Search

Hepatocellular carcinoma (HCC) is a global health burden with increasing incidence, poor prognosis and limited therapeutic options. Natural killer (NK) cells exhibit potent anti-tumoral activity and therefore represent potential targets for immunotherapeutic approaches in HCC treatment. However, the anti-tumoral activity of NK cells in HCC associated with different etiologies, and the impact of the heterogeneous NK cell subset, e.g., adaptive and conventional subsets, are not understood in detail. By comparatively analyzing the NK-cell repertoire in 60 HCC patients, 33 liver cirrhosis patients and 36 healthy donors (HD), we show in this study that the NK-cell repertoire is linked to HCC etiology, with increased frequencies of adaptive NK cells in Hepatitis B virus (HBV)-associated HCC. Adaptive NK cells exhibited limited anti-tumoral activity toward liver cancer cells, however, this was not a result of a specific NK-cell impairment in HCC but rather represented an intrinsic feature, since the characteristics of circulating and intra-tumoral adaptive NK cells were conserved between HD, HCC and liver cirrhosis patients. Hence, the expansion of adaptive NK cells with reduced anti-tumoral activity, detectable in HBV-associated HCC, may have implications for tumor surveillance and therapy.

Background & Aims Phenotypic and functional natural killer (NK)-cell alterations are well described in chronic hepatitis B virus (cHBV) infection. However, it is largely unknown whether these alterations result from general effects on the overall NK-cell population or the emergence of distinct NK-cell subsets. Human cytomegalovirus (HCMV) is common in cHBV and is associated with the emergence of memory-like NK cells. We aimed to assess the impact of these cells on cHBV infection. Methods To assess the impact of memory-like NK cells on phenotypic and functional alterations in cHBV infection, we performed in-depth analyses of circulating NK cells in 52 patients with cHBV, 45 with chronic hepatitis C virus infection and 50 healthy donors, with respect to their HCMV serostatus. Results In patients with cHBV/HCMV+, FceRIγ- memory-like NK cells were present in higher frequencies and with higher prevalence than in healthy donors with HCMV+. This pronounced HCMV-associated memory-like NK-cell expansion could be identified as key determinant of the NK-cell response in cHBV infection. Furthermore, we observed that memory-like NK cells consist of epigenetically distinct subsets and exhibit key metabolic characteristics of long-living cells. Despite ongoing chronic infection, the phenotype of memory-like NK cells was conserved in patients with cHBV/HCMV+. Functional characteristics of memory-like NK cells also remained largely unaffected by cHBV infection with the exception of an increased degranulation capacity in response to CD16 stimulation that was, however, detectable in both memory-like and conventional NK cells. Conclusions The emergence of HCMV-associated memory-like NK cells shapes the overall NK-cell response in cHBV infection and contributes to a general shift towards CD16-mediated effector functions. Therefore, HCMV coinfection needs to be considered in the design of immunotherapeutic approaches that target NK cells in cHBV. Lay summary In chronic hepatitis B virus infection, natural killer (NK)-cell phenotype and function is altered. In this study, we demonstrate that these changes are linked to the emergence of a distinct NK-cell subset, namely memory-like NK cells. The emergence of these memory-like NK cells is associated with coinfection of human cytomegalovirus that affects the majority of patients with chronic hepatitis B.

Injuries to the lower extremity are common in racquet sports. These can be either acute or chronic. Although acute injuries usually respond to treatment, chronic injuries are often less amenable to treatment. The occurrence of both kinds of injuries, however, can often be prevented by proper training techniques including stretching and strengthening exercises. These exercises are also important components of a proper rehabilitation program.

Between 1990 to 1993, 21 patients with tibial plateau or proximal tibial fractures resulting from high-energy trauma were treated with the Monticelli-Spinelli external fixator. There were 13 men and 8 women (mean age, 45.2 years; range, 26 to 78). There were a total of 5 type A, 2 type B, and 14 type C fractures, using the Arbeitsgemeinschaft Fur Osteosynthesefragen (AO) classification system. Immediate postoperative reductions were good or excellent, according to strict radiographic criteria, in 16 of 21 patients. All patients obtained at least 90 degrees of knee flexion, and only one patient lost more than 5 degrees of full extension. Complications included seven superficial pin-tract infections and one deep vein thrombosis with resultant pulmonary embolism. Nineteen patients were available for follow-up (mean, 14 months). Clinically, 13 patients had satisfactory results where good or excellent radiographic reductions were maintained, knee extension was within 5 degrees of full, flexion wasor = 90 degrees, withor = 5 degrees valgus/varus angulation. Six patients had unsatisfactory results, not meeting the above criteria. The Monticelli-Spinelli external fixator is a much-needed tool in the treatment of high-energy tibial plateau fractures that are not amenable to more extensive surgical procedures because of the associated soft-tissue injuries.

From April 1990 to August 1994, the GSH supracondylar intramedullary nail (SmithNephew/Richards, Memphis, Tennessee) was used to treat 23 supracondylar femur fractures in 22 patients. Nineteen of the 23 fractures were highly comminuted and intra-articular. Fifteen patients with 16 fractures were followed up to healing or declaration of nonunion for an average of 10 months. All fractures were treated with direct reduction through a median parapatellar incision. Fixation of the intercondylar fractures was with 6.5-mm cannulated screws, and the GSH nail was then inserted between the screws to secure the articular segment to the shaft. Fifteen of the 16 fractures healed (94%) with excellent and good results at an average of 3.3 months. Initial postoperative fracture reduction was maintained in all patients until union, as shown by follow-up radiographs. Thirteen of the 16 patients were treated with immediate continuous passive motion of the knee. Average knee range-of-motion was 109 degrees. Complications included 1 nonunion, 1 delayed union, 1 hardware failure secondary to premature full weight-bearing, and 1 patient with impingement of the nail in the intercondylar notch. This impingement resolved with removal of the nail after fracture healing. The GSH supracondylar intramedullary nail is an excellent alternative for the treatment of supracondylar and intercondylar femur fractures.

Injuries to the lower extremity are common in racquet sports. These can be either acute or chronic. Although acute injuries usually respond to treatment, chronic injuries are often less amenable to treatment. The occurrence of both kinds of injuries, however, can often be prevented by proper training techniques including stretching and strengthening exercises. These exercises are also important components of a proper rehabilitation program.