The most frequent site of ocular metastasis is the choroid. The occurrence of choroidal metastases has increased steadily due to the longer survival of metastatic patients and the improvement of diagnostic tools. Fundoscopy, ultrasonography, and fluorescein angiography are now complemented by indocyanine green angiography and optical coherence tomography. Choroidal tumor biopsy may also confirm the metastatic nature of the tumor and help to determine the site of the primary malignancy. There is currently no consensus on the treatment strategy. Most patients have a limited life expectancy and for these complex treatments are generally not recommended. However, recent advances in systemic therapy have significantly improved survival of certain patients who may benefit from an aggressive ocular approach that could preserve vision. Although external beam radiation therapy is the most widely used treatment, more advanced forms of radiotherapy that are associated with fewer side effects can be proposed in select cases. In patients with a shorter life expectancy, systemic therapies such as those targeting oncogenic drivers, or immunotherapy can induce a regression of the choroidal metastases, and may be sufficient to temporarily decrease visual symptoms. However, they often acquire resistance to systemic treatment and ocular relapse usually requires radiotherapy for durable control. Less invasive office-based treatments, such as photodynamic therapy and intravitreal injection of anti-VEGF, may also help to preserve vision while reducing time spent in medical settings for patients in palliative care. The aim of this review is to summarize the current knowledge on choroidal metastases, with emphasis on the most recent findings in epidemiology, pathogenesis, diagnosis and treatment.

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Chronic lymphocytic leukemia (CLL) cells express high-levels of Bcl-2-family proteins that inhibit apoptosis, enhancing leukemia-cell survival and drug-resistance. AT-101 (Ascenta Therapeutics, Inc.) is an orally active BH3-mimetic that inhibits the anti-apoptotic activity of Bcl-2, Bcl-XL, and Mcl-1, and induces CLL cells to undergo apoptosis. (Prada et. al., ASH 2005). AT-101 also enhanced the cytotoxicity of rituximab for CLL cells in vitro (James et. al., ASH 2005). These in vitro effects of AT-101 were concentration and time-dependent. We are conducting a phase 2 trial to evaluate the safety and activity of AT-101 by two dosing schedules, used in combination with rituximab to treat patients with relapsed/refractory CLL. We previously reported (Castro et. al., ASH 2006) on 12 patients who received up to 12 weeks of AT-101, 30 mg daily for 3 out of every 4 weeks, with rituximab, 375 mg/m2 for 12 doses (total dose = 4,500 mg/m2) on days 1, 3, 5, 8, 15, 22, 29, 31, 33, 40, 57, 59, 61. Here we describe initial results from a second cohort (n=6) treated with intermittent, “pulse” AT-101, 80 mg/d on days 1–3 and 15–17 of each 28-day cycle, in combination with weekly rituximab, 375 mg/m2/week. To date, 6 patients have received “pulse” AT-101. Patient demographic characteristics and risk prognostic status (ZAP70, IgVH mutational status, and cytogenetics / FISH) are comparable between the two dose cohorts. Gastrointestinal (GI) toxicity, the most notable adverse effect of AT-101 with daily administration, appears reduced with intermittent AT-101; 2/6 patients have had NCI-CTCAE Grade 1–2 GI toxicity, and 0/6 have had Grade 3–4 ileus, compared with 11/12 and 2/12 patients, respectively, in the daily dose cohort. Apoptosis of CLL cells evaluated by Annexin V FACS at the time of maximum AT-101 concentration, was present in 18–45% of cells in 4 of the 6 patients after a single 80 mg dose of AT-101. By comparison, apoptosis after a 30 mg AT-101 dose appeared lower and was detected in approximately 1–15% of cells. After 80 mg of AT-101, plasma concentrations of up to 6.6 μM have been observed compared with concentrations of approximately 0.8–1.8 μM after a 30 mg dose in the daily dose cohort. In the “pulse” AT-101 cohort we have observed partial responses (PR) in 3 patients while the other 3 are still receiving treatment. Five (5) out of 12 patients had a PR in the previously reported AT-101 continuous administration group. Intermittent administration of AT-101 with a “pulse” dose regimen appears associated with an increased pro-apoptotic effect in vivo and higher plasma concentrations, as well as reduced toxicity, when compared with daily dosing. Enrollment continues to confirm these observations and assess whether clinical activity in combination with rituximab is increased with “pulse” dosing of AT-101.

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6605 Background: CLL pts with early stage disease are often observed under a “watch and wait” approach. Unmutated immunoglobulin variable-region gene (IgVH); expression of zeta chain associated kinase (ZAP-70); CD38 expression; and cytogenetics abnormalities identify pts with a tendency for early disease progression. Whether pts with these high-risk features may benefit from early intervention warrants investigation in clinical trials. Gossypol, a naturally occurring compound in cotton seeds has been extensively studied in clinical trials and is well tolerated with a favorable safety profile. AT-101, a derivative of R-(-)-gossypol binds to Bcl-2 family proteins and induces apoptosis of CLL cells in vitro. Dysregulated expression of Bcl-2 proteins is critical for CLL leukemogenesis and is an attractive therapeutic target. Methods: We conducted a phase I study to evaluate the safety and tolerability of single agent AT-101 in treatment naïve CLL pts with high-risk features. Clinical activity, pharmacokinetics, and pharmacodynamics were assessed. Results: 7 pts were treated with AT-101 at doses of 20–40mg daily. Pt characteristics: median age 55, median Rai stage II, elevated ZAP-70 (57%), high CD38 (71%), unmutated IgVH (57%), trisomy 12 (43%), and loss of 17p (43%). AT-101 was well tolerated with no grade 4 toxicities, hospitalizations, deaths. Maximum toxicity in 6 evaluable pts was grade III transaminase elevation at week 7, with complete resolution following discontinuation of AT-101. Other most common adverse events, all Grade 1–2 include: elevated transaminases; nausea; fatigue; diarrhea; and hypokalemia. No hematologic toxicity was observed. 5/6 pts had decrease in lymphocyte count, 6/6 had reduction in lymphadenopathy, and 5/5 with palpable spleens had reduction in spleen size. Cmax for 30mg (n=3) and 40mg (n=2) dose of AT-101 was 570ng/ml and 660ng/ml at a Tmax of 4.3 and 4.4 hrs. Tmax correlated with in vivo apoptosis studies revealing maximum leukemic cell apoptosis occurring at 4hrs and poly(ADP-ribose) polymerase cleavage. Conclusions: AT-101 is safe and well tolerated, induces in vivo leukemia cell apoptosis, and may have clinical activity in previously untreated pts with CLL and high risk features. No significant financial relationships to disclose.

Purpose: To evaluate quantitative alterations of the choriocapillaris in swept-source optical coherence tomography angiography in diabetic patients.Methods: We included normal patients and diabetic patients with and without diabetic retinopathy (DR), excluding patients with macular edema. Angiograms in 3 • 3 mm were acquired with Plexelite 9000 swept-source optical coherence tomography angiography. Choroidal flow voids were analyzed after removal of projection artifacts. The main evaluation was the correlation between choroidal flow voids area (FVA-CC) and DR stage.Results: A total of 120 eyes of 72 patients were analyzed. There were 17 eyes from healthy subjects, 30 eyes without DR, 22 eyes with minimal nonproliferative DR, 30 eyes with moderate nonproliferative DR, 16 eyes with severe nonproliferative DR, and 5 eyes with proliferative DR (PDR). The percentage of FVA-CC for each group was, respectively,

Spondyloarthritis (Spa), Behçet’s disease (BD) and sarcoidosis are major systemic inflammatory diseases worldwide. They are all multisystem pathologies and share a possible ocular involvement, especially uveitis. We hereby describe selected cases who were referred by ophthalmologists to our internal medicine department for unexplained uveitis. Physical examination and/or the use of laboratory and imaging investigations allowed to make a diagnosis of a systemic inflammatory disease in a large proportion of patients. In our tertiary referral center, 75 patients have been diagnosed with Spa (n = 20), BD (n = 9), or sarcoidosis (n = 46) in the last two years. There was a significant delay in the diagnosis of Spa-associated uveitis. Screening strategies using Human Leukocyte Antigen (HLA)-B27 determination and sacroiliac magnetic resonance imaging in patients suffering from chronic low back pain and/or psoriasis helped in the diagnosis. BD’s uveitis affects young people from both sexes and all origins and usually presents with panuveitis and retinal vasculitis. The high proportion of sarcoidosis in our population is explained by the use of chest computed tomography (CT) and 18F-fluorodeoxyglucose positron emission tomography CT that helped to identify smaller hilar or mediastinal involvement and allowed to further investigate those patients, especially in the elderly. Our results confirm how in these sight- and potentially life-threatening diseases a prompt diagnosis is mandatory and benefits from a multidisciplinary approach.

Ocular metastases are the most frequent ocular malignant tumors; their prevalence is estimated around 5–10% and is even higher in patients with breast or lung cancer. They represent various clinical situations, but they share the same hierarchical multidisciplinary therapeutic challenge with respect to the way systemic and local therapies should be selected in combination or sequentially in the personalized medical history of a patient. The challenges include tumor control, eye preservation, and the minimization of iatrogenic damage to sensitive tissues surrounding the tumor in order to preserve vision. These aims should further contribute to maintaining quality of life in patients with metastases. Many patients with choroidal metastases have systemic molecular treatment for their primary tumor. However, secondary resistance to systemic treatment is common and may ultimately be associated with cancer relapse, even after an initial response. Therefore, it makes sense to propose local treatment concomitantly or after systemic therapy to provide a more sustainable response. The aim of this review is to present current therapeutic strategies in ocular metastases and discuss how to tailor the treatment to a specific patient.