrophils impart anti‐tumoral activity via neutrophil extracellular traps. Furthermore, increased fraction of CD16^high CD62L^dim neutrophils was shown to correlate with an increased survival rate. Our study demonstrates the clinical relevance of the CD16^high CD62L^dim neutrophil subset, providing evidence for its increased migration capacity, its anti‐tumor activity including increased NET formation and finally its correlation with increased survival in HNSCC patients.     

A comparison between ultrasound and gynecologic examination for detection of enlarged ovaries in a group of women at risk for ovarian carcinoma

In order to evaluate the quality of ultrasound and gynecologic examination of the ovaries in women at risk for ovarian carcinoma, a group of 115 women all relatives to women with ovarian carcinoma, were examined. Although this small group of women was considered a risk group, no carcinoma was found. In premenopausal women 92% of the ovaries could be identified and measured using ultrasound. In postmenopausal women this figure was 87%, while only 30% could be identified at the gynecologic examination. This indicates that ultrasound examination of the ovaries is a much more reliable method for examining the ovary than gynecologic palpation.