Bita Esmaeli

Phase II Study of Weekly Docetaxel and Trastuzumab for Patients With HER-2–Overexpressing Metastatic Breast Cancer

PURPOSE To evaluate the safety and efficacy of weekly docetaxel plus trastuzumab in women with HER-2-overexpressing metastatic breast cancer. Efficacy was correlated with serum HER-2 extracellular domain (ECD) levels. PATIENTS AND METHODS Thirty women with metastatic breast cancer were treated with weekly docetaxel and trastuzumab as first- or second-line therapy. Both docetaxel 35 mg/m(2)/wk and trastuzumab 2 mg/kg/wk were delivered in 4-week cycles consisting of three weekly treatments followed by 1 week of rest. A loading dose of trastuzumab 4 mg/kg was administered 1 day before the start of the first cycle. RESULTS The median delivered dose-intensity of docetaxel was 24 mg/m(2)/wk (range, 18 to 27 mg/m(2)/wk). The intent-to-treat overall response rate (ORR) was 63% (95% confidence interval [CI], 44% to 80%). The ORR in patients whose tumors were HER-2-positive by fluorescence in situ hybridization was 67% (16 of 24 patients; 95% CI, 45% to 84%). In patients with elevated serum HER-2 ECD at baseline, the ORR was 76% (95% CI, 53% to 92%), compared with 33% (95% CI, 7% to 70%) in patients with low HER-2 ECD levels (P =.04). Variations in HER-2 ECD concentrations during treatment correlated with response to treatment. Median time to progression was 9 months. Acute toxicity, including myelosuppression, was mild. Fatigue, fluid retention, and excessive tearing became more common with repetitive dosing. CONCLUSION Weekly docetaxel and trastuzumab is an active combination for treating patients with HER-2-overexpressing metastatic breast cancer. Serum HER-2 ECD testing may be a promising method for monitoring patients on trastuzumab-based therapy.

Metastatic tumors of the orbit and ocular adnexa.

Purpose of review The management of cancer metastatic to the orbit and ocular adnexa (eyelid and periocular structures) has changed in recent decades. The purpose of this article is to review the incidence, presentation, and clinical features of metastatic tumors of the orbit and ocular adnexa and discuss their multidisciplinary care. Recent findings The improved survival of patients with common cancers such as breast cancer and prostate cancer, together with aging of the population has led to a higher incidence of patients living with metastatic disease in unusual sites such as the orbit and ocular adnexa. Furthermore, vigilant surveillance and advances in diagnostics have led to increased detection of orbital metastases. Treatment of metastatic lesions in the orbit and ocular adnexa is usually palliative and may include radiotherapy, chemotherapy, hormonal therapy, surgery, or a combination of these modalities. Summary Breast carcinoma continues to account for the majority of metastatic lesions of the orbit and ocular adnexa. Although the overall prognosis for patients with such lesions remains poor, the longer survival time for patients with breast carcinoma, the availability of novel targeted treatment options and new investigational agents, and advances in radiotherapy techniques may lead to better quality of life and preservation of ocular function for patients with metastatic orbital tumors.

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.

Outcomes in Patients with Adenoid Cystic Carcinoma of the Lacrimal Gland

Purpose To evaluate the outcomes among patients with adenoid cystic carcinoma of the lacrimal gland treated at various stages of their disease at a tertiary care cancer center. Methods A retrospective case series of 20 patients with adenoid cystic carcinoma of the lacrimal gland treated at a single institution between 1952 and 2002. Clinical records were available for all 20 patients; histologic sections from 12 of the 20 patients were available for review. Disease-free survival was measured from the completion of treatment; overall survival was measured from the date of initial diagnosis. Results The study included 6 men and 14 women. The mean age at diagnosis was 39.5 years. The median follow-up time was 34 months (range, 6 to 264 months). The local/regional treatment modalities included exenteration with bone removal and radiation therapy (RT) in 5 patients, exenteration with RT (no bone removal) in 8 patients, exenteration (no RT or bone removal) in 1 patient, exenteration with bone removal (no RT) in 1 patient, local resection with RT in 3 patients, and local resection without RT in 2 patients. Overall, 16 patients had RT as part of their treatment regimen. Seven patients (35%) had local recurrence. Sixteen patients (80%) had distant metastasis during the study period. At the time of this report, 13 (65%) of the patients had died of disease. The median disease-free survival for the entire group was 18 months. Eight patients had a predominantly basaloid histologic pattern. Ten patients had verifiable histologic evidence of perineural invasion. Conclusions This study underscores the generally grave prognosis for patients with adenoid cystic carcinoma of the lacrimal gland and the difficulty in making any conclusive recommendations for local therapy for this disease.

Phase 3 study comparing the use of docetaxel on an every-3-week versus weekly schedule in the treatment of metastatic breast cancer†

Previous studies have evaluated 3‐week and weekly docetaxel schedules in patients with metastatic breast cancer (MBC). The varying efficacy results and toxicity profiles noted in these earlier studies led to a comparison of the schedules to determine which was safer and more efficacious.

Meta-analyses of the association between Chlamydia psittaci and ocular adnexal lymphoma and the response of ocular adnexal lymphoma to antibiotics.

There are conflicting reports regarding the association between Chlamydia psittaci (Cps) and ocular adnexal lymphoma (OAL) and the efficacy of antibiotics for OAL. In the current study, the authors attempted to clarify the association between Cps and OAL and the efficacy of antibiotics for OAL.

Combination Small Molecule MEK and PI3K Inhibition Enhances Uveal Melanoma Cell Death in a Mutant GNAQ and GNA11 Dependent Manner

Purpose: Activating Q209L/P mutations in GNAQ or GNA11 (GNAQ/11) are present in approximately 80% of uveal melanomas. Mutant GNAQ/11 are not currently therapeutically targetable. Inhibiting key down-stream effectors of GNAQ/11 represents a rational therapeutic approach for uveal melanomas that harbor these mutations. The mitogen-activated protein/extracellular signal–regulated kinase/mitogen-activated protein kinase (MEK/MAPK) and PI3K/AKT pathways are activated in uveal melanoma. In this study, we test the effect of the clinically relevant small molecule inhibitors GSK1120212 (MEK inhibitor) and GSK2126458 (pan class I PI3K inhibitor) on uveal melanoma cells with different GNAQ/11 mutation backgrounds. Experimental Design: We use the largest set of genetically annotated uveal melanoma cell lines to date to carry out in vitro cellular signaling, cell-cycle regulation, growth, and apoptosis analyses. RNA interference and small molecule MEK and/or PI3K inhibitor treatment were used to determine the dependency of uveal melanoma cells with different GNAQ/11 mutation backgrounds on MEK/MAPK and/or PI3K/AKT signaling. Proteomic network analysis was done to unveil signaling alterations in response to MEK and/or PI3K small molecule inhibition. Results: GNAQ/11 mutation status was not a determinant of whether cells would undergo cell-cycle arrest or growth inhibition to MEK and/or phosphoinositide 3-kinase (PI3K) inhibition. A reverse correlation was observed between MAPK and AKT phosphorylation after MEK or PI3K inhibition, respectively. Neither MEK nor PI3K inhibition alone was sufficient to induce apoptosis in the majority of cell lines; however, the combination of MEK + PI3K inhibitor treatment resulted in the marked induction of apoptosis in a GNAQ/11 mutant–dependent manner. Conclusions: MEK + PI3K inhibition may be an effective combination therapy in uveal melanoma, given the inherent reciprocal activation of these pathways within these cells. Clin Cancer Res; 18(16); 4345–55. ©2012 AACR.

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.

Patterns of regional and distant metastasis in patients with conjunctival melanoma: Experience at a cancer center over four decades

OBJECTIVE The regional lymph nodes generally are believed to be the most common first site of metastasis for conjunctival malignant melanoma, but the pattern of nodal metastasis in this disease has not been well established. The goal of this study was to determine the frequency, location, and timing of regional lymph node metastasis in patients with conjunctival melanoma treated at one cancer center over four decades. DESIGN Retrospective case series. PARTICIPANTS Twenty-seven patients. METHODS The clinical records of 27 patients with conjunctival malignant melanoma were reviewed retrospectively. MAIN OUTCOME MEASURES The rates of local conjunctival recurrence, regional nodal metastasis, and distant metastasis were analyzed along with overall survival. The follow-up time ranged from 2.5 to 17 years (median, 6 years). RESULTS Eleven patients (41%) experienced clinical regional lymph node metastasis 1.5 to 6.0 years (mean, 3.2 years) after the initial diagnosis. The involved lymphatics were the preauricular (parotid) nodes in 8 patients (73%), the submandibular nodes in 1 patient (9%), and the deeper cervical nodes in 2 patients (18%). In seven patients (26%), distant metastasis developed without evidence of prior or concurrent regional nodal disease. Patients in whom distant metastasis developed without clinical evidence of regional nodal involvement were more likely to have had local conjunctival recurrence (P = 0.03) and a higher number of local recurrences (P = 0.05) compared with patients with regional lymph nodes as the site of first metastasis. The 5- and 10-year overall survival rates were 74% and 41%, respectively. CONCLUSIONS Regional lymph node metastasis occurred in a higher percentage of patients with conjunctival malignant melanoma than has been reported previously. Preauricular lymph nodes were most commonly involved. Distant metastasis without prior or concurrent lymph node involvement was not a rare event.

Experience with sentinel lymph node biopsy for eyelid and conjunctival malignancies at a cancer center.

Purpose: To describe one center’s experience with sentinel lymph node (SLN) biopsy in patients with eyelid and conjunctival malignancies performed with a smaller volume of technetium than was initially used and a small incision directly overlying the sentinel node(s). Methods: A noncomparative interventional case series of 13 patients with clinically negative regional lymph nodes who underwent SLN biopsy for eyelid or conjunctival malignancies at The University of Texas M. D. Anderson Cancer Center between May 2002 and July 2003. Preoperative lymphoscintigraphy was performed with an injection of 0.3 mCi of technetium Tc-99m sulfur colloid in a volume of 0.2 mL. Images were taken as soon as the first SLN was detected through the gamma camera. Intraoperative mapping was performed with the same volume and concentration of technetium Tc-99m sulfur colloid along with an injection of isosulfan blue dye. Results: Five patients had conjunctival melanoma, 6 had sebaceous cell carcinoma of the eyelid, and 2 had eyelid melanoma. SLN(s) were identified in all patients. In 12 patients, more than 1 SLN was identified. During surgery, no SLNs were blue. One patient with conjunctival melanoma had an SLN that was positive on histologic examination. There were no ocular or extraocular complications from the procedure except for mild temporary weakness of the marginal mandibular branch of the facial nerve in 2 patients that resolved completely within 4 to 6 weeks and without any further intervention. None of the patients had permanent blue tattooing of the conjunctival surface or eyelid skin. Conclusions: Our experience suggests that lymphoscintigraphy and SLN biopsy with a small volume of technetium Tc-99m sulfur colloid and small incisions, even without the use of the blue dye, can identify SLNs in patients with conjunctival and eyelid malignancies, and can be performed safely.