Stabilization of the atlantoaxial complex via C-1 lateral mass and C-2 pedicle screw fixation in a multicenter clinical experience in 102 patients: modification of the Harms and Goel techniques

OBJECT: Stabilization of the atlantoaxial complex has proven to be very challenging. Because of the high mobility of the C1-2 motion segment, fusion rates at this level have been substantially lower than those at the subaxial spine. The set of potential surgical interventions is limited by the anatomy of this region. In 2001 Jürgen Harms described a novel technique for individual fixation of the C-1 lateral mass and the C-2 pedicle by using polyaxial screws and rods. This method has been shown to confer excellent stability in biomechanical studies. Cadaveric and radiographic analyses have indicated that it is safe with respect to osseous and vascular anatomy. Clinical outcome studies and fusion rates have been limited to small case series thus far. The authors reviewed the multicenter experience with 102 patients undergoing C1-2 fusion via the polyaxial screw/rod technique. They also describe a modification to the Harms technique. METHODS: One hundred two patients (60 female and 42 male) with an average age of 62 years were included in this analysis. The average follow-up was 16.4 months. Indications for surgery were instability at the C1-2 level, and a chronic Type II odontoid fracture was the most frequent underlying cause. All patients had evidence of instability on flexion and extension studies. All underwent posterior C-1 lateral mass to C-2 pedicle or pars screw fixation, according to the method of Harms. Thirty-nine patients also underwent distraction and placement of an allograft spacer into the C1-2 joint, the authors' modification of the Harms technique. None of the patients had supplemental sublaminar wiring. RESULTS: All but 2 patients with at least a 12-month follow-up had radiographic evidence of fusion or lack of motion on flexion and extension films. All patients with an allograft spacer demonstrated bridging bone across the joint space on plain x-ray films and computed tomography. The C-2 root was sacrificed bilaterally in all patients. A postoperative wound infection developed in 4 patients and was treated conservatively with antibiotics and local wound care. One patient required surgical debridement of the wound. No patient suffered a neurological injury. Unfavorable anatomy precluded the use of C-2 pedicle screws in 23 patients, and thus, they underwent placement of pars screws instead. CONCLUSIONS: Fusion of C1-2 according to the Harms technique is a safe and effective treatment modality. It is suitable for a wide variety of fracture patterns, congenital abnormalities, or other causes of atlantoaxial instability. Modification of the Harms technique with distraction and placement of an allograft spacer in the joint space may restore C1-2 height and enhance radiographic detection of fusion by demonstrating a graft-bone interface on plain x-ray films, which is easier to visualize than the C1-2 joint.     

Mechanisms underlying the suppression of established immune responses by ultraviolet radiation

The ultraviolet radiation present in sunlight is immune suppressive. Recently we showed that solar-simulated ultraviolet radiation (ultraviolet A + B; 295-400 nm), applied after immunization, suppressed immunologic memory and the elicitation of delayed-type hypersensitivity to the common opportunistic pathogen, Candida albicans. Further, we found that wavelengths in the ultraviolet A region of the solar spectrum (320-400 nm), devoid of ultraviolet B, were equally effective in activating immune suppression as ultraviolet A + B radiation. Here we report on the mechanisms involved. Maximal immune suppression was found when mice were exposed to solar-simulated ultraviolet radiation 7-9 d post immunization. No immune suppression was found in ultraviolet-irradiated mice injected with monoclonal anti-interleukin-10 antibody, or mice exposed to solar-simulated ultraviolet radiation and injected with recombinant interleukin-12. Suppressor lymphocytes were found in the spleens of mice exposed to ultraviolet A + B radiation. In addition, antigen-specific suppressor T cells (CD3+, CD4+, DX5+) were found in the spleens of mice exposed to ultraviolet A radiation. Applying liposomes containing bacteriophage T4N5 to the skin of mice exposed to solar-simulated ultraviolet A + B radiation, or mice exposed to ultraviolet A radiation, blocked immune suppression, demonstrating an essential role for ultraviolet-induced DNA damage in the suppression of established immune reactions. These findings indicate that overlapping immune suppressive mechanisms are activated by ultraviolet A and ultraviolet A + B radiation. Moreover, our findings demonstrate that ultraviolet radiation activates similar immunologic pathways to suppress the induction of, or the elicitation of, the immune response.     

Herpes simplex virus load in bronchoalveolar lavage fluid is related to poor outcome in critically ill patients

Objective  To evaluate the relationship between the HSV-1 and -2 loads in BAL fluid (BALF) and clinical outcome. Design  Retrospective study. Setting  The general intensive care unit of the University Hospital Maastricht. Patients  Five hundred and twenty-one BALF samples from 462 patients were included. Patients were divided into three groups; (1) patients admitted to the hospital <48 h before lavage (Community), (2) patients admitted to the ICU >48 h before lavage (ICU) and (3) the remaining patients (non-ICU group). Interventions  No additional interventions were conducted. Measurements and results  HSV-1 and HSV-2 loads were determined by real-time polymerase chain reaction (PCR). HSV-1 DNA was detected in 4.3% (4/92) of samples in the community group, 15% (18/121) in the non-ICU group and in 32% (99/308) of the ICU group. In the age group <50 years HSV-1 DNA was less frequently isolated compared to the age group ≥50 years (16/129 (12%) versus 187/376 (25%), respectively, OR = 2.6; P < 0.001). HSV-1 loads of >10⁵ genome equivalents (ge)/ml were associated with an increased 14-day in-hospital mortality compared to patients with a HSV-1 load ≤10⁵ ge/ml in BALF (41 vs. 20%, respectively, P = 0.001). HSV-1 pneumonia was histologically proven in two patients with a HSV-1 load exceeding 10⁵ ge/ml. Conclusions  HSV-1 occurred more in critically ill patients and high loads in BALF were associated with an increased mortality. The higher mortality observed in patients with HSV-1 load >10⁵ ge/ml enforces its clinical relevance and necessitates to start randomized medical intervention studies. The abstract of this article was published in ESCV/SGM Conference, Birmingham, as an oral presentation.     

Rationale and clinical application of alkylphospholipid analogues in combination with radiotherapy

Concurrent treatment with radiotherapy and chemotherapy has emerged as an effective strategy to improve clinical outcome of cancer. In addition to combining radiation with classical anticancer agents, several new biological response modifiers are under investigation in pre-clinical and clinical studies. Synthetic alkylphospholipids are anticancer agents that in contrast to most anticancer drugs, do not target DNA, but insert in the plasma membrane and subsequently induce a broad range of biological effects, ultimately leading to cell death. Alkylphospholipids kill tumor cells directly by induction of both apoptotic and non-apoptotic cell death, and indirectly by interference with critical signal transduction pathways involved in phospholipid metabolism and survival. Due to their distinct mode of action, these drugs are considered as attractive candidates to combine with radiotherapy. In this review, we will discuss several alkylphospholipids that reached clinical application. These include first-generation alkyl-lysophospholipids edelfosine and ilmofosine, second-generation alkylphosphocholine-prototype miltefosine and more recently developed analogues perifosine and erucylphosphocholine. We focus on mechanisms of action and the rationale to combine these agents with radiotherapy. The preclinical results on molecular targeting underlying this approach will be reviewed, concluded with first clinical data on combined treatment of radiotherapy with perifosine.     

Time-varying prognostic value of primary tumor sidedness in metastatic colorectal cancer: A population-based study and meta-analysis

We studied the prognostic value of primary tumor sidedness in metastatic colorectal cancer over time and across treatment lines. Population data on synchronous metastatic colorectal cancer patients were extracted from the Netherlands Cancer Registry and SEER database. Pubmed, EMBASE and Cochrane library were searched for prospective studies on metastatic colorectal cancer to conduct a meta-analysis. Inclusion criteria consisted of metastatic disease, systemic treatment with palliative intent and specification of primary tumor location. Data were pooled using a random-effects model. For the population-based data, multivariable Cox models were constructed. The Grambsch-Therneau test was conducted to evaluate the potential time-varying nature of sidedness. Meta-regression incorporating treatment-line as variable was conducted to test the pre-specified hypothesis that the prognostic value of sidedness varies over time. Analysis of 12 885 and 16 160 synchronous metastatic colorectal cancer patients registered in the Netherlands Cancer Registry and SEER database, respectively, indicated a time-varying prognostic value of sidedness (P < .01). Thirty-one studies were selected for the meta-analysis (9558 patients for overall survival analysis). Pooled univariable hazard ratio_{left-sided/right-sided} for overall survival was 0.71 (95% CI: 0.65-0.76) in 1st-line, 0.76 (0.54-1.06) in 2nd-line and 1.01 (0.86-1.19) in 3rd-line studies. Hazard ratios were significantly influenced by treatment line (P = .035). The prognostic value of sidedness of the primary tumor in metastatic colorectal cancer patients treated with palliative systemic therapy decreases over time since diagnosis, suggesting that sidedness may not be a useful stratification factor in late-line trials. This decrease in prognostic value should be taken into account when providing prognostic information to patients.     

Sandwich corrected standard errors in family-based genome-wide association studies

Given the availability of genotype and phenotype data collected in family members, the question arises which estimator ensures the most optimal use of such data in genome-wide scans. Using simulations, we compared the Unweighted Least Squares (ULS) and Maximum Likelihood (ML) procedures. The former is implemented in Plink and uses a sandwich correction to correct the standard errors for model misspecification of ignoring the clustering. The latter is implemented by fast linear mixed procedures and models explicitly the familial resemblance. However, as it commits to a background model limited to additive genetic and unshared environmental effects, it employs a misspecified model for traits with a shared environmental component. We considered the performance of the two procedures in terms of type I and type II error rates, with correct and incorrect model specification in ML. For traits characterized by moderate to large familial resemblance, using an ML procedure with a correctly specified model for the conditional familial covariance matrix should be the strategy of choice. The potential loss in power encountered by the sandwich corrected ULS procedure does not outweigh its computational convenience. Furthermore, the ML procedure was quite robust under model misspecification in the simulated settings and appreciably more powerful than the sandwich corrected ULS procedure. However, to correct for the effects of model misspecification in ML in circumstances other than those considered here, we propose to use a sandwich correction. We show that the sandwich correction can be formulated in terms of the fast ML method.