Recurrent shield ulcer following penetrating keratoplasty for keratoconus associated with vernal keratoconjunctivitis

Though penetrating keratoplasty for keratoconus secondary to vernal keratoconjunctivitis (VKC) invariably carries a good prognosis, the postoperative course may be complicated by recurrent epitheliopathy. Despite good medical control of VKC shield ulcer is still a possibility.     

The impact of posterior approach for total hip arthroplasty on early complications

The optimal approach for total hip arthroplasty is hotly debated. We analysed 121 consecutive patients who underwent primary total hip arthroplasty during the first three years of practice of a newly appointed consultant. Patients were analysed for pain scores (1-6), function scores (1-6) and satisfaction levels (1-5). All complications, during and after surgery, were noted with special emphasis on incidence of dislocation and factors contributing to it. The results were gratifying and were comparable with major series of total hip replacement via the posterior approach. No patient had a dislocation. One hundred and five patients (89%) had no or minimal pain after the surgery. Eighty-six patients (73%) were mobilising without a stick. There were no major intra-operative complications and most (84%) patients rated the operation 'very good' at one year follow-up. We conclude that the posterior approach, already known to cause less blood loss and optimum component positioning, is compatible with a low overall rate of early complications especially dislocation.     

Use of autologous cultured limbal and conjunctival epithelium in a patient with severe bilateral ocular surface disease induced by acid injury: a case report of unique application

PURPOSE: Reconstruction of the ocular surface in a case of severe bilateral partial limbal stem cell deficiency (LSCD) with extensive symblephara using autologous cultured conjunctival and limbal epithelium. CASE REPORT: A 31-year-old woman presented with severe bilateral ocular surface disease with partial limbal stem cell deficiency, symblephara, lid and facial scarring, with a vision of 20/400 and counting fingers at 1 m in both eyes. Limbal and conjunctival tissue was harvested from the healthy-appearing left eye and used to generate two sheets of composite epithelium consisting of central limbal and peripheral conjunctival cells. The limbal tissues were explanted in the central region while the conjunctival tissues were explanted on the periphery of the deepithelialized human amniotic membrane (HAM) and nurtured using human corneal epithelial cell medium. After successful generation of a monolayer from both tissues had been confirmed, the composite of cultivated limbal and conjunctival epithelium with HAM was transplanted in each eye after excision of fibrous tissue and release of symblephara. One year postoperatively, the patient had a best spectacle-corrected visual acuity of 20/40 in the right eye (preoperative acuity 20/400) and counting fingers at 1 m in the left eye (same as preoperative) with a stable ocular surface. CONCLUSIONS: Autologous cultured epithelial transplantation is as an excellent option in selected patients with bilateral partial LSCD with small area(s) of healthy limbus in either eye and avoids the attendant risk of rejection and cost and potential toxicity of immunosuppression in allogeneic tissue transplantation. This case also highlights the feasibility of generating a composite culture of limbal and conjunctival epithelium using a single amniotic membrane.     

Engineering high-affinity PD-1 variants for optimized immunotherapy and immuno-PET imaging

Signaling through the immune checkpoint programmed cell death protein-1 (PD-1) enables tumor progression by dampening antitumor immune responses. Therapeutic blockade of the signaling axis between PD-1 and its ligand programmed cell death ligand-1 (PD-L1) with monoclonal antibodies has shown remarkable clinical success in the treatment of cancer. However, antibodies have inherent limitations that can curtail their efficacy in this setting, including poor tissue/tumor penetrance and detrimental Fc-effector functions that deplete immune cells. To determine if PD-1:PD-L1–directed immunotherapy could be improved with smaller, nonantibody therapeutics, we used directed evolution by yeast-surface display to engineer the PD-1 ectodomain as a high-affinity (110 pM) competitive antagonist of PD-L1. In contrast to anti–PD-L1 monoclonal antibodies, high-affinity PD-1 demonstrated superior tumor penetration without inducing depletion of peripheral effector T cells. Consistent with these advantages, in syngeneic CT26 tumor models, high-affinity PD-1 was effective in treating both small (50 mm³) and large tumors (150 mm³), whereas the activity of anti–PD-L1 antibodies was completely abrogated against large tumors. Furthermore, we found that high-affinity PD-1 could be radiolabeled and applied as a PET imaging tracer to efficiently distinguish between PD-L1–positive and PD-L1–negative tumors in living mice, providing an alternative to invasive biopsy and histological analysis. These results thus highlight the favorable pharmacology of small, nonantibody therapeutics for enhanced cancer immunotherapy and immune diagnostics.Lymphocyte activity is regulated by a complex series of stimulatory, costimulatory, and inhibitory cues. Although the central regulator of T-lymphocyte function is the T-cell receptor (TCR), the balance between positive and negative signaling inputs deeply shapes the response that lymphocytes mount upon exposure to reactive peptide/MHC complexes (1). As a cause and consequence of their development, cancer cells accumulate somatic mutations that distinguish them from noncancerous cells. These tumor “neo-antigens” can be recognized by the TCRs of cytotoxic T lymphocytes and in many cases prompt an endogenous antitumor response by the immune system (2). Thus, immunogenic tumors must exploit, or at least indirectly benefit from, immunosuppressive pathways to escape immune destruction (3).Expression of the inhibitory programmed cell death ligand-1 (PD-L1) in the tumor environment is a key exemplar of this phenomenon. PD-L1 normally serves to prevent autoimmunity by engaging its receptor, programmed cell death protein-1 (PD-1), on activated T cells (4). Upon binding to either of its two ligands, PD-L1 and PD-L2, PD-1 initiates an inhibitory signaling cascade through its intracellular signaling domains, including an immunoreceptor tyrosine-based inhibitory motif and immunoreceptor tyrosine-based switch motif (5). The result is activation of SHP phosphatases that oppose TCR signaling. Although beneficial in preventing excessive or harmful inflammation under normal conditions, in the context of cancer, tumor and stromal PD-L1 expression presents a barrier to immune function by contributing to the exhaustion of the antitumor lymphocytes that might otherwise clear the malignancy (6). Consequently, the PD-1:PD-L1 pathway has emerged as a critical target for cancer immunotherapy, and monoclonal antibodies that block either side of this inhibitory interaction have demonstrated impressive activity across a broad set of cancer subtypes, even at advanced and metastatic stages of disease (7–11).Despite their proven utility, antibodies have specific drawbacks as therapeutics, which may be especially pertinent when targeting the PD-1:PD-L1 signaling pathway. For example, PD-1–expressing effector T cells are found infiltrated within solid tissue of PD-L1–expressing tumors (6). This is problematic for antibodies, which are impeded from entering tumors due to their large size (12). It follows that antibodies may therefore fail to completely antagonize PD-1:PD-L1 signaling at the intended therapeutic site within tumors, leading to suboptimal efficacy. An additional limitation of antibodies is their ability to activate cytotoxic immune responses through natural killer cells and macrophages (e.g., ADCC/ADCP) (13). Although this Fc-mediated effect is in fact required for the efficacy of some immunotherapeutic antibodies (14), it may in part be counterproductive in the case of this receptor–ligand pair. Both PD-1 and PD-L1 are expressed on the surface of antitumor cytotoxic T cells (15, 16), and as such, antibodies targeting PD-1 and PD-L1 may paradoxically result in the undesirable depletion of the very lymphocytes they are intended to activate. Consistent with this hypothesis, treatment with anti–PD-1 antibodies of anti–PD-1 antibodies has been reported to correlate with lower circulating T-cell numbers in patients (17).To date, most studies of PD-1 or PD-L1 blockade have used monoclonal antibodies. In principle, a soluble fragment of the PD-1 ectodomain could be administered as a competitive antagonist of PD-L1. At 14 kDa in size, this agent would be approximately an order of magnitude smaller than a monoclonal antibody (150 kDa) and also lack an antibody Fc moiety. We thus sought to determine whether such an alternative agent could exhibit improved antitumor responses by avoiding antibody-intrinsic limitations.     

Significance of Cardiac Computed Tomography Incidental Findings in Acute Chest Pain

Background

Coronary computed tomography angiography might improve the management of patients presenting to the emergency department with acute chest pain; however, noncoronary incidental findings are frequently detected. The prevalence and clinical significance of these findings have not been well described.

Methods

Consecutive patients presenting to the emergency department with acute chest pain and inconclusive initial evaluation between May 2005 and May 2007 underwent 64-slice coronary computed tomography angiography before hospital admission with noncoronary incidental findings immediately reported. An expert panel adjudicated which incidental findings changed in-hospital patient management, and projections for additional testing were based on standard medical practice.

Results

Among 395 patients (37.0% were female, mean age 53 ± 12 years), incidental findings were detected in 44.8% (n = 177): noncalcified pulmonary nodules (n = 94, 23.8%), simple liver cysts (n = 26, 6.6%), calcified pulmonary nodules (n = 16, 4.1%), and contrast-enhancing liver lesions (n = 9, 2.3%). In-hospital management was changed because of incidental finding reporting in 5 patients (1.3%), and a potential alternative diagnosis was offered in another 16 patients (4.1%). Subsequent diagnostic imaging tests were recommended in 81 patients (20.5%), including 74 chest computed tomography scans. After 6 months, biopsy was performed in 3 patients, revealing cancer in 2 (0.5%) who underwent successful tumor resection.

Conclusion

Clinically important findings are detected in up to 5% of patients with a lead symptom of acute chest pain and low to intermediate likelihood of acute coronary syndrome, but only few directly change patient management; 21% are recommended for further imaging tests, resulting in invasive procedures and detection of cancer in few patients.