Thyroid Doses and Risks to Adult Patients Undergoing Neck CT Examinations.

OBJECTIVE: The purpose of this study was to estimate absorbed thyroid dose and consequent cancer risks in adult patients undergoing neck CT examinations. MATERIALS AND METHODS: We used data from neck CT examinations of 68 consecutive adult patients to calculate the thyroid dose and estimate the corresponding cancer risk. Age and sex were recorded along with the volume CT dose index (CTDIvol) that was used to perform the examination. CTDIvol values were used to estimate thyroid doses in the mathematic phantom used in the ImPACT patient CT dosimetry calculator. Corresponding doses in patients were estimated by modeling each patient's neck as an equivalent cylinder of water and applying correction factors for varying neck size and scanning length and the variation of radiation intensity due to automatic exposure control. RESULTS: The mean (± SD) adult patient age was 59 ± 16 years, and the mean equivalent water cylinder diameter used for modeling the patient neck was 19.4 ± 4.2 cm. The average adult patient neck size was about 3 cm larger than the mathematic anthropomorphic phantom (16.5 cm), decreasing the estimated thyroid doses by 15%. Thyroid doses were independent of age and sex, with an average of 50 ± 23 mGy. The average cancer risk for a 20-year-old woman was six times higher than the corresponding risk for a 20-year-old man. Increasing patient age of either sex from 40 to 60 years reduced the cancer risk by approximately an order of magnitude. CONCLUSION: Patient sex and age are the most important factors in determining thyroid cancer risk, with the thyroid dose being secondary.

Spectrum of RB1 mutations identified in 403 retinoblastoma patients.

BACKGROUND: Retinoblastoma (RB) is a malignant, childhood tumour of the developing retina that occurs with an estimated frequency of 1 in 20 000. Identification of oncogenic mutations in the RB1 gene aids in the clinical management of families with a heritable predisposition to RB. Here we present the spectrum of genetic and epigenetic changes identified in 194 tumours and 209 blood samples, from 403 unrelated RB patients. METHODS: Mutation screening was carried out across all 27 RB1 exons and their associated splice sites. Small coding sequence changes were detected using fluorescent conformation analysis followed by sequencing. Large exonic deletions were detected by quantitative fluorescent PCR. Methylation specific PCR of the RB1 promoter was performed to detect epigenetic alterations. Polymorphism analysis was used to determine loss of heterozygosity in tumour samples. RESULTS: 95% of the expected mutations were identified in the tumour samples, with 16 samples exhibiting only one mutation, while two samples had no detectable RB1 mutation. 96% of bilateral/familial RB blood samples and 9.5% of unilateral sporadic blood samples, yielded mutations. 111 were novel mutations. CONCLUSIONS: The full range of screening techniques is required to achieve a high screening sensitivity in RB patients.

Autonomic cardio-respiratory reflex reactions and superselective ophthalmic arterial chemotherapy for retinoblastoma.

OBJECTIVE: To describe our experience with superselective ophthalmic artery chemotherapy (SOAC) in retinoblastoma and to report the serious adverse cardio-respiratory reactions we have observed. METHODS: SOAC was performed using a standardized protocol for general anesthesia, ophthalmic artery catheterization, and pulsed infusion of melphalan. Adverse reactions were defined as those in which the patient required active treatment to maintain cardio-respiratory stability. RESULTS: Between December 2008 and May 2012, 54 eyes in 52 patients were treated. 143 catheterization procedures were performed, with a technical success rate of 93% (n = 133). There were no deaths or major complications. Adverse cardio-respiratory reactions developed during 35 procedures (24%; 95% CI, 18-32%). All reactions occurred during second or subsequent catheterization procedures (39%; 95% CI, .29-49%) and were characterized by hypoxia, reduced lung compliance, systemic hypotension and bradycardia. Adverse events were successfully treated in all patients. One procedure was abandoned due to prolonged hemodynamic instability. CONCLUSION: Adverse cardio-respiratory reactions are commonly observed in SOAC for retinoblastoma. We believe that the adverse clinical signs represent an autonomic reflex response, akin to the trigemino-cardiac or oculo-respiratory reflexes, and all patients should be considered at-risk. Reactions occur only during second or subsequent procedures and can be life-threatening. The routine use of intravenous atropine does not seem to have altered the incidence or severity of these reactions. Anesthetists and interventional neuroradiologists involved in SOAC must be vigilant to ensure adverse reactions, when they develop, are treated quickly and effectively.

Recurrence of treated ciliary body melanoma following trabeculectomy.

A 69-year-old man was treated for a right ciliary body melanoma with plaque radiotherapy. One year later, he had uncomplicated cataract extraction but developed prolonged postoperative inflammation and secondary glaucoma. The tumour remained unchanged on yearly ultrasound B scans but intraocular pressures became uncontrolled despite maximal medical therapy. After radiotherapy, he underwent trabeculectomy with 5-fluorouracil and revision with mitomycin C 2 years later. The melanoma recurred with extrascleral extension under the trabeculectomy bleb 14 years after plaque radiotherapy and 5 years after trabeculectomy surgery. Enucleation was performed and histological analysis showed a ring melanoma involving the root of the iris, filling the trabecular meshwork and extending into the anterior chamber. The predominant cell type was epithelioid with large nuclei and prominent nucleoli. Trabeculectomy surgery may increase the risk of extrascleral extension of ciliary body melanoma even after apparently successful plaque radiotherapy and long-term local tumour control.

Analysis of Long-term Outcomes of Radiotherapy and Verteporfin Photodynamic Therapy for Circumscribed Choroidal Hemangioma.

PURPOSE: To determine the long-term therapeutic outcome for different treatments of circumscribed choroidal hemangioma (CCH). DESIGN: Retrospective observational study. SUBJECTS: Patients with newly diagnosed CCH. METHODS: Observation, verteporfin (Visudyne) photodynamic therapy (PDT), lens-sparing external beam radiotherapy (LS-EBRT), or plaque brachytherapy. MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA) at baseline and throughout follow-up, tumor dimensions, and OCT central thickness (where available) at baseline and throughout follow-up were recorded. RESULTS: There were 60 treatment-naïve consecutive cases with CCH between January 2000 and June 2014; 42 (70%) received treatment. These were LS-EBRT (23/60 [38%]; mean follow-up, 45.5 months), PDT (16/60 [27%]; mean follow-up, 38 months), and plaque radiotherapy (3/60 [5%]; mean follow-up, 92 months). Macular location, mottled or orange pigment, and absence of drusen were significantly more frequent in the treatment group. In the LS-EBRT group, median thickness reduction on ultrasound B scan was 1.6 mm (mean ± standard deviation, 1.65±1.6; range, -6.5 to +0.7). The mean ± standard deviation BCVA gain was 0.22±0.34, with >3 Snellen lines in 48% of cases. Kaplan-Meier estimates were 80% for any gain and 40% for >3 Snellen lines gain at 5 years. In the PDT group, the median decrease in thickness was 0.95 mm (mean ± standard deviation, 1.0±0.8; range, -2.5 to +0.2). The mean ± standard deviation BCVA gain was at 0.3±0.51, with >3 Snellen lines in 30% of cases. Kaplan-Meier estimates were 93% for any gain and 68% for >3 Snellen lines at 5 years. Double versus single duration PDT had more favorable outcomes with a greater reduction in tumor thickness (P = 0.04), central retinal thickness (P = 0.02), and improvement in visual acuity (median, 0.33 vs -0.05). There was no difference in decrease in tumor thickness or BCVA gain between the LS-EBRT and PDT groups. With plaque brachytherapy, the mean decrease in thickness was 2.5 mm, but BCVA loss of >2 Snellen lines was noted in all 3 cases at the end of follow-up. Radiation complications developed in 10 of 23 cases (43.5%) from the LS-EBRT group and 2 of 3 cases (67%) from the plaque brachytherapy group. CONCLUSIONS: LS-EBRT is equivalent to PDT in CCH management for post-treatment BCVA and tumor thickness reduction. The risk of LS-EBRT and plaque brachytherapy was late radiation-related complications. Double duration PDT was more favorable than single duration.

Secondary acute myelogenous leukemia in patients with retinoblastoma: is chemotherapy a factor?

PURPOSE: To describe a series of patients with secondary acute myelogenous leukemia (sAML) and retinoblastoma (RB). DESIGN: Retrospective observational cases series. PARTICIPANTS: Ocular and pediatric oncologists at referral centers in Europe and the Americas and the RB databases at the National Institutes of Health and the Ophthalmic Oncology Service at Memorial Sloan-Kettering Cancer Center. METHODS: Physician survey, retrospective database review, and literature search. MAIN OUTCOME MEASURES: History of RB and development of sAML, management of RB (surgery, radiotherapy, chemotherapy), age at diagnosis of RB and leukemia, French-American-British (FAB) subtype, and current status of patient (alive or dead). RESULTS: Fifteen patients with sAML were identified; 13 occurred in childhood. Mean latent period from RB to AML diagnosis was 9.8 years (median, 42 months). Nine cases were of the M2 or M5 FAB subtypes. Twelve patients (79 %) had received chemotherapy with a topoisomerase II inhibitor, 8 (43%) had received chemotherapy with an epipodophyllotoxin. Ten children died of their leukemia. CONCLUSIONS: Acute myelogenous leukemia is a rare secondary malignancy among retinoblastoma patients, many of whom were treated with primary or adjuvant chemotherapy. Additional studies are needed to assess potential risk factors contributing to sAML development in this cohort.

Presence and phenotype of dendritic cells in uveal melanoma.

BACKGROUND: Uveal melanoma arises in an immune-privileged site and can itself add to the immunosuppressive environment. Previous studies on cutaneous melanoma have shown the presence of tolerogenic dendritic cells (DCs), which could play an important role in the progression of the tumour. AIM: To examine the presence and functional status of DCs in a small series of uveal melanomas. METHODS: 10 cases of uveal melanoma were examined for the expression of FXIIIa, CD68, human leucocyte antigen (HLA)-DR, CD40, CD83, transforming growth factor betaR1 and indolamine 2,3 dioxygenase by immunohistochemical analysis on sections embedded in paraffin wax. RESULTS: CD68-positive macrophages were present in all of the tumours and were evenly distributed throughout. DCs expressing FXIIIa-positive were seen in 7 cases, and were often found concentrated in foci within the tumour mass. These cells were dendritic and expressed high levels of HLA-DR. The DCs did not express the maturation markers CD83 or CD40. In one case, concentration of DCs around the area of tumour necrosis was observed, and some of these cells expressed CD83. CONCLUSION: Numerous tolerising antigen-presenting cells may play a role in melanoma-related immunosuppression in the eye, although activation of DCs may be associated with tumour necrosis.

Gastric metastases from conjunctival melanoma.

The aim of the study is to discuss the pattern and risk factors for metastatic disease in conjunctival melanoma. We draw comparisons with cutaneous metastatic melanoma. We describe the clinical course of a patient with recurrent conjunctival melanoma in the context of primary acquired melanosis with atypia. The local disease was eventually treated with a lid splitting exenteration. The patient suffered from an isolated distant metastasis to the gastric wall that was managed by partial gastrectomy. Conjunctival melanoma has many similarities with its cutaneous counterpart. In both conditions the regional lymph nodes are the most common site for metastases, however, isolated distant metastases can occur. Gastric metastases are frequently seen in cutaneous melanoma. This is the first report of an isolated gastric metastasis from a conjunctival melanoma.

Choroidal neovascularization induced by transcleral microdiathermy for localization of a juxtapapillary choroidal melanoma.

Transcleral transillumination is a useful tool for the localization of juxtapapillary uveal tract tumors that do not cast a shadow with conventional transpupil-lary transillumination. The main choice of treatment for juxtapapillary uveal tract melanoma consists of either episcleral plaque brachytherapy or proton beam radiotherapy. In both instances, an external surgical approach is required that involves localization of the tumor and marking of the overlying sclera. Transcleral microdiathermy often creates corresponding areas of chorioretinal atrophy. This article describes the technique of transcleral transillumination coupled with microdiathermy to mark the sclera in a patient in whom a choroidal neovascular membrane developed adjacent to a microdiathermy-induced area ofchorioretinal atrophy after the described surgical technique. To avoid the postoperative development of a choroidal neovascular membrane, transcleral transillumination can be used without the application of microdiathermy.

Strabismus in adults with uveal melanoma following episcleral plaque brachytherapy.

PURPOSE: To ascertain the incidence of persistent strabismus in patients treated with plaque brachytherapy and its subsequent treatment. METHODS: A single center retrospective case note review of adult patients with persistent diplopia or strabismus following plaque brachytherapy for all types of intraocular tumors between 1996 and 2004. RESULTS: A total of 929 consecutive adults underwent plaque brachytherapy during the study period at a single center. Sixteen patients (1.7%) with treated uveal melanoma developed persistent diplopia or strabismus. In 11 patients (69%) the timing of onset was in the first year, in 2 (13%) in the second year, and one each (6% each) in years 5, 7, and 8. Two patients (13%) did not require any intervention. Fourteen patients (88%) required treatment: 7 (50%) were treated with prisms only, 3 (21%) underwent botulinum toxin (BTXA) injections, and 4 (29%) were treated with extraocular muscle surgery (3 required one operation and one required 2 procedures). CONCLUSIONS: The incidence of ocular motility disorders following plaque brachytherapy in our cohort was 1.7% over 8 years and we include this in the consent process for conservative treatment of intraocular tumors. Options for treatment for persistent diplopia or strabismus include prisms, botulinum toxin injection, or surgery.

MESECTODERMAL LEIOMYOMA OF THE CILIARY BODY PRESENTING AS ANTERIOR STAPHYOMA.

PURPOSE: To report two cases of mesectodermal leiomyoma of the ciliary body presenting as anterior staphyloma. METHODS: Two case reports with cytopathologic correlation. RESULTS: First patient (15-year-old boy) presented with a nodular lesion in the sclera. Second patient (31-year-old woman) was found to have a brown ciliary body mass. Growth of the lesion and extrascleral extension was noticed after several years of follow-up. Ultrasonography, light microscopy, and immunohistochemistry of both cases are described confirming mesectodermal leiomyoma of the ciliary body. CONCLUSION: Mesectodermal leiomyoma, despite its rarity, should be considered in the differential diagnosis of uveal tract tumors. Clinically, the diagnosis is difficult and histopathological and immunohistochemical assesment is necessary to avoid inappropriate diagnosis and erroneous treatment.

Endovascular treatment for AIS with underlying ICAD.

BACKGROUND: Acute large vessel occlusion (LVO) can result from thromboemboli or underlying intracranial atherosclerotic disease (ICAD). Although the technique for revascularization differs significantly for these two lesions (simple thrombectomy for thromboemboli and balloon angioplasty and stenting for ICAD), the underlying etiology is often unknown in acute ischemic stroke (AIS). OBJECTIVE: To evaluate whether procedural complications, revascularization rates, and functional outcomes differ among patients with LVO from ICAD or thromboembolism. METHODS: A retrospective review of thrombectomy cases from 2008 to 2015 was carried out for cases of AIS due to underlying ICAD. Thirty-six patients were identified. A chart and imaging review was performed to determine revascularization rates, periprocedural complications, and functional outcomes. Patients with ICAD and acute LVO were compared with those with underlying thromboemboli. RESULTS: Among patients with ICAD and LVO, mean National Institutes of Health Stroke Scale (NIHSS) score on admission was 12.9±8.5, revascularization (Thrombolysis In Cerebral Infarction, TICI ≥2b) was achieved in 22/34 (64.7%) patients, 11% had postprocedural intracerebral hemorrhage (PH2), and 14/33 (42.4%) had achieved a modified Rankin Scale (mRS) score of 0-2 at the 3-month follow-up. Compared with patients without underlying ICAD, there was no difference in NIHSS on presentation, or in the postprocedural complication rate. However, procedure times for ICAD were longer (98.5±59.8 vs 37.1±34.2 min), there was significant difference in successful revascularization rate between the groups (p=0.001), and a trend towards difference in functional outcome at 3 months (p=0.07). CONCLUSIONS: Despite AIS with underlying ICAD requiring a more complex, technically demanding recanalization strategy than traditional thromboembolic AIS, it appears safe, and good outcomes are obtainable.

Impact of ASPECT scores and infarct distribution on outcomes among patients undergoing thrombectomy for acute ischemic stroke with the ADAPT technique.

OBJECTIVE: To investigate the associations between Alberta Stroke Program Early CT Score (ASPECTS) or distribution and sidedness of acute infarction and clinical outcomes following intervention with a direct aspiration first pass technique (ADAPT). METHODS: A review was performed of patients who had undergone thrombectomy with ADAPT for emergent large vessel occlusions of the middle cerebral artery (MCA) between December 2012 and May 2015. Preintervention CT scans were reviewed by a blinded radiologist to calculate ASPECTS and determine the distribution of infarction. Clinical outcomes were compared for subsets of patients depending upon ASPECTS and regional infarction distribution (cortical, subcortical, or both). RESULTS: One hundred and fifty-four patients (50% female, mean age 67) underwent thrombectomy using ADAPT for MCA emergent large vessel occlusion. The median presenting National Institute of Health Stroke Scale score was 15. Fifty-five per cent of patients had left-side occlusions. Similar good outcomes were achieved for patients with perfect and non-perfect ASPECTS (modified Rankin Scale (mRS) 0-2: 63% vs 51%, respectively; p=0.20). Similar outcomes were also achieved for patients with 'poor' ASPECTS (≤6) compared with those with ASPECTS >6 (mRS 0-2: 52% vs 53%, respectively; p=0.91). Regional distribution and sidedness of core infarction on preintervention CT also did not correlate with worse outcomes. CONCLUSIONS: Patients with moderate-sized core infarcts involving various distributions in either hemisphere can potentially achieve similar good outcomes compared with those with no core infarction at presentation. A treatment algorithm for acute ischemic stroke, which employs hardline ASPECTS thresholds or excludes patients with basal ganglia infarcts, might preclude patients who would potentially benefit from mechanical thrombectomy with ADAPT.

Post-menopausal bleeding: a rare presentation of metastatic uveal melanoma.

Uveal melanoma differs from cutaneous melanoma in many ways, including its pattern of metastasis, and exhibits latency with clinical evidence of metastasis sometimes appearing many years after primary diagnosis. Most patients develop metastasis within the liver, but some may present with metastasis to other sites. We report a case of uveal melanoma that presented with post-menopausal bleeding due to metastasis. Further investigation revealed widespread metastatic disease and the patient was not fit for chemotherapy. She died two months after presentation: autopsy revealed metastases in many sites, including the uterus, right ovarian fibroma, kidney, mesentery, liver, lung, thyroid, bone marrow and skin. The immediate cause of death was cardiac tamponade due to a malignant effusion secondary to cardiac metastasis. This case illustrates the widespread metastatic potential of uveal melanoma and highlights the potential for unusual presentation of metastatic disease from this eye tumor.

Conjunctival melanoma: the role of conservative surgery and radiotherapy in regional metastatic disease.

OBJECTIVE: To evaluate prognostic factors and determine the role of conservative surgery and radiotherapy in managing metastatic conjunctival malignant melanoma (MM) involving preauricular/submandibular lymph nodes. METHOD: A retrospective analysis (1990-2003) of clinical and histopathologic data from 12 patients presenting with regional metastases after failed local treatment for conjunctival MM. Patients received a common, multispecialty, conservative management approach: wide local excision, topical cryotherapy or radiotherapy to conjunctival MM (orbital exenteration for more advanced local disease), lumpectomy, and adjuvant "ring" radiotherapy of regional metastases, with chemotherapy for distant metastases. RESULTS: Median age at primary diagnosis was 51 (range 28-86) years with equal sex predilection. Six of the 12 patients had primary tumors of the bulbar conjunctiva; the remainder arose in the palpebral conjunctiva, the caruncle, or the fornix. Of 11 originating in primary acquired melanosis (PAM), 2 were amelanotic. Epithelioid tumor cells were noted histologically in seven of eight specimens in which cell type could be determined. Eight tumors metastasised to preauricular nodes, three to submandibular and one to both, with a median interval of 23 (range 12-108) months after primary diagnosis. After conservative surgery and "ring irradiation," 7 of 12 patients remained free of regional nodal relapse at median interval of 16 (range 3-126) months. Five patients developed regional nodal recurrence at median interval of 11 (range 6-13) months, 3 of whom were within radiotherapy portals. Eight patients developed distant metastasis at median interval of 44 (range 22-138) months. Eleven patients had tumor-related death. The mean Kaplan-Meier adjusted survival time after primary diagnosis was 76 months with death ensuing postregional metastasis within a median 18 (range 4-127) months. The sole survivor's follow-up duration was 56 months. CONCLUSION: Locoregional metastasis after treatment for conjunctival MM is associated with a poor prognosis. Both epithelioid tumor cells and PAM are associated with disseminating disease and poorer outcome. Literature review has failed to demonstrate advantages of mutilating radical surgery over a conservative approach in this rare disease.

The breadth of imaging findings of groove pancreatitis.

The pathogenesis of groove pancreatitis involves progressive cystic degeneration of hamartomatous pancreas rests which lie within the duodenal wall. Hamartomatous pancreatic rests can occur in other locations, but when located within the pancreaticoduodenal groove can lead to a particular clinical presentation following the development of fibrotic and inflammatory tissue. Although this is not a disease of the pancreas itself, the pancreatic duct and biliary system is frequently secondarily involved in this regional process. Identification of this entity and its varied appearances as a distinct pathology is essential given the unique management issues of groove pancreatitis.

Anterior Segment Seeding in Eyes With Retinoblastoma Failing to Respond to Intraophthalmic Artery Chemotherapy.

IMPORTANCE: Anterior chamber seeding following intraophthalmic artery chemotherapy is rarely reported. OBJECTIVES: To describe clinicopathologic observations in eyes in which intraophthalmic artery chemotherapy for retinoblastoma failed and to report anterior chamber involvement. OBSERVATIONS: A retrospective case series of 12 enucleated eyes (11 patients) with retinoblastoma refractory to intraophthalmic artery chemotherapy between March 1, 2010, and October 31, 2013, at University College London Institute of Ophthalmology and the Retinoblastoma Service, Royal London Hospital. Data analysis was conducted from June 1, 2014, to March 1, 2015. The International Classification of Retinoblastoma groups were B in 1 eye (8%), C in 4 eyes (33%), and D in 7 eyes (58%). Systemic chemotherapy with vincristine sulfate, etoposide, and carboplatin had failed in 10 patients (91%) and 6 eyes (50%) received additional local treatments. In 6 eyes (50%) anterior chamber invasion was clinically detectable. On histopathologic examination, 4 eyes (33%) had no viable retinal tumor; the remainder had poorly differentiated tumor (6 eyes [50%]) or moderately differentiated tumor (2 eyes [17%]). Anterior segment involvement occurred in the ciliary body and/or ciliary muscle (7 eyes [58%]), iris (6 eyes [50%]), and cornea (4 eyes [33%]). CONCLUSIONS AND RELEVANCE: Intraophthalmic artery chemotherapy can fail in eyes with retinoblastoma. In contrast to previous reports on outcomes following intraophthalmic artery chemotherapy, our series shows involvement of the anterior segment of the eye, including the ciliary body, iris, and cornea. Careful case selection and follow-up are advised.

Mutational analysis of selected genes in the TGFbeta, Wnt, pRb, and p53 pathways in primary uveal melanoma.

PURPOSE: It is known that the pRb pathway cell-cycle inhibitor p16(INK4A) plays a significant role in cutaneous melanoma and that alteration of p16(INK4A), which resides within the 9p21-22 locus that also contains p15(INK4B) and p14(ARF), may occur in up to one third of uveal melanomas. The absence of TGFbeta responsiveness noted in cultured uveal melanoma cells also suggests that the TGFbeta pathway plays a role in the formation of this tumor. Therefore, mutational screening was performed in several key genes in tumor-suppressor pathways that are known to be altered in some uveal melanomas. METHODS: Using denaturing high-performance liquid chromatography (DHPLC) analysis and DNA sequencing, a series of 67 uveal melanomas were screened for inactivating mutations in the TGFbeta pathway members Smad4 and TGFbeta receptor type 2 (TGFbetaR2), the downstream cell-cycle inhibitor p15(INK4B), and the cell-cycle inhibitors p14(ARF) and p16(INK4A). p16(INK4A) was also investigated for promoter hypermethylation. Mutational analysis was also performed on the Wnt pathway gene beta-catenin, known to be mutated in approximately one quarter of cutaneous melanoma cell lines. RESULTS: Polymorphisms in p16(INK4A) were detected in 3 of 50 samples, but no inactivating mutations were detected in any of the genes screened. Promoter hypermethylation of p16(INK4A) was detected in 5 of 55 tumors, and loss of heterozygosity of the p16(INK4A) locus was detected in 5 of 16 tumors. CONCLUSIONS: Most primary uveal melanomas do not appear to contain somatic mutations in Smad4, TGFbetaR2, p14(ARF), p15(INK4B), p16(INK4A), or beta-catenin. However, methylation of the p16(INK4A) promoter and loss of heterozygosity of the p14(ARF)-p16(INK4A) locus occurs in some tumors.

The chemosensitivity profile of retinoblastoma.

Retinoblastoma is a rare malignant tumour of the developing retina with an incidence of 1 in 20,000 live births in all human races. Chemotherapy is used in retinoblastoma as adjuvant therapy to prevent the growth of metastases and to treat metastatic disease once this has become clinically apparent. Current regimens are based on empirical drug combinations, and few clinical trials have been conducted because of the rarity of this tumour. Chemosensitivity testing offers a way of testing a large number of agents against tumours. The ATP-based chemosensitivity assay (ATP-TCA) has already helped to design new regimens for melanoma and breast and ovarian cancer. Primary retinoblastoma tumour material was obtained from 10 eyes, 7 of which contained sufficient viable cells for ATP-TCA. The results show very high sensitivity to single agents, particularly cisplatin, doxorubicin and vinca aLkaloids. Of the anti-metabolites tested, 5-FU is relatively disappointing (although still active), and gemcitabine shows considerable activity consistent with a cytotoxic effect. The shape of the inhibition curves is interesting. There is a plateau effect with the topoisomerase inhibitors and vinblastine, which is not present with the cisplatin. One tumour was much more resistant than the others tested, particularly to vinblastine but also to the topoisomerase inhibitors, which failed to achieve complete kill at any concentration tested, consistent with a multidrug resistance phenotype. Of the combinations (VAC and VEC), the VAC regimen looks marginally more active in the more resistant of the two cases tested to date. These data confirm that retinoblastoma is a rapidly growing malignancy that is very susceptible to cytotoxic drugs of all types. Chemosensitivity testing provides a practical method of testing new regimens before clinical trials in retinoblastoma patients.