Amer Sami

Extrapulmonary small cell cancer: a Canadian province's experience.

The objective of this study was to determine variables that correlate with the survival of patients with extrapulmonary small cell carcinoma (EPSCC).

HER2-directed therapy: current treatment options for HER2-positive breast cancer

Over the past decade, the management of HER2-positive breast cancer has evolved dramatically. In addition to advances in screening, genetic testing, imaging, surgical and radiation techniques, innovations in medical therapy including widespread use of HER2-directed therapy in early and advanced breast cancer have revolutionized breast cancer care and changed the natural history of HER2-positive breast cancer. A substantial number of HER2-targeted agents are being developed including monoclonal antibodies, small molecule inhibitors, and antibody drug conjugates. Trastuzumab is the prototype HER2-directed therapy that was introduced in the late 1990s for the management of metastatic breast cancer and later showed efficacy in early stage disease. Despite the practice changing impact of trastuzumab and improvement in outcomes of women with HER2-positive breast cancer resistance to trrastuzumab is a major clinical issue, occurring in both early stage and advanced disease, and new treatment strategies are clearly required. Combining HER2-targeted agents and dual HER2 blockade has been successful in early and advanced breast cancer. Furthermore, selected delivery of potent chemotherapeutic agent coupled with HER2 inhibition promises new treatment options. This review is focused on current HER2-directed treatments for women with HER2-positive breast cancer including monoclonal antibodies, small molecule inhibitors, and antibody drug conjugates.

Early Discontinuation but Not the Timing of Adjuvant Therapy Affects Survival of Patients With High-Risk Colorectal Cancer: A Population-Based Study

BACKGROUND: Adjuvant therapy results in significant improvement in survival of patients with high-risk colorectal cancer. Little is known about the significance of timing and early discontinuation of adjuvant treatment in such patients. Our study aims to determine the prognostic impact of timing and completion of adjuvant therapy in patients with high-risk colorectal cancer. METHODS: Medical records of patients with stage III colon and stage II/III rectal cancer diagnosed between 1993 and 2000 in the province of Saskatchewan were reviewed. Cox proportional hazards models were used to analyze the impact of timing and completion of adjuvant therapy on survival. RESULTS: Six hundred sixty-three eligible patients with a median age of 66 years were identified. Sixty-five percent patients received adjuvant <56 days after surgery and 79% patients completed planned treatment. Median follow-up was 54.6 months. Five-year disease-free survival and overall survival of patients who received adjuvant therapy <56 days after surgery was 54.6% and 59.5%, respectively, compared with 51.9% and 57.1%, respectively, of patients who received therapy ≥56 days after surgery (P = NS). The five-year disease disease-free survival and overall survival of patients who completed planned treatment was 56.7% and 62.3%, respectively, compared with 42.1% and 45%, respectively, of patients who required early treatment discontinuation (P < .0001). On multivariate analysis, age ≥65 years, T4 tumor, grade 3 cancer, node-positive disease, rectal tumor, and early treatment discontinuation were identified as poor prognostic factors. CONCLUSIONS: Although time to adjuvant therapy following surgical resection did not impact the outcomes, failure to complete planned therapy was associated with adverse prognosis.

Heterologous human/rat HER2-specific exosome-targeted T cell vaccine stimulates potent humoral and CTL responses leading to enhanced circumvention of HER2 tolerance in double transgenic HLA-A2/HER2 mice

DNA vaccines composed of heterologous human HER2 and rat neu sequences induce stronger antibody response and protective antitumor immunity than either HER2 or neu DNA vaccines in transgenic mice. We previously developed HER2-specific exosome-targeted T-cell vaccine HER2-TEXO capable of stimulating HER2-specific CD8+ T-cell responses, but only leading to partial protective immunity in double-transgenic HLA-A2/HER2 mice with self-immune tolerance to HER2. Here, we constructed an adenoviral vector AdVHuRt expressing HuRt fusion protein composed of NH2-HER21-407 (Hu) and COOH-neu408-690 (Rt) fragments, and developed a heterologous human/rat HER2-specific exosome-targeted T-cell vaccine HuRt-TEXO using polyclonal CD4+ T-cells uptaking exosomes released by AdVHuRt-transfected dendritic cells. We found that the HuRt-TEXO vaccine stimulates enhanced CD4+ T-cell responses leading to increased induction of HER2-specific antibody (∼70 µg/ml) compared to that (∼40 µg/ml) triggered by the homologous HER2-TEXO vaccine. By using PE-H-2Kd/HER223-71 tetramer, we determined that HuRt-TEXO stimulates stronger HER2-specific CD8+ T-cell responses eradicating 90% of HER2-specific target cells, while HER2-TEXO-induced CD8+ T-cell responses only eliminating 53% targets. Furthermore, HuRt-TEXO, but not HER2-TEXO vaccination, is capable of suppressing early stage-established HER2-expressing 4T1HER2 breast cancer in its lung metastasis or subcutaneous form in BALB/c mice, and of completely protecting transgenic HLA-A2/HER2 mice from growth of HLA-A2/HER2-expressing BL6-10A2/HER2 melanoma. HuRt-TEXO-stimulated HER2-specific CD8+ T-cells not only are cytolytic to trastuzumab-resistant HLA-A2/HER2-expressing BT474/A2 breast tumor cells in vitro but also eradicates pre-established BT474/A2 tumors in athymic nude mice. Therefore, our novel heterologous human/rat HER2-specific T-cell vaccine HuRt-TEXO, circumventing HER2 tolerance, may provide a new therapeutic alternative for patients with trastuzumab-resistant HER2+ breast tumor.

Largest series of extrapulmonary small cell carcinoma (ESCC): The Saskatchewan Experience

9681 Background: : Although ESCC has been recognized as a rare and distinct clinicopathologic entity, limited data is available about its clinical behavior and outcome. Our experience with ESCC over the past 3 decades is presented here. METHODS Patients with ESCC were identified using Saskatchewan Cancer Registry - Canada, from 1971-2002. Diagnosis was based on immunohistochemistry and/or morphology. Patients with abnormal chest radiology at diagnosis or with well-differentiated neuroendocrine tumor or Merkel cell carcinoma were excluded. Survival was calculated using the Kaplan-Meier method. RESULTS A total of 101 eligible patients with ESCC were identified. Median age was 72 yrs (24-100) and M:F was 1.4:1. Median duration of symptoms prior to definitive diagnosis was 2 months [m] (0.25-40). 51 patients had localized disease and 50 had extensive disease.No significant difference was noted in age, gender distribution, comorbid illness, and incidence of of secondary cancer, however 96% of patients with limited disease (LD) had ECOG performance status of ≤2 compared with 52% in extensive disease (ED) [p=<0.0001]. The primary disease sites were as follows: Breast n=9; gastrointestinal n=20, genitourinary n=18, gynecologic n=11, head & neck n=10, thymus n=2, and unknown primary n=31 . Ninety percent of patients with LD received treatment and 98% of them had an objective response (OR). In contrast, 54% patients with ED received therapy and 44% of them had OR(p<0.0001). Median progression/relapse free survival in responding patients with LD was 20+ m (2-276) compared with 12+ m (2-68) in ED (p<0.0001). All the patients with LD had median OS of 34+ m (0.2-276) compared with 2+ m (0.1-108) in patients with ED (p<0.0001). 5 year survival in patients with LD was 31% compared with 2% in patients with ED. CONCLUSIONS Our results reveal that natural history of ESCC seems comparable to small cell carcinoma of lung and that extent of disease is an important factor predicting survival. No significant financial relationships to disclose.

Extra-Pulmonary Small Cell Cancer: Diagnosis, Treatment, and Prognosis

Small cell carcinoma (SCC) is a high grade epithelial cancer of neuroendocrine origin, which is considered to be a distinct cinicopathological entity. It has been reported in the literature by using various terminologies including oat cell carcinoma, anaplastic carcinoma, small cell undifferentiated carcinoma, undifferentiated carcinoma, microcytoma, reserve cell carcinoma, small cell neuroendocrine carcinoma, Kulchitsky cell carcinoma, and carcinoma with amineprecursor uptake and decarboxylase (APUD) cell differentiation. Small cell carcinoma is, however, the recommended pathological term (Beasley et al., 2005). It is most commonly of bronchogenic origin and accounts for about 20–25% of all pulmonary malignancies (Hoffman et al., 2006). Small cell carcinoma of lung is well recognized for its aggressive clinical behavior and an increased propensity for early metastases. Uncommonly, SCCs can originate in non-pulmonary organs and are collectively known as “extrapulmonary small cell carcinoma” (Remick et al., 1987; Remick and Ruckdeschel, 1992). Extrapulmonary small cell carcinoma (EPSCC) often represents a diagnostic and therapeutic challenge. In 1930, it was first reported in the mediastinal glands without pathologic evidence of primary pulmonary involvement (Duguid and Kennedy, 1930). Since its first description, EPSCC has been reported in virtually all anatomical sites. The primary sites most frequently involved are gynecologic organs, especially the cervix; genitourinary organs, especially the urinary bladder and the prostate gland; the gastrointestinal tract, especially the esophagus, and head and neck region. In addition, SCC has been reported in the breast, thyroid, skin, and thymus gland. If the primary site remains undetected, these tumors are known as small cell carcinoma of unknown primary. Limited data are available regarding its clinical behavior and outcome. The available literature is predominantly based on reviews of published cases or analysis of institutional data (Remick and Ruckdeschel, 1992; Vrouvas and Ash, 1995). In general, EPSCCs resemble their pulmonary counterparts with respect to purported histogenesis, morphology, and behavior. The clinico-pathological features, diagnosis, and general management of EPSCC are reviewed here, followed by a brief description of

A phase II trial of alternating cycles of carboplatin/paclitaxel and carboplatin/gemcitabine for stage IIIB/IV non-small cell lung cancer

19113 Background: Combination chemotherapies have demonstrated response rate (RR) of 30–50% with median survival of only approx 10 months for patients with stage IIIB/ IV NSCLC. Therefore it is important to search for new agents or new combinations of existing regimens. Goldie and Codman model proposed that alternating non-cross resistant combinations would prevent the overgrowth of resistant cancer cells and improve the probability of tumor control. We conducted a phase II study at Saskatoon Cancer Ctr, (Canada) to determine clinical response of Carboplatin/Paclitaxel (C/P) alternating with Carboplatin/Gemcitabine (C/G) for advanced NSCLC. Methods: Patients with chemotherapy naive Stage IIIB or IV NSCLC, ECOG PS ≤2, with measurable or evaluable disease and no known CNS metastases were eligible. Chemotherapy consisted of Paclitaxel (175 mg/m2) and Carboplatin (AUC=5) day 1 alternating with Carboplatin (AUC=5) day 1 and Gemcitabine 1000 mg/m2 days 1 and 8 every three weeks for a total of six cycles. Primar...

Long term outcomes in malignant hemangiopericytoma

9072 Background: Malignant hemangiopericytoma (MH) is a rare entity, arising from the capillary pericyte. Limited data is available regarding its clinical behavior and outcome. We present a series of patients with long term follow up period. Methods: Clinical characteristics, pathologic data and treatment of 14 patients diagnosed with MH between 1972 and 1992, at our centre, were reviewed retrospectively. All cases were biopsy proven. Survival was determined by using Kaplan-Meier curve. Results: The median age was 49 yrs. (range 34 - 74) and male: female ratio was 1:6. The primary disease sites were as follows: intracranial meningeal 5 (35.7%), extremities 3 (21.4%), uterus 3 (21.4%), metastatic 2 (14.3%), sinonasal 1 (7.1%). Thirteen patients had complete surgical resection of tumor at initial presentation. Two patients got post operative RT. No patient got adjuvant chemotherapy. Two patients got chemotherapy on disease recurrence. Median survival was 14 years. Out of 12 patients with localized disease, ...