T cell memory,anergy and immunotherapy in breast cancer

T cell immunity in breast cancer is suggested to play a role in tumor dormancy, a period of stability which can correspond to the time interval between primary treatment and tumor recurrence. Bone marrow in breast cancer patients seems to be particularly important because it is highly enriched with cancer specific memory T cells. Similar cells can be found in peripheral blood, but these appear to be functionally anergic. The immune system of primary operated breast cancer patients does not seem to be completely anergized. Bone marrow derived memory T cells can be reactivated ex vivo and show functional reactivity, including tumor rejection in NOD/SCID mice. Promising results were obtained from a postoperative phase-II active specific immunotherapy study. In this study, 32 patients treated with an optimal formulation of a virus-modified autologous tumor vaccine (ATV-NDV) appeared to have a significant 5-year survival benefit. Our results suggest that cancer reactive memory T cells which are enriched in the bone marrow of breast cancer patients, can be activated ex vivo via autologous dendritic cells pulsed with breast cancer tumor antigens, or they can be activated in situ via a tumor vaccine, which combines tumor antigens with virus infection. The findings should encourage further studies in breast cancer on active specific immunotherapy with tumor vaccines or adoptive immunotherapy with activated memory T cells.     

Acute rejection after paediatric heart transplantation: far less common and less severe

Despite improved immunosuppression, rejection accounts for significant morbidity and mortality in children after heart transplantation. We report the incidence and outcome of rejection of 105 children (male = 50; mean age of 8.3 ± 5.8 years) following heart transplantation between January 2002 and August 2007. A multi-variant model was constructed for risk factors associated with significant rejection. In 271.9 patient-years of follow-up, there were 23 episodes of significant rejection (≥3A) in 21 patients (20%). Five presented in haemodynamic collapse requiring extracorporeal membrane oxygenation support 1.6–35.9 months after transplantation; four of five survived the rejection episode. Overall rejection episodes were more common in older children, boys and those treated with sirolimus. Whereas the risk for rejection in patients on an immunosuppression regime containing tacrolimus was significantly lower. The latter finding persisted on multivariate analysis ( P  < 0.002). Interestingly, none of the patients who presented with haemodynamic collapse was on mycophenolate mofetil. While our experience is of a far lower incidence of rejection than registry data, rejection remains a serious problem after paediatric heart transplantation. Sirolimus without a calcineurin inhibitor was associated with more rejection episodes, whereas tacrolimus and mycophenolate appeared to provide the best protective profile.     

Acute pathophysiological processes after ischaemic and traumatic brain injury

Ischaemic stroke and brain trauma are among the leading causes of mortality and long-term disability in the western world. Enormous endeavours have been made to elucidate the complex pathophysiology of ischaemic and traumatic brain injury with the intention of developing new therapeutic strategies for patients suffering from these devastating diseases. This article reviews the current knowledge on cascades that are activated after ischaemic and traumatic brain injury and that lead to progression of tissue damage. Main attention will be on pathophysiological events initiated after ischaemic stroke including excitotoxicity, oxidative/nitrosative stress, peri-infarct depolarizations, apoptosis and inflammation. Additionally, specific pathophysiological aspects after traumatic brain injury will be discussed along with their similarities and differences to ischaemic brain injury. This article provides prerequisites for understanding the therapeutic strategies for stroke and trauma patients which are addressed in other articles of this issue.     

Decrease in the expression of the type 1 PTH/PTHrP receptor (PTH1R) on chondrocytes in animals with osteoarthritis

Background  

To evaluate the expression of the type 1 PTH/PTHrP receptor (PTH1R) on chondrocytes from hyaline cartilage over the course of osteoarthritis (OA).     

Survivorship and Patient-Reported Outcomes of an Uncemented Vitamin E–Infused Monoblock Acetabular Cup: A Multicenter Prospective Cohort Study

BackgroundAddition of vitamin E to polyethylene is theorized to reduce the potential for oxidative wear in acetabular components. This paper presents a multicenter prospective cohort study that reports on outcomes from use of a Vitamin E–infused highly cross-linked polyethylene acetabular cup.MethodsPatients were recruited across nine medical institutions. Clinical outcome measures recorded were the Harris Hip Score, visual analogue score for pain and satisfaction. Evidence of implant loosening or osteolysis was collected radiologically. Cup survival and reasons for revision in relevant cases were also recorded. Data collection was undertaken preoperatively, at 6-12 weeks, 6 months, 1 year, 2 years, and 5 years. A total of 675 patients were recruited, with 450 cases available at final review. Data regarding cup survival was available to 8 years and 9 months postoperatively.ResultsImprovements in both the Harris Hip Score and visual analogue score for pain and satisfaction were recorded at all time points, with these being maintained through the length of follow-up. In total, 89% of cups were implanted within the Lewinnek safe zone. A lucent line was identified in one case, with no evidence of acetabular osteolysis observed throughout the follow-up period. Cup survival was 98.9% at 8 years and 9 months. No revisions for aseptic loosening were observed.ConclusionsThe use of a vitamin E–infused polyethylene acetabular cup demonstrates reassuring patient-reported outcomes, radiological measures, and cup survival at medium to long-term follow-up.     

Combined temporal and prefrontal transcranial magnetic stimulation for tinnitus treatment: a pilot study.

OBJECTIVES: Low-frequency repetitive transcranial magnetic stimulation (rTMS) of the temporal cortex has been proposed as a new treatment strategy for patients with chronic tinnitus. However, functional abnormalities in tinnitus patients also involve brain structures used for attentional and emotional processing, such as the dorsolateral prefrontal cortex. Therefore, we have developed a new rTMS treatment strategy for tinnitus patients that consists of a combination of high-frequency prefrontal and low-frequency temporal rTMS. STUDY DESIGN: A total of 32 patients received either low-frequency temporal rTMS or a combination of high-frequency prefrontal and low-frequency temporal rTMS. Treatment effects were assessed with a standardized tinnitus questionnaire (TQ). RESULTS: Directly after therapy there was an improvement of the TQ-score for both groups, but no differences between groups. An evaluation after 3 months revealed a remarkable benefit from the use of combined prefrontal and temporal rTMS treatment. CONCLUSION: These results support recent data that suggest that auditory and nonauditory brain areas are involved in tinnitus pathophysiology.     

Insall Proximal Realignment of the Patella for Recurrent Dislocation or Subluxation

Objective

Proximal realignment of the patella for the treatment of patellar subluxation or dislocation consisting of a lateral release and advancement of the vastus medialis.

Indications

Recurrent lateral subluxation or dislocation of the patella despite a supervised exercise program. Recurrent subluxation or dislocation of the patella.

Contraindications

Congenital dislocation of the patella. Generalized degenerative arthritis of the patellofemoral joint. Excessive valgus deformity of the knee. Moderate to severe muscular atrophy of the vastus medialis muscle (i.e., in neurologic disorders).

Surgical Technique

Lateral parapatellar incision of skin. Detachment of the fibers of the iliotibial tract and the lateral retinaculum from the lateral patella. Medial capsular incision extending from the quadriceps tendon over the patella into the patellar ligament. The quadriceps expansion is shaved from the medial third of the patella preserving the longitudinal continuity. The vastus medialis is advanced and sutured onto the middle and distal aspects of the patella.

Results

Out of 21 patients (16 women, five men) who received a proximal realignment procedure during 1989 and 1993, all could be evaluated after 6.3 years (minimum follow-up of 4 years 5 months, maximum of 8 years 3 months). In 13 patients the diagnosis was recurrent dislocationof the patella, in eight patients a true primary traumatic dislocation was noted. A generalized ligamentous laxity was seen in three patients. One patient had a superficial wound infection postoperatively. Two patients had an excellent, 13 patients a good, six patients a fair and no patient a poor result according to the subjective score of Turba et al. Three patients experienced a recurrence of instability (one to three events) after the operation. One of these patients had to be revised for postoperative recurrent dislocation of the patella. The other two patients experienced no more symptoms of instability after muscle strengthening exercises of the vastus medialis muscle.     

Local cooling reduces regional bone blood flow

Local cooling is very common after bone and joint surgery. Therefore the knowledge of bone blood flow during local cooling is of substantial interest. Previous studies revealed that hypothermia leads to vasoconstriction followed by decreased blood flow levels. The aim of this study was to characterize if local cooling is capable of inducing reduced blood flow in bone tissue using a stepwise‐reduced temperature protocol in experimental rabbits. To examine bone blood flow we utilized the fluorescent microsphere (FM) method. In New Zealand white rabbits one randomly chosen hind limb was cooled stepwise from 32 to 2°C, whereas the contra lateral hind limb served as control. Injection of microspheres was performed after stabilization of bone and muscle temperature at each temperature level. Bones were removed, dissected and fluorescence intensity was determined to calculate blood flow values. We found that blood flow of all cooled regions decreased relative to the applied external temperature. At maximum cooling blood flow was almost completely disrupted, indicating local cooling as powerful regulatory mechanism for regional bone blood flow (RBBF). Postoperative cooling therefore may lead to strongly decreased bone blood flow values. As a result external cooling has capacity to both diminish bone healing and reduce bleeding complications. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:1820–1827, 2013     

Single‐Center Experience With Extracorporeal Life Support in 103 Nonpostcardiotomy Patients

Extracorporeal membrane oxygenation (ECMO) has been successfully used to support patients with cardiac arrest failing to respond to conventional cardiopulmonary resuscitation (CPR). Preimplant factors being indicative for success are unknown up to now. The study describes single center experience with special focus on differences between survivors and nonsurvivors. Between 2002 and 2009, 103 patients were supported within the scope of CPR by means of ECMO. Besides primary diagnosis, duration, and outcome, pH, lactate, mean arterial pressure, aspartate aminotransferase, bilirubin, catecholamine dosage, and oxygenation ratio before ECMO, after 2 h, 1 day, and at explantation were analyzed. One hundred three patients (51.2 ± 16 years, 35 women, 68 men) were analyzed. Primary cardiac failure led to CPR in 54%. Duration of support was 4.8 ± 0.6 days. Twenty‐nine (28.1%) patients survived to hospital discharge. On ECMO support, pH, lactate, and mean arterial pressure improved significantly. Catecholamine dosage was significantly reduced after ECMO implantation. Demographic data and primary diagnosis revealed no significant influence on outcome. pH, lactate, creatinine, and bilirubin differed significantly between survivors and nonsurvivors in the course of ECMO support. ECMO support during CPR reliably improves the circulatory and respiratory situation. Considering observed survival critical patient selection is mandatory. Although there are several significant differences between surviving patients and patients with fatal outcome, patient selection turns out to be difficult as clinically relevant factors show only limited predictive value. Future research should focus on better defining a population that may be best of all suited for the use of ECMO support in CPR.     

Radiofrequency-ablation of unresectable primary and secondary liver tumors: results in 88 patients

Background and aims Radiofrequency-ablation (RFA) is increasingly used for destruction of unresectable primary and secondary liver tumors. We report our experience in the use of RFA for the management of unresectable hepatic malignancies. Patients and methods Between February 2000 and December 2004 we have undertaken 120 RFA procedures to ablate 426 unresectable primary or metastatic liver tumors in 88 patients. RFA was performed via laparotomy (n=68), laparoscopy (n=9) or a percutaneous approach (n=43). Primary liver cancer was treated in seven patients (8%) and metastatic liver tumors were treated in 81 patients (92%). All patients were followed to assess complications, treatment response and recurrence of malignant disease. Results Procedure-related complication rate was low (3.4%). During a mean follow-up of 21.2 months, 15 patients had local tumor progression (17%), 21 patients (23,9%) had new malignant disease and 27 patients (30.7%) died from intervention-unrelated complications of their malignant disease. Additional liver lesions were identified in 27 (35%) of 77 cases by intraoperative ultrasound. Thirty-six patients received simultaneous resection and RFA. Conclusion RFA is a safe, well-tolerated and effective treatment for patients with unresectable primary and secondary liver malignancies.