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.     

Reoperation rates and risk factors for revision 4 years after dynamic stabilization of the lumbar spine

Background Context

The concept of dynamic stabilization (DS) of the lumbar spine for treatment of degenerative instability has been introduced almost two decades ago. Dynamic stabilization follows the principle of controlling movement in the coronal plane by providing load transfer of the spinal segment without fusion and, at the same time, reducing side effects such as adjacent segment disease (ASD). So far, only little is known about revision rates after DS due to ASD and screw loosening (SL).

3D FEA of cemented steel, glass and carbon posts in a maxillary incisor.

OBJECTIVES: A comparative study on the stress distribution in the dentine and cement layer of an endodontically treated maxillary incisor has been carried out by using Finite Element Analysis (FEA). The role of post and cement rigidity on reliability of endodontic restorations is discussed. METHODS: A 3D FEM model (13,272 elements and 15,152 nodes) of a central maxillary incisor is presented. A chewing static force of 10 N was applied at 125 degree angle with the tooth longitudinal axis at the palatal surface of the crown. Steel, carbon and glass fiber posts have been considered. The differences in occlusal load transfer ability when steel, carbon and glass posts, fixed to root canal using luting cements of different elastic moduli (7.0 and 18.7 GPa) are discussed. RESULTS AND SIGNIFICANCE: The more stiff systems (steel and carbon posts) have been evaluated to work against the natural function of the tooth. Maximum Von Mises equivalent stress values ranging from 7.5 (steel) to 5.4 and 3.6 MPa (respectively, for carbon posts fixed with high and low cement moduli) and to 2.2 MPa (either for glass posts fixed with high and low cement moduli) have been observed under a static masticatory load of 10 N. A very stiff post works against the natural function of the tooth creating zones of tension and shear both in the dentine and at the interfaces of the luting cement and the post. Stresses in static loading do not reach material (dentine and cement) failure limits, however, they significantly differ leading to different abilities of the restored systems to sustain fatigue loading. The influence of the cement layer elasticity in redistributing the stresses has been observed to be less relevant as the post flexibility is increased.     

Autologous Unpurged Bone Marrow Transplantation for Acute Non Lymphoblastic Leukemia in First Remission

Forty consecutive adult patients under the age of 50 with acute non-lymphoblastic leukemia (ANLL) in first complete remission, underwent autologous bone marrow transplantation (ABMT) between March 1984 and April 1990. The conditioning regimen employed included cyclophosphamide and total body irradiation, followed by the administration of unpurged ABMT. The median time from diagnosis to transplant was 7 months (3-15 months), and the median time from complete remission to ABMT was 4 months (range 3-9 months). Twenty-two (51%) patients remain in complete remission 6-81 months (median 24 months) after ABMT.

The causes of death were, recurrent leukemia (11 patients), parenchymal toxicities such as acute respiratory distress syndrome and veno-occlusive disease (3 patients), hemorrhage (2 patients) and infection (2 patients). Eleven patients relapsed after 3-12 months (median 5 months). This study has produced survival data comparable to those of other institutions employing TBI for either allo or autotransplants.     

Axonal neuropathy in a patient with monoclonal IgM kappa reactive with Schmidt-Lantermann incisures

We report a patient with a progressive, predominantly sensory neuropathy and a IgM kappa M-protein that binds to Schmidt-Lantermann incisures. A sural nerve biopsy showed primary axonal damage and IgM deposits at Schmidt-Lantermann incisures were seen by direct immunoperoxidase. Serum from the patient injected into rat sciatic nerve reacts with the incisures as with those in the patient's nerve. The IgM kappa M-protein reacts with chondroitin sulfate C and binds to a broad nerve protein band with a mobility of between 170 and 118 kDa. Peripheral neuropathy may be related to the M-protein, which had immunocytochemical reactivity not previously described for patients with polyneuropathy and IgM monoclonal gammopathy.     

Looking for resilience: Understanding the longitudinal trajectories of responses to stress

Taking advantage of two large, population-based, and longitudinal datasets collected after the 1999 floods in Mexico (n = 561) and the September 11, 2001 terrorist attacks in New York (n = 1267), we examined the notion that resilience may be best understood and measured as one member of a set of trajectories that may follow exposure to trauma or severe stress. We hypothesized that resistance, resilience, recovery, relapsing/remitting, delayed dysfunction, and chronic dysfunction trajectories were all possible in the aftermath of major disasters. Semi-parametric group-based modeling yielded the strongest evidence for resistance (no or mild and stable symptoms), resilience (initially moderate or severe symptoms followed by a sharp decrease), recovery (initially moderate or severe symptoms followed by a gradual decrease), and chronic dysfunction (moderate or severe and stable symptoms), as these trajectories were prevalent in both samples. Neither Mexico nor New York showed a relapsing/remitting trajectory, and only New York showed a delayed dysfunction trajectory. Understanding patterns of psychological distress over time may present opportunities for interventions that aim to increase resilience, and decrease more adverse trajectories, after mass traumatic events.     

Circumferential choledochoplasties with autologous venous and arterial grafts

Circumferential choledochoplasties with vascular grafts have rarely been attempted either experimentally or in clinical practice. In this study, choledochoplasties using autologous venous and arterial grafts were performed in rats. Sixty-four rats were randomly selected into five treatment groups: A) venous interpositional graft replacement of a choledochus gap without a stent; B) venous graft with prolene stent; C) venous graft with polyethylene stent; D) arterial graft; E) a control group with simple resection between ligatures in the choledochus. The operative mortality in treatment groups B, C, D, and E, was 0, and 13% in group A. At 12 weeks follow-up, all the rats in group E had died, whereas, 52.2% (P <.05) of the rats in group A, 30% of the rats in group B, 57% of the rats in group C, and 92.8% of the rats in group D survived treatment. Surviving animals were sacrificed at 3 months for further examination. The morphology and caliber of the common bile duct of these rats were normal in 25% of the rats in group A, 33% of the rats in group B, 25% of the rats in group C, and 84.6% of the rats in group D. Proximal dilations were found in the rats presenting with abnormal morphology. The dilations were less marked in the group treated by arterial choledochoplasties. Laboratory and clinical cholestatic parameters were within normal ranges in the presence of common bile duct dilations less than four times the normal duct caliber. Electron microscopic examination of the venous and arterial graft at 3 months follow-up revealed a fibrous ring composed of collagen fibers, fibroblasts, and remnants of elastic fibers. Regenerated ductal epithelium encompassed both types of grafts. Epithelialization was more pronounced in venous grafts as compared to arterial grafts. Biliary epithelium was able to colonize the venous grafts and resume cell specialization and function as in normal biliary epithelium. The most satisfactory results were obtained using venous grafts with stents or by using arterial grafts. © 1993 Wiley-Liss Inc.     

Introns and gene evolution

In one scenario of gene evolution, exon shuffling has a fundamental role in increasing gene diversity. As DNA sequences accumulate in the databases, the picture of the intron/exon structures of genes becomes more and more clear. We discuss in this review some features of this picture that suggest that introns have been present since the early stages of evolution, and that exon shuffling was a fundamental process in the construction of ancient as well as modern genes.