Posttransplant Lymphoproliferative Disorder After Clinical Islet Transplantation: Report of the First Two Cases.

We report the first two cases of posttransplant lymphoproliferative disorder (PTLD) in recipients of islet transplants worldwide. First, a 44-year-old recipient of three islet infusions developed PTLD 80 months after his initial transplantation, presenting with abdominal pain and diffuse terminal ileum thickening on imaging. He was treated with surgical excision, reduction of immunosuppression, and rituximab. Seven months later, he developed central nervous system PTLD, presenting with vertigo and diplopia; immunosuppression was discontinued, resulting in graft loss, and he was given high-dose methotrexate and underwent consolidative autologous stem cell transplantation. He remains in remission 37 months after the initial diagnosis. Second, a 58-year-old female recipient of two islet infusions developed PTLD 24 months after initial islet infusion, presenting with pancytopenia secondary to extensive bone marrow involvement. Immunosuppression was discontinued, resulting in graft loss, and she received rituximab and chemotherapy, achieving complete remission. Both patients were monomorphic B cell PTLD subtype by histology and negative for Epstein-Barr virus in tissue or blood. These cases document the first occurrences of this rare complication in islet transplantation, likely secondary to prolonged, intensive immunosuppression, and highlight the varying clinical manifestations of PTLD. Further studies are needed to determine incidence rate and risk factors in islet transplantation.

Low-loss reciprocal optical terminals for two-way time-frequency transfer.

We present the design and performance of a low-cost, reciprocal, compact free-space terminal employing tip/tilt pointing compensation that enables optical two-way time-frequency transfer over free-space links across the turbulent atmosphere. The insertion loss of the terminals is ∼1.5 dB with total link losses of 15 dB, 24 dB, and 50 dB across horizontal, turbulent 2-km, 4-km, and 12-km links, respectively. The effects of turbulence on pointing control and aperture size, and their influence on the terminal design, are discussed.

Canadian consensus: inhibition of ALK-positive tumours in advanced non-small-cell lung cancer.

Anaplastic lymphoma kinase (alk) is an oncogenic driver in non-small-cell lung cancer (nsclc). Chromosomal rearrangements involving the ALK gene occur in up to 4% of nonsquamous nsclc patients and lead to constitutive activation of the alk signalling pathway. ALK-positive nsclc is found in relatively young patients, with a median age of 50 years. Patients frequently have brain metastasis. Targeted inhibition of the alk pathway prolongs progression-free survival in patients with ALK-positive advanced nsclc. The results of several recent clinical trials confirm the efficacy and safety benefit of crizotinib and ceritinib in this population. Canadian oncologists support the following consensus statement: All patients with advanced nonsquamous nsclc (excluding pure neuroendocrine carcinoma) should be tested for the presence of an ALK rearrangement. If an ALK rearrangement is present, treatment with a targeted alk inhibitor in the first-line setting is recommended. As patients become resistant to first-generation alk inhibitors, other treatments, including second-generation alk inhibitors can be considered.

Comb-calibrated laser ranging for three-dimensional surface profiling with micrometer-level precision at a distance.

Non-contact surface mapping at a distance is interesting in diverse applications including industrial metrology, manufacturing, forensics, and artifact documentation and preservation. Frequency modulated continuous wave (FMCW) laser detection and ranging (LADAR) is a promising approach since it offers shot-noise limited precision/accuracy, high resolution and high sensitivity. We demonstrate a scanning imaging system based on a frequency-comb calibrated FMCW LADAR and real-time digital signal processing. This system can obtain three-dimensional images of a diffusely scattering surface at stand-off distances up to 10.5 m with sub-micrometer accuracy and with a precision below 10 µm, limited by fundamental speckle noise. Because of its shot-noise limited sensitivity, this comb-calibrated FMCW LADAR has a large dynamic range, which enables precise mapping of scenes with vastly differing reflectivities such as metal, dirt or vegetation. The current system is implemented with fiber-optic components, but the basic system architecture is compatible with future optically integrated, on-chip systems.

Clinicopathologic characteristics and survival outcomes of patients with advanced esophageal, gastroesophageal junction, and gastric adenocarcinoma: a single-institution experience.

UNLABELLED: Most patients with gastric or gastroesophageal junction (gej) cancer are diagnosed with inoperable advanced or metastatic disease. In these cases, chemotherapy is the only treatment demonstrating survival benefit. The present study compares clinicopathologic characteristics and survival outcomes for patients with advanced esophageal, gej, and gastric adenocarcinoma treated with first-line chemotherapy [epirubicin-cisplatin-5-fluorouracil (ecf), epirubicin-cisplatin-capecitabine (ecx), or etoposide-leucovorin-5-fluorouracil (elf)] or best supportive care (bsc) at our institution with those for historical controls. METHODS: We retrospectively reviewed medical information for 401 patients with newly diagnosed advanced esophageal, gej, or gastric adenocarcinoma treated with first-line chemotherapy (ecf, ecx, or elf) or bsc from January 1, 2004, through December 31, 2010. Descriptive statistics were used to compare the data collected with data for historical control patients. RESULTS: Of the study patients, 93% were diagnosed with metastatic disease (n = 374), and 63% received bsc only (n = 251). The main reasons that patients received bsc only included poor Eastern Cooperative Oncology Group performance status (55%), patient decision (31%), and comorbidities (14%). Of the remaining patients, 98 (24%) received ecf or ecx and 52 (13%) received elf as first-line treatment. Median overall survival was significantly longer in patients treated with ecf or ecx or with elf than in those receiving bsc (12.7 months vs. 12.7 months vs. 5.5 months respectively). Chemotherapy also significantly reduced the risk of death (64% reduction with ecf or ecx, 58% with elf). CONCLUSIONS: We confirmed the substantial overall survival benefit of combination chemotherapy compared with bsc, with better survival in our patient population than in historical controls. However, novel treatment options are still warranted to improve outcomes in this patient population.

The immunology of the eye and its systemic interactions.

Advances in immunology have provided us with new insights about the ocular inflammatory response. Still, the etiology and pathophysiology of many uveitides remain unclear. Factors such as the blood-ocular barrier, sequestration of retinal antigens, local immunomodulators in the aqueous humor, and anterior chamber-associated immune deviation (ACAID) interact and render the eye an immunologically "privileged" site. On the other hand, human leukocyte antigen complex (HLA) interactions, the immunopathology of hypersensitivity reactions, T-cell mediated disease, and autoimmunity are associated pathogenic mechanisms of immune-related ocular disease. In this paper, we review some of the immunologic characteristics of the eye and their relationship to intraocular inflammation. Clinocopathologic correlations are presented. Also, perspectives of current and future research, as well as diagnostic and treatment strategies, are discussed.

The immunology of corneal graft rejection.

Corneal transplantation is the most successful of organ transplants due to the fact that the eye is an immunologically privileged site, and the cornea is an immunologically privileged tissue. The factors responsible for this include presence of the blood-aqueous barrier, the avascularity of the cornea, the absence of classic antigen-presenting cells (APCs) in the central cornea, inhibitory factors in the aqueous humor, the phenomenon known as anterior chamber-associated immune deviation (ACAID), and the intraocular expression of Fas ligand. Loss of ocular immune privilege can occur with breaching of the blood-ocular barrier, corneal neovascularization, migration of classic APCs to the center of the cornea, loss of inhibitory factors in aqueous humor, abrogation of ACAID, and loss of Fas ligand expression within the anterior chamber. The purpose of this review is to analyze these events and how they relate to corneal graft rejection. A discussion on future research and therapeutic modalities is provided.

The role of ultrasound biomicroscopy in predicting the result of temporal artery biopsy in temporal arteritis patients: a preliminary study.

PURPOSE: Temporal artery biopsy is considered the gold standard for the diagnosis of temporal arteritis (TA). However, complications following this procedure may occur. The goal of this study is to evaluate if ultrasound biomicroscope (UBM) findings are useful in predicting the result (positive or negative) of temporal artery biopsy in patients with TA. METHODS: Twenty-six consecutive patients with clinical diagnosis of TA seen at the Department of Ophthalmology, Royal Victoria Hospital, Montreal, Canada, were involved in this study. All patients were submitted to UBM before temporal artery biopsy. Eight patients presented histopathologic findings consistent with the diagnosis of TA. Thus, UBM findings of these patients were compared with those from 18 patients with negative biopsy. On UBM we searched for the presence of a hypoechoic effect surrounding the walls of the temporal arteries, the so-called halo sign, as well as an intra-arterial middle reflexive filling, the so-called intra-arterial filling. RESULTS: The halo sign and/or the intra-arterial filling were found in 8 (100%) of 8 patients with biopsy-proven TA. However, 10 (55.5%) of 18 patients with a negative biopsy presented one or both of these two UBM findings. On the other hand, the absence of these two parameters on the UBM of a patient with TA strongly suggests that the temporal artery biopsy will be negative (negative predictive value=100%). CONCLUSIONS: This preliminary work suggests that UBM may play a role in predicting a negative result of the temporal artery biopsy in patients with TA. In the present series approximately 30% of the patients could be spared this surgical procedure and its possible complications.

Invited Article: A compact optically coherent fiber frequency comb.

We describe the design, fabrication, and performance of a self-referenced, optically coherent frequency comb. The system robustness is derived from a combination of an optics package based on polarization-maintaining fiber, saturable absorbers for mode-locking, high signal-to-noise ratio (SNR) detection of the control signals, and digital feedback control for frequency stabilization. The output is phase-coherent over a 1-2 µm octave-spanning spectrum with a pulse repetition rate of ∼200 MHz and a residual pulse-to-pulse timing jitter <3 fs well within the requirements of most frequency-comb applications. Digital control enables phase coherent operation for over 90 h, critical for phase-sensitive applications such as timekeeping. We show that this phase-slip free operation follows the fundamental limit set by the SNR of the control signals. Performance metrics from three nearly identical combs are presented. This laptop-sized comb should enable a wide-range of applications beyond the laboratory.

Nucleolar organizer regions (NOR) in hyperplastic and neoplastic prostate disease.

Nucleolar organizer regions (NOR) are DNA loops encoding ribosomal RNA production. Detectable by the argyrophilia (AgNOR) of associated proteins, AgNOR numbers correlate with growth fraction and may have diagnostic and prognostic utility in human tumors. Because nucleolar size is important in the diagnosis of prostate carcinoma, we compared AgNOR counts in benign, atypical, and malignant prostate lesions and correlated them with nucleolar diameter. We counted AgNOR in benign prostatic hyperplasia, atypical adenomatous hyperplasia, intraductal dysplasias, and carcinomas of various Gleason grades. The mean AgNOR count per nucleus for benign prostatic hyperplasia nuclei was 4.51; for atypical adenomatous hyperplasia, 5.64; for intraductal dysplasias, 7.35; for carcinoma of Gleason grades 2 + 3, 8.87; and for carcinoma Gleason grades 4 + 5, 10.42. Counts in the carcinomas and intraductal dysplasias were significantly different from those of benign prostatic hyperplasia. Mean AgNOR counts of the carcinomas and intraductal dysplasias did not overlap with those of benign prostatic hyperplasia, suggesting that intraductal dysplasia shares more with carcinoma than benign prostatic hyperplasia. Nucleolar diameters increased from benign prostatic hyperplasia to atypical adenomatous hyperplasia, intraductal dysplasias, and the carcinomas, correlating with increasing AgNOR counts. Nucleolar diameters in the carcinomas were significantly different than those of benign prostatic hyperplasia; those in intraductal dysplasias were not. Our findings suggest that AgNOR counts are superior to nucleolar diameters alone in separating intraductal dysplasias from benign prostatic hyperplasia but provide no additional information in diagnosing carcinoma.

Increased immunohistochemical expression of neutral metalloendopeptidase (enkephalinase; EC 3.4.24.11) in villi of the human placenta with pre-eclampsia.

The purpose of this study was to identify the presence of placental neutral metalloendopeptidase (NEP; enkephalinase; EC 3.4.24.11) in human normotensive and pre-eclamptic pregnancy. The localization of NEP in placentae from normotensive, chronic hypertensive and pre-eclamptic pregnancies was carried out on fresh frozen tissues by using a monoclonal primary antibody developed against human common acute lymphoblastic leukaemia antigen (CD10) together with the avidin-biotin-peroxidase method. In placentae from normotensive, chronic hypertensive and superimposed pre-eclamptic pregnancies, intense staining was found in the extravillous trophoblast, and also in fibroblasts of the chorionic plate and stem villi. Light to moderate staining was noted in the villous-associated trophoblast and in some cells from the villous core. In cases of pre-eclampsia, very intense staining was detected not only on the surface, but also in the cytoplasm of the villous-associated trophoblast. The increased expression of placental NEP in pre-eclampsia suggests that this enzyme may be involved in the regulation of the local concentration of circulating biologically active peptides at the fetomaternal interface, and thus could be implicated in the pathophysiological changes of this syndrome.

Lymphocyte subpopulations in uveitis.

We have used a fluorescence-activated cell sorter to study the lymphocyte subpopulations in the intraocular fluids and peripheral blood of 27 patients with uveitis. T lymphocytes predominated in intraocular fluids. A wide variation in the ratio of Leu 3a-positive (helper) cells to Leu 2a-positive (suppressor) cells was found. No correlation was seen between the specific lymphocyte subpopulations and the clinical uveitis activity or steroid treatment. A statistically significant correlation was found between T-cell subsets present in aqueous humor and peripheral blood. Many lymphocytes seem to be present in intraocular fluids secondary to a breakdown of the blood-ocular barrier.

Primary choroidal melanoma in a patient with previous cutaneous melanoma.

A 67-year-old woman with a history of a skin melanoma that was excised 7 years previously had a 6-month history of decreased vision in her right eye. A choroidal melanoma was diagnosed clinically, and the eye was enucleated. The results of a histopathological examination revealed a primary uveal melanoma. Slides of the skin melanoma were obtained, and the initial diagnosis was confirmed. In an attempt to illustrate a biological difference between the 2 melanomas, immunohistochemical studies were performed on sections of the 2 specimens using S-100 protein, HMB-45, and S-100-beta. Primary cutaneous and choroidal melanomas appearing in a patient with no predisposition are rare; this is believed to be only the fifth such case reported in the literature.

The VF-14 index of functional visual impairment in candidates for a corneal graft.

PURPOSE: To validate the Visual Function-14 (VF-14) index of functional visual impairment in candidates for a corneal graft. METHODS: One hundred thirty-four patients who were candidates for a corneal graft participated in this study between August 1996 and February 1997. Demographic, ocular history, best-corrected visual acuity, and detailed ocular examination data were collected. Functional visual impairment information was obtained by telephone interviews using the following: VF-14, SF-36 (Short Form-36, a more generic measure of general health function), and Visual Symptom Score, and four questions measuring the overall amount of trouble with vision, dissatisfaction with vision, ocular pain, and discomfort. RESULTS: The average age of corneal graft candidates was 64 +/- 18 years (range, 18 to 90 years) and 60% were women. The most frequent corneal disease was pseudophakic bullous keratopathy (41%). Ocular comorbidities included glaucoma or ocular hypertension (30%) and cataract (19%). The mean best-corrected visual acuity of the eye scheduled for surgery was 1.33 +/- 0.56 logMAR whereas the best eye best-corrected visual acuity was 0.36 +/- 0.44 logMAR. The mean VF-14 score was 73% +/- 26%, and the internal consistency was high, with a Cronbach alpha value of 0.94. The VF-14 correlated strongly with the best eye best-corrected visual acuity. It also correlated strongly with the Visual Symptom Score, the global measures of trouble and dissatisfaction with vision. Candidates for a corneal graft had low scores for all eight general health concepts evaluated with the SF-36, and the VF-14 correlated with seven of the eight SF-36 subscales. CONCLUSION: The VF-14 is a valid measure of functional visual impairment in candidates for a corneal graft. The Visual Symptom Score and the SF-36 are also useful indices in such patients.

Racial bias in using USMLE step 1 scores to grant internal medicine residency interviews.

PURPOSE: To determine whether the United States Medical Licensing Examination (USMLE) Step 1 score, commonly used in screening residency applicants for interviews, eliminates a greater proportion of African-American applicants from the interview process at an internal medicine residency program. METHOD: A survey of internal medicine residency programs was performed to determine the prevalence of using USMLE Step 1 scores to grant interviews. A cohort of applicants was analyzed by constructing a database of USMLE Step 1 scores from the Electronic Residency Application Service (ERAS) database of applications from U.S., Canadian, and osteopathic medical schools to one residency program in 2000. Each applicant was classified as African American or non-African American. Rejection rates were then calculated for each five-point increment from a hypothetical threshold rejection score of <180 to <215. RESULTS: Responses were received from 259 residency programs (69%), and 92% used the USMLE Step 1 score in deciding which applicants to interview. A cohort of 626 non-African-American and 47 African-American applicants was analyzed. The proportion of applicants below each incremental threshold score was significantly higher for African-American applicants (p <.05 at each level). Depending on the threshold score used, an African-American applicant was three to six times less likely to be offered an interview. CONCLUSIONS: When USMLE Step 1 scores are used to screen applicants for a residency interview, a significantly greater proportion of African-American students will be refused an interview.

Activated T lymphocytes in uveitis.

Two colour flow cytometry techniques were used to assess the activation stages of peripheral and intraocular T lymphocytes in uveitis. Increased numbers of T lymphocytes bearing the interleukin-2 (IL-2) receptors were found in intraocular fluids or peripheral blood or both of 35/51 patients with uveitis. This increased expression of IL-2 receptors on lymphocytes correlated with increased expression of other early T lymphocyte activation markers, HLA-DR and L-35. Both T helper cells (Leu-3A+) and suppressor cells (Leu 2A+) were activated in vivo. A positive correlation was seen between lymphocyte activation and clinical uveitis activity. In idiopathic uveitis activation of Leu-3A lymphocytes (helper/inducer) was significantly increased, and intraocular activation of the Leu-2A lymphocytes (cytotoxic/suppressor) was significantly decreased. These data show that some patients with idiopathic uveitis have a perturbation of T helper cells. Twenty-two of 31 patients with idiopathic uveitis, not associated with systemic disease, had increased peripheral T lymphocyte activation. This finding indicates that in some inflammations believed to be restricted to the eye an abnormal systemic immune activation exists.

Intraocular lymphoma: immunological and cytological analysis.

We retrospectively reviewed the cytology and immunohistology of vitreous specimens from nine patients with intraocular lymphoma (ocular reticulum cell sarcoma). A single vitreous biopsy specimen was not always adequate to establish the diagnosis in this condition. Cytological evaluation was more accurate than lymphocyte surface marker analysis to differentiate lymphoma from uveitis. The immunological features of these tumours indicate a heterogeneous group of intraocular lymphomas.

DNA index and S phase fraction in uveal malignant melanomas.

AIMS: To predict 5 year survival in patients with uveal malignant melanomas DNA indices were studied. METHODS: Using 45 paraffin embedded uveal malignant melanomas, the DNA index and S phase fraction of each tumour were the predictor variables recorded. RESULTS: Using the Cox proportional hazards model, aneuploid tumours and tumours which had an S phase fraction greater than 4% were significant predictors of early death. In order to demonstrate a biological gradient between a larger DNA index and shorter survival time, linear regression and transformed linear regression models were used. However, no such gradient could be demonstrated. CONCLUSION: Although this study shows promise for the use of DNA studies in the prognosis of uveal malignant melanoma, the exact role of these techniques remains to be determined.

Contrast and glare testing in the assessment of visual performance of candidate eyes for penetrating keratoplasty.

PURPOSE: To determine whether visual acuity (VA) measurements performed at low levels of contrast and glare are a better diagnostic tool for determining whether corneal clouding warrants surgery. METHODS: Fifty-nine subjects were recruited from among the candidates for corneal graft. Monocular VA was measured with three Regan contrast VA charts: 96, 25, and 11%, with and without glare provided by the Brightness Acuity Tester (BAT). The discriminative ability of the tests was estimated using the area (AR) under receiver operating characteristic (ROC) curves. Associations between the different VA tests and the Visual Function Index (VF-14) score were studied, using Spearman coefficients. RESULTS: When comparing candidate eyes with contralateral eyes with corneal disease, lower contrasts VA tests provided greater discriminative power. VA measurements made with glare also tended to provide greater discrimination. In fact, discrimination was best with 11% contrast VA with glare, but "testability" was poor. The most practical test in a clinical setting, which retained high discriminative ability (0.798), was the 25% contrast VA with glare. The eye with the best VA correlated strongly with the VF-14, especially at 25% contrast without glare, resulting in an Rs of -0.729. CONCLUSION: Twenty-five percent contrast VA with BAT could help the practitioner to decide whether a corneal transplant is warranted when symptoms of reduced vision are more important than what high-contrast VA might indicate.

Corneal allograft rejection in rabbits.

We performed a phase I study to assess the therapeutic efficacy of an anti-T cell monoclonal antibody conjugated with ricin A-chain in a corneal graft rejection model. Corneal allografts were exchanged between Dutch and New Zealand rabbits. Rejections occurred within 16-22 days in untreated animals. Graft rejection was delayed by topical or retrobulbar cyclosporine, but not by subconjunctival injections of a murine anti-rabbit T cell monoclonal antibody, nor by either subconjunctival or intravenous F(ab')2-ricin conjugate.