Prospective trial of targeted radioimmunotherapy with Y-90 ibritumomab tiuxetan (Zevalin) for front-line treatment of early-stage extranodal indolent ocular adnexal lymphoma.

BACKGROUND: To determine the efficacy and side-effects of (90)Y ibritumomab tiuxetan (Zevalin) as front-line treatment in patients with early-stage extranodal indolent lymphoma of the ocular adnexa (orbit, conjunctiva, or eyelid). PATIENTS AND METHODS: From August 2004 to November 2007, 12 patients with stages I-E extranodal indolent lymphoma of the ocular adnexa were enrolled in a prospective trial of rituximab followed by (90)Y ibritumomab tiuxetan (Zevalin therapeutic regimen). For each patient, clinical examinations and imaging studies were used to document response to therapy using the The International Working Group response criteria. All patients had (111)In ibritumomab tixuetan imaging to confirm expected biodistribution before (90)Y-Zevalin therapy; in addition, three patients had an optional single photon emission computed tomography-computed tomography scan to estimate the absorbed radiation dose to the orbital and ocular tissues. RESULTS: The study included seven women and five men. The median age was 60 years (range 22-79). Nine patients had mucosa-associated lymphoid tissue lymphoma of conjunctiva or orbit; three patients had grades 1-2 follicular lymphoma of orbit. One patient who had been deemed stage I-E initially was found to have another lesion in her deltoid muscle on positron emission tomography 2 weeks after enrollment. She was kept on trial although her disease was reclassified as stage IV due to this single additional (biopsy-proven) site. Ten patients had a complete response and two partial response (PR) within 3 months of treatment. One patient had a recurrence in the upper eyelid 6 months after an initial PR; he then received 30 Gy of external-beam radiotherapy (EBRT). His disease later progressed again in the orbit and he is currently being considered for other treatments. A second patient who attained a PR has remained stable with no progression 12 months after treatment. With a median follow-up time of 20 months (range 6-44 months), there were no cases of distant (extraorbital) relapse. All 12 patients experienced grade I or II transient pancytopenia during the first 3 months after enrollment in the trial. There were no episodes of grade III or IV myelosuppression. The estimated absorbed radiation dose to the orbital soft tissues was <3 Gy, 10 times lower than that with EBRT. CONCLUSIONS: Rituximab followed by (90)Y ibritumomab tiuxetan is an effective and safe front-line treatment for early-stage extranodal indolent B-cell lymphoma of the ocular adnexa.

Imaging characteristics of dacryocystocele diagnosed after surgery for sinonasal cancer.

BACKGROUND AND PURPOSE: A dacryocystocele forms when tears accumulate within the lacrimal sac as a result of an obstruction more distally in the lacrimal drainage apparatus, which may occur as a complication of sinonasal surgery. The purpose of this study was to define the imaging characteristics of a postoperative dacryocystocele occurring after surgery for sinonasal cancer and to review the anatomy of the nasolacrimal drainage apparatus. MATERIALS AND METHODS: We reviewed the clinical records and imaging findings of 8 patients who underwent surgery for sinonasal cancer and were diagnosed with a postoperative dacryocystocele between August 2001 and November 2005. The imaging studies performed at the time of diagnosis of dacryocystocele were CT in 6 patients and MR imaging in 2 patients. RESULTS: On both CT and MR imaging, dacryocystoceles had a characteristic appearance of a fluid collection with thin rim enhancement along the course of the affected nasolacrimal duct, with no adjacent solid components. In none of the patients was the dacryocystocele confused with a recurrent tumor. CONCLUSION: Dacryocystocele after surgery for sinonasal cancer has a characteristic appearance on CT and MR imaging. Familiarity with this complication of sinonasal surgery and its appearance on imaging will enable radiologists to avoid misinterpreting dacryocystocele as a recurrent tumor or another process.

Imaging Features of Malignant Lacrimal Sac and Nasolacrimal Duct Tumors.

The purpose of this study was to present the imaging features of primary and secondary malignant lacrimal sac and nasolacrimal duct tumors and their pattern of tumor spread in 18 patients. The most common tumor histology in our series was squamous cell carcinoma. In 15/18 patients, tumor involved both the lacrimal sac and duct at the time of diagnosis. In 11/16 patients on CT, the nasolacrimal bony canal was smoothly expanded without erosive changes. The medial canthus region (16/18) was a frequent site of direct tumor spread. Two patients had intraconal orbital spread of tumor. Tumor spread to the sinus or nasal cavity was observed in 5/13 primary tumors. Only 1 patient presented with nodal metastasis. There was no intracranial tumor extension, perineural tumor spread along the infraorbital nerve, distant metastasis, or dacryocystocele formation in any of the patients at the time of diagnosis.

Loss of epithelial p53 and αv integrin cooperate through Akt to induce squamous cell carcinoma yet prevent remodeling of the tumor microenvironment.

Most of the squamous cell carcinomas (SCCs) of the skin and head and neck contain p53 mutations. The presence of p53 mutations in premalignant lesions suggests that they represent early events during tumor progression and additional alterations may be required for SCC development. Here we show that codeletion of the p53 and αv integrin genes in mouse stratified epithelia induced SCCs in 100% of the mice, more frequently and with much shorter latency than deletion of either gene alone. The SCCs that lacked p53 and αv in the epithelial tumor cells exhibited high Akt activity, lacked multiple types of infiltrating immune cells, contained a defective vasculature and grew slower than tumors that expressed p53 or αv. These results reveal that loss of αv in epithelial cells that lack p53 promotes SCC development, but also prevents remodeling of the tumor microenvironment and delays tumor growth. We observed that Akt inactivation in SCC cells that lack p53 and αv promoted anoikis. Thus, tumors may arise in these mice as a result of the increased cell survival induced by Akt activation triggered by loss of αv and p53, and by the defective recruitment of immune cells to these tumors, which may allow immune evasion. However, the defective vasculature and lack of a supportive stroma create a restrictive microenvironment in these SCCs that slows their growth. These mechanisms may underlie the rapid onset and slow growth of SCCs that lack p53 and αv.

Surgical treatment of canalicular stenosis in patients receiving docetaxel weekly.

OBJECTIVE: To describe the surgical treatment and outcomes in patients with metastatic breast cancer and canalicular stenosis caused by weekly treatment with docetaxel. METHODS: This case series included 10 patients with persistent epiphora due to weekly docetaxel treatment, who were evaluated by probing and irrigation of the tear drainage apparatus and were found to have significant canalicular stenosis. The severity of canalicular stenosis was graded clinically. Each patient underwent bicanalicular silicone intubation or dacryocystorhinostomy (DCR) with placement of either a silicone tube (canaliculo DCR) or a pyrex glass tube (conjunctivo DCR). RESULTS: Seven patients (12 eyes) underwent bicanalicular silicone intubation. Three patients (5 eyes) required canaliculo DCR with the placement of a silicone tube. In 2 patients (3 eyes), the degree of canalicular stenosis was severe enough to require conjunctivo DCR with the placement of a pyrex glass tube. All 10 patients had complete resolution of epiphora immediately after surgery. Four patients continued to receive docetaxel after surgery. In patients who underwent bicanalicular silicone intubation, the silicone stent was kept in place for the duration of docetaxel therapy. There were no surgical or anesthesia-related complications. At a mean follow-up time of 9 months after surgery, all but 1 patient (1 eye) remained asymptomatic. The interval between initiation of docetaxel therapy and surgery was significantly higher in patients who required DCR compared with those who had silicone intubation. The mean cumulative dose of docetaxel at the time of surgery was higher in patients who required DCR than in patients who had silicone intubation, but this difference was not statistically significant. CONCLUSIONS: Canalicular stenosis secondary to weekly treatment with docetaxel should be treated with bicanalicular silicone intubation early in the course of docetaxel therapy. Failure to treat this adverse effect early may likely lead to severe and irreversible canalicular stenosis, which may necessitate conjunctivo DCR with the placement of a permanent pyrex glass tube.

Orbital mass secondary to precursor T-cell acute lymphoblastic leukemia: a rare presentation.

We describe a 40-year-old woman with a history of precursor T-cell acute lymphoblastic leukemia who developed an orbital mass associated with diffuse infiltration of the paranasal sinuses. The clinical and radiologic findings suggested an orbital abscess. Examination of orbital and ethmoid sinus biopsy specimens revealed relapse of precursor T-cell acute lymphoblastic leukemia. Although orbital involvement by granulocytic sarcoma (also known as extramedullary myeloid cell tumor and chloroma) with or without concurrent acute myeloid leukemia is well described in the literature, similar presence of acute lymphoblastic leukemia of either precursor T-cell or B-cell lineage is rare.

Late choroidal metastasis secondary to papillary thyroid carcinoma.

PURPOSE: To report a case of late choroidal metastasis from papillary thyroid carcinoma. METHODS: Interventional case report. A 43-year-old woman who had been treated for papillary thyroid carcinoma 30 years earlier presented for evaluation of vision loss in the left eye. Eight weeks before this presentation, an ophthalmologist had diagnosed a metastatic uveal mass in the left eye of the patient. The clinical record was retrospectively reviewed. Ocular sonography was performed to confirm the diagnosis of choroidal metastasis. RESULTS: The choroidal mass had the typical characteristics of a metastatic lesion. The patient was treated with a combination of brachytherapy and chemotherapy. CONCLUSION: Papillary thyroid carcinoma can metastasize to the choroid many years after the initial diagnosis.

Interferon therapy for orbital infiltration secondary to Erdheim-Chester disease.

PURPOSE: To describe a 55-year-old male with Erdheim-Chester disease with bilateral orbital infiltration and visual loss who was successfully treated with interferon-alpha. METHODS: Interventional case report. RESULTS: The patient was treated with interferon-alpha and had an improvement in his clinical signs, including his visual acuity, after 4 weeks of interferon therapy. CONCLUSION: Interferon-alpha can be effective in the treatment of orbital infiltration secondary to Erdheim-Chester disease.

Wilson's disease: presymptomatic patients and Kayser-Fleischer rings.

PURPOSE: We evaluated patients with Wilson's disease to determine (1) whether presymptomatic patients who have Kayser-Fleischer (K F) rings demonstrate a more significant alteration of copper metabolism than those who do not have K F rings, and (2) whether presymptomatic patients have smaller K F rings than symptomatic Wilson's disease patients. METHODS: Thirty-two patients with presymptomatic Wilson's disease were retrospectively analyzed. Sixteen of these had received no prior anti-copper therapy and underwent testing for baseline copper metabolism (24-hour urine copper, liver copper, and plasma ceruloplasmin). Quantitative measurements of K F rings were made for the group of untreated presymptomatic patients and a control group of symptomatic Wilson's disease patients. RESULTS: We hypothesized that the 24-hour urine copper, in particular, would correlate with the presence of a K F ring. However, no significant difference was found between any of the baseline copper variables for presymptomatic patients who had K F rings compared to those who did not. K F rings of presymptomatic patients were found to be significantly smaller than K F rings of patients with symptomatic Wilson's disease (p < 0.05). CONCLUSIONS: While this study does not show any relationship between urinary copper excretion and the presence of K F rings, it suggests that the larger K F ring size correlates with Wilson's disease severity.

Regression of Kayser-Fleischer rings during oral zinc therapy: correlation with systemic manifestations of Wilson's disease.

Fourteen patients presenting with neuropsychiatric manifestations of Wilson's disease were treated with oral tetrathiomolybdate (TM) for 8 weeks followed by oral zinc (Zn) maintenance therapy. The patients were evaluated prospectively at baseline and at yearly intervals for up to 5 years by slit-lamp biomicroscopy and photography, quantitative neurologic and speech pathology examinations, 24-h urine copper collection, and a quantitative scoring of magnetic resonance imaging (MRI) of the brain. Kayser-Fleischer (KF) ring size decreased significantly during the 5-year study period (p < 0.0001). Although results of neurologic examination, speech pathology examination, and 24-h urine copper level analysis in symptomatic Wilson's disease patients improved during the study period, KF ring regression did not correlate with the improvement in these clinical parameters (p > 0.05). However, there was a correlation between MRI scores and KF ring regression (p = 0.02). Anticopper therapy with TM followed by zinc maintenance therapy is a safe and effective treatment for patients with neurologically symptomatic Wilson's disease. This treatment leads to reduction in KF ring size; however, KF ring reduction is not a good predictor of clinical improvement for patients with neuropsychiatric manifestations of Wilson's disease.

Ocular adnexal diffuse large B-cell lymphoma: local disease correlates with better outcomes.

PURPOSE: To describe the clinical, immunohistochemical and prognostic features, as well as outcomes of a large series of patients with orbital and periorbital diffuse large B-cell lymphoma (DLBCL). DESIGN: This study is a multicentre, retrospective non-comparative consecutive case series. METHODS: The setting for this study was institutional. A total of 37 consecutive patients identified from the institutions' databases with periorbital and orbital DLBCL were enrolled in the study. A retrospective chart review was used for observation. The main outcome measures were patient demographics, clinical features, imaging, immunohistochemical and histopathological data, treatments administered, and survival. RESULTS: A total of 20 out of 37 cases (54.1%) represented localised periorbital disease (group L), 11 of 37 (29.7%) had systemic disease at presentation with periorbital disease (group S1), and 6 of 37 (16.2%) had previous history of systemic lymphoma (group S2). In all, 28 out of 30 (93.3%) patients were CD20+, 5 of 25 (20%) were CD3+, and 11 of 11 (100%) were CD79a+ (varying denominators reflect the different numbers of patients tested). A total of 25 out of 32 patients (78.1%) received chemotherapy, 14 (43.8%) received rituxmab plus chemotherapy, and 19 (59.3%) received radiotherapy. Nine deaths occurred, one in group L (not lymphoma related), six in group S1, and two in group S2. Five-year Kaplan-Meier survival estimates were 55.9% for all cases, 90.9% for group L, 36.0% for group S1, and 0% for group S2. One-year progression-free survival estimates in groups S1 and S2 combined were 58.3% for patients treated with rituximab and 28.6% for those who were not. CONCLUSIONS: To our knowledge, this report represents the largest series of patients with periorbital and orbital DLBCL in the literature. The difference in survival between groups L, S1 and S2 was striking, reflecting the grave prognosis of systemic DLBCL, but conversely the relatively optimistic outlook for patients with localised disease. Rituximab plus chemotherapy may be associated with increased survival.

Fungal endophthalmitis in a tertiary care cancer center: a review of 23 cases.

Few data exist on the etiology, presentation, prognosis, and management of fungal endophthalmitis (FE) in cancer patients. FE cases were identified by reviewing the ophthalmology reports and microbiology cultures of patients at The University of Texas M. D. Anderson Cancer Center. We retrospectively reviewed the medical records and obtained information related to malignancy, fungal infection and its management, visual outcome, and mortality. We compared FE caused by Candida spp. (CE) to FE caused by molds (ME). Of the 102 cancer patients with a fungal infection for whom an ophthalmology consult was requested, 23 met the criteria for definite (N = 6) or probable (N = 17) FE (8 with CE, 15 with ME). All of the patients with ME had hematologic malignancies, whereas half of the patients with CE had solid tumor (P = .008). Only patients with CE had a history of surgery within 30 days of FE diagnosis (38%, P = .03). Fungal pneumonia [17 (74%)] and disseminated infection [14, (61%)] were common. The most common presenting symptoms were decreased vision [16 (70%)] and ocular pain [14 (61%)]. All treated patients received systemic antifungals (combination therapy in 72% of the cases). Seven patients (30%) underwent vitrectomy. Only one patient received intraocular injection of amphotericin B along with systemic antifungals. Four-week mortality was high [13 (57%)], especially in ME (73%, P = .04). Among the eight surviving patients where visual acuity could be assessed, visual outcome improved or remained stable in five (63%). FE in cancer patients occurs in the setting of severe, frequently disseminated opportunistic mycoses, is caused predominantly by hyalohyphomycetes, and is a marker for high 4-week mortality.

Receptor expression in orbital inflammatory syndromes and implications for targeted therapy.

To investigate the expression of multiple therapeutic targets in tissue specimens from patients with orbital inflammatory syndromes, the clinical records of 16 patients treated for orbital inflammation between January 2003 and November 2005 for whom tissue blocks were available were reviewed retrospectively. Immunohistochemical staining was performed on archived specimens using commercially available monoclonal antibodies against CD3, CD20, CD22, CD23, CD25, and CD52 antigens. The histologic diagnoses were confirmed, and the immunohistochemical staining patterns were agreed upon by both collaborating pathologists (JLJ and PC-B). The study included 13 women and 3 men who ranged in age from 4 to 79 years (mean, 46 years). The histologic diagnoses were as follows: orbital pseudotumor in six patients; sarcoidosis, three; eosinophilic granuloma, one; necrobiotic xanthogranuloma, one; nonspecified granulomatous inflammation, one; Graves' ophthalmopathy, one; Wegener's granulomatosis, one; and reactive lymphoid hyperplasia, two. One orbital lymphoma specimen and one foreign body reaction specimen were used as controls. CD20 was strongly expressed in all specimens except three (Wegener's granulomatosis, eosinophilic granuloma, and nonspecified granulomatous inflammation specimens), and CD25 was strongly expressed in all specimens except the Wegener's granulomatosis specimen, in which this antigen was only moderately expressed. CD20 and CD25 were strongly or moderately expressed in most of the tested specimens of orbital inflammation. If our findings are confirmed in a larger study, rituximab, which targets CD20, and denileukin diftitox (ONTAK), which targets CD25, should be considered for future clinical trials for orbital inflammatory syndromes.

Ocular findings in patients with solid tumours treated with the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839) in Phase I and II clinical trials.

PURPOSE: To describe the strategy used for large-scale ophthalmological monitoring in the clinical development of the novel anticancer agent gefitinib ('Iressa', ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, which had demonstrated ocular effects in preclinical animal models. METHODS: In this extensive clinical trial programme, patients in Phase I and II trials underwent frequent and intensive ophthalmological monitoring at baseline and during the trials. Data were reviewed by an external independent Ophthalmology Advisory Board. RESULTS: Ophthalmological data for 221 patients in Phase I trials of gefitinib and 425 patients in Phase II trials revealed no evidence of any consistent or drug-related ophthalmological toxicity. Interestingly, the baseline data revealed that, in an asymptomatic population, transient ophthalmological events are identified during monitoring. CONCLUSIONS: This study reports the methodology and normative data in an ophthalmological screening programme that should prove useful for future studies.

Squamous cell carcinoma with perineural invasion presenting as a Tolosa-Hunt-like syndrome: a potential pitfall in diagnosis.

PURPOSE: To describe a case of perineural invasion resulting from squamous cell carcinoma of forehead. METHODS: Case report. RESULTS: Perineural invasion resulting from squamous cell carcinoma of the periocular skin can present as a Tolosa-Hunt-like syndrome with lack of radiologic findings on magnetic resonance imaging (MRI) in its early stages. CONCLUSION: A high level of suspicion for perineural invasion is required when assessing multiple cranial nerve palsies in patients with a history of cutaneous malignancy, despite negative sequential MRI. Perineural invasion must be ruled out by a biopsy of the involved nerves, whenever possible, before empiric therapy with systemic steroids is contemplated.

Immunohistochemical evidence for estrogen receptors in meibomian glands.

PURPOSE: To look for sex hormone receptor distribution in three structures contributing to the normal human tear film: the conjunctiva, the accessory lacrimal glands, and the meibomian glands. DESIGN: An immunohistochemical study. TISSUES AND CONTROLS: Forty-one upper eyelid specimens were collected from 15 male and 26 female patients (age range, 1.5-85 years) during blepharoptosis surgery via posterior tarsoconjunctival mullerectomy (Fasanella-Servat or Gavaris). In addition, control sections of histologically normal breast, prostate, and skin tissue were obtained. METHODS: Immunohistochemical staining using mouse monoclonal antibodies against estrogen, progesterone, and androgen receptors was performed on all tissues and controls. Quantitation of the receptors was performed and expressed as percentage nuclear positivity. Specimens were divided into three groups based on the age of the patient: <12 years (n = 9); 18-55 years (n = 1); >55 years (n = 12). RESULTS: Forty-one specimens contained conjunctiva. All were negative for estrogen, progesterone, and androgen receptors. Twenty-four specimens contained accessory lacrimal glands of Wolfring. All were negative for the three receptors. Twenty-two specimens contained meibomian glands. All were positive for estrogen receptors; one was positive for progesterone receptors and one for androgen receptors. Using Minitab statistical software (Minitab Inc. State College, PA), analysis of variation revealed no statistical difference between sexes or between age groups studied. The sebaceous glands of skin were uniformly positive for androgen receptors. Sebaceous glands of the face and scalp (3 of the 15 skin samples) were also positive for estrogen receptors. CONCLUSIONS: Estrogen receptors are present in the meibomian glands of the upper eyelid. Unlike sebaceous glands elsewhere on the skin, the meibomian glands lack androgen receptors. Estrogen receptors may play a role in modulation of the lipid layer of the tear film, and their activity may be linked to meibomian gland dysfunction and dry eye syndrome.

Long-term results of frontalis suspension using irradiated, banked fascia lata.

This study was undertaken to study the long-term rate of recurrence of ptosis and other postoperative complications after frontalis suspension using banked irradiated fascia lata. One hundred thirty-two lids of 72 patients underwent frontalis suspension between 1980 and 1989. The preoperative diagnoses included severe congenital ptosis (83%), blepharophimosis (10%), third nerve palsy (4%), and chronic progressive external ophthalmoplegia (3%). The age at the time of surgery ranged from 5 months to 19 years, with an average of 3 years and 5 months. In 46 patients (64%), surgery was done before age 3 years. The follow-up time ranged from 6 to 15 years, with a mean and median of 10 years. Good to excellent lid height was achieved immediately after surgery in all but three patients. Recurrence of ptosis occurred in 20 cases (28%), and 28 lids (21%). The time to reoperation ranged from 1 to 7 years, with an average of 3 years. Sixteen patients (80%) with recurrence were younger than 3 years of age. Reaction to donor fascia lata occurred in only two patients (3%). Only one patient suffered from excessive exposure keratopathy and required revision of the sling. Banked fascia lata is easy to use and should be considered as an alternative suspensory material in children younger than 3 years of age with congenital ptosis. The long-term reoperation rate in this cohort of patients was higher than the 5% rate reported for autogenous fascia, but lower than that previously reported for banked fascia lata (50% at 8 years).

Interferon-induced retinopathy in asymptomatic cancer patients.

OBJECTIVES: Interferon-induced ocular complications, including retinal ischemia and ischemic optic neuropathy, can be associated with significant visual loss. We report three cases of asymptomatic ischemic retinopathy in cancer patients receiving interferon. DESIGN: Retrospective, interventional, noncomparative small case series. METHODS: Retrospective review of the medical records and fundus photographs. RESULTS: Interferon-induced ischemic retinopathy can occur in asymptomatic cancer patients. The retinal changes are usually reversible with discontinuation of interferon therapy. CONCLUSIONS: These three cases underscore the importance of dilated funduscopic examination at baseline and during follow-up, at least every 3 months, for all cancer patients receiving interferon to identify retinal toxicity at its earliest stages. A prospective study evaluating the incidence and severity of interferon retinopathy in cancer patients would be prudent.

Canalicular stenosis secondary to docetaxel (taxotere): a newly recognized side effect.

OBJECTIVE: To report a newly recognized side effect of a commonly used antineoplastic agent, docetaxel, in three patients with metastatic breast cancer. DESIGN: Observational case reports. PARTICIPANTS: Three patients with metastatic breast cancer who received weekly docetaxel chemotherapy. MAIN OUTCOME MEASURES: Occurrence of epiphora and severity of punctal and canalicular fibrosis secondary to docetaxel. RESULTS: In three patients receiving weekly docetaxel, canalicular stenosis and resultant epiphora developed shortly after start of their treatment. Discontinuation of drug several months after initiation of therapy did not lead to resolution of symptoms in two of the three patients. CONCLUSIONS: Epiphora is a newly recognized side effect of docetaxel and may occur more frequently with weekly cycles of this drug. The mechanism for epiphora seems to be punctal and canalicular stenosis. This side effect, in advanced cases, is not reversible with discontinuation of the drug. Patients being administered weekly cycles of docetaxel should be screened for epiphora and canalicular stenosis, and treatment in the form of silicone intubation or punctoplasty should be considered in early stages to prevent the need for conjunctivodacryocystorhinostomy.