Immune checkpoint inhibitors in advanced nasopharyngeal carcinoma: Beyond an era of chemoradiation?

Now is an exciting era of development in immunotherapy checkpoint inhibitors and their effect on the treatment of NPC. While the general prognosis of R/M disease is poor, immunotherapy offers some promise in a malignancy associated with EBV and characterized by a peritumoural immune infiltrate. Our study aims to review past and on-going clinical trials of monoclonal antibody therapies against the checkpoint inhibitors (e.g. PD1 and CTLA-4), in R/M NPC. All randomized and nonrandomized controlled trials involving immune checkpoint inhibitor interventions for treatment of NPC were included in the study. We utilized a validated “risk of bias” tool to assess study quality. Four separate Phase I–II trials report the potential of PD1 inhibitor treatment for patients with NPC. Within the observed groups, camrelizumab combined with chemotherapy achieved an objective response in 91% of patients as first-line treatment for metastatic NPC (PFS 68% at 1-year) but this was associated with a high rate of grade >3 adverse events (87%; CTCAE version 4.03). The remaining three studies focused on recurrent NPC disease in patients who had received at least one line of prior chemotherapy. Within this group, camrelizumab monotherapy achieved an objective response in 34% of patients (PFS 27% at 1-year; range across all three studies 20.5–34%). No NPC trial has yet reported on specific outcomes for non-PD1 checkpoint inhibitors but 11 on-going studies include alternative targets (e.g. PD-L1/CTLA-4) as combination or monotherapy treatments. In considering checkpoint immunotherapies for NPC, initial results show promise for anti-PD1 interventions. Further phase I–III trials are in progress to clarify clinical outcomes, fully determine safety profiles, and optimize drug combinations and administration schedules.     

Constraints on Social Activities of Care-Givers: A Sociological Perspective

Newer policies of community care for those with disabilities have resulted in the home becoming the usual site of care. Policy makers must now give attention to the needs of those at home giving this care. This article explores the constraints on sociability opportunities of 73 mothers who were caring for children with disabilities. These opportunities are often built into leisure pursuits for women without caring responsibilities. However, choice of out-of-house leisure activity was circumscribed for the mothers in this study and their reported leisure activities revolved around home and neighbourhood. Even these sites offered limited scope for sociability because of the way in which caring affected domestic space and because of the characteristics of the modern Australian suburb. It is argued in this paper that personal time and personal domestic space are needed by care-givers so their sociability needs can be fulfilled. An understanding of the constraints imposed by use of the home as a place of care may make possible the planning of a rearrangement of domestic space to increase sociability opportunities for carers.     

Factitious illness in children: the social worker's role in identification and management

Factitious illness in children is a phenomenon that results in adverse consequences for the child. Munchausen by proxy is a factitious disorder, first described by Meadow (1977), in which a parent induces or creates the appearance of illness in the child. This article highlights the importance of social work skills in the identification and management of this syndrome, and proposes a format for decision making at various points in the process.     

Relaxin down-regulates renal fibroblast function and promotes matrix remodelling in vitro.

BACKGROUND: Renal fibroblasts are important effector cells in tubulointerstitial fibrosis, with experimental antifibrotic strategies focusing on the functional down-regulation of these cells. Several experimental models of fibrosis have provided evidence for the effectiveness of the polypeptide hormone relaxin as a potential antifibrotic agent. This study was conducted to further elucidate the antifibrotic mechanisms of relaxin on renal fibroblasts in vitro. METHODS: Rat cortical fibroblasts were obtained from outgrowth culture of renal tissue isolated from kidneys 3 days post-unilateral ureteric obstruction and constituted 100% of cells studied. A relaxin radio-receptor assay was used to establish binding of relaxin to renal fibroblasts in vitro. Functional studies then examined the effects of H2 relaxin (0, 1, 10 and 100 ng/ml) on fibroblast kinetics, expression of alpha-smooth muscle actin (alpha-SMA), total collagen synthesis, collagenase production and collagen-I lattice contraction. CTGF mRNA expression was also measured by northern analysis. RESULTS: H2 relaxin bound with high affinity to rat renal fibroblasts, but receptor numbers were low. Consistent with its previously reported bimodal effect, transforming growth factor (TGF-beta 1) reduced fibroblast proliferation, an effect abrogated by H2 relaxin. Fibroblasts exposed to H2 relaxin (100 ng/ml) for 24 h demonstrated decreased immunostaining for alpha-SMA and reduced alpha-SMA protein expression compared with controls. There was a trend for a relaxin-mediated reduction in total collagen synthesis and alpha 1(I) mRNA expression with large dose-related increases in collagenase protein expression being observed. TGF-beta 1-stimulated collagen-I lattice contraction was significantly inhibited following co-incubation with 100 ng/ml relaxin. Incremental doses of H2 relaxin had no significant effect on CTGF mRNA expression. CONCLUSIONS: The findings of this study suggest that the antifibrotic effects of relaxin involve down-regulation of fibroblast activity, increase in collagenase synthesis and restructuring of collagen-I lattices, which are consistent with its known physiological role of matrix remodelling. Although there appears to be an interaction between TGF-beta 1 and H2 relaxin, this does not appear to involve a reduction in CTGF mRNA expression.     

Assessment of quality of life in children with peanut allergy

Children with a peanut allergy (PA) are faced with food and social restrictions due to the potentially life-threatening nature of their disease, for which there is no cure or treatment. This inevitably impacts upon their quality of life (QoL). QoL of 20 children with PA and 20 children with insulin-dependent diabetes mellitus (IDDM) was measured using two disease-specific QoL questionnaires (higher scores correspond to a poorer QoL). One questionnaire was designed by us and the other was adapted from the Vespid Allergy QoL questionnaire. We gave subjects cameras to record how their QoL is affected over a 24-h period. Response rates for both questionnaires were 100%. Mean ages were 9.0 and 10.4 years for PA and IDDM subjects, respectively. Children with a PA reported a poorer quality of life than children with IDDM: mean scores were 54.85 for PA subjects and 46.40 for diabetics (p = 0.004) in questionnaire 1 and 54.30 and 34.50 (p≤0.001) in questionnaire 2. PA children reported more fear of an adverse event and more anxiety about eating, especially when eating away from home. Photographs fell into seven common categories: food, management, environment, away from home, physical activities, restaurant and people. Most photographs related to food and management issues and revealed difficulties for both groups regarding food restrictions. PA subjects felt more threatened by potential hazards within their environment, felt more restricted by their PA regarding physical activities, and worried more about being away from home. However, they felt safe when carrying epinephrine kits and were positive about eating at familiar restaurants. The QoL in children with PA is more impaired than in children with IDDM. Their anxiety may be considered useful in some situations, promoting better adherence to allergen avoidance advice and rescue plans.     

Cementless total hip arthroplasty in the treatment of severe hip dysplasia or dislocated hips

We present our experience over 6 years with the use of uncemented total hip arthroplasty (THA) for developmental dysplasia of the hip (DDH) with a mean follow-up of 3 years. In a 6-year period, 26 THAs were performed in 19 patients with Hartofilakidis grades 2 and 3 dislocation of the hips. Out of 19 patients, seven had bilateral dislocations. Uncemented acetabular and femoral components were used in all patients. Patients with a minimum follow-up of 1 year were included in the study. The average age at the time of surgery was 38 (range 20–69) years. Approaches used include trochanteric osteotomy in 14 (54%) patients and a lateral approach in 12 (46%) patients. In addition, subtrochanteric osteotomy was performed in four (15%) patients. A Mallory-head femoral stem was used in 15 (58%) patients; a DDH femoral stem was in nine (35%), and the S-ROM femoral prosthesis in two (8%). A Mallory head acetabular shell was used in all cases, a 22.2-mm chrome cobalt head was used in 18 (69%), and a 28-mm chrome cobalt head was used in eight (31%). The average follow-up was 3 (range 1–6) years. The Harris hip score (HHS) improved in the cohort from a mean preoperative score of 51 to a mean postoperative score of 86 (p<0.05). The mean preoperative SF36v2 score was 42 compared to postoperatively of 67(p<0.05). The complication rate was 11% with nonunion of a subtrochanteric osteotomy in one patient, dislocation in one, and trochanteric bursitis due to fracture of Dall-Miles cables in one. THA for DDH is a technically demanding procedure. This short-term follow-up of THA for DDH using uncemented implants is encouraging for arthrosis secondary to DDH. It provides better function compared to arthrodesis or excision arthroplasty, especially in young individuals. A long-term follow-up is required in order to establish the role of this management strategy.     

Effects of tumor necrosis factor alpha on parathyroid hormone-induced increases in osteoblastic cell cyclic AMP

Summary Tumor necrosis factor α (10⁻¹⁰–10⁻⁸M) had no effects on cyclic AMP production by the osteoblastic osteosarcomal cells, Saos-2 and G292, or normal rat calvarial cells. The cytokine did, however, inhibit the parathyroid hormone (PTH)-induced effect on cyclic AMP in the Saos-2 and normal rat osteoblastic cells. This inhibitory effect did not occur on prostaglandin E₂-induced cyclic AMP increases in the osteoblastic cells. Interleukin-1 (10 U/ml −100 U/ml) did not produce any effect on basal levels or PTH-induced cyclic AMP increases in these cells.