Delaying Chemotherapy in the Treatment of Stage IV Non-Small Cell Lung Cancer Does Not Adversely Affect Survival Outcome

Background: Whether a delay in the initiation of chemotherapy for advanced non-small cell lung cancer (NSCLC) can affect overall survival is not well studied. We aim to evaluate the effect of the time interval between diagnosis and initiation of chemotherapy on overall survival in patients with stage IV NSCLC. Methods: A retrospective review of newly diagnosed stage IV NSCLC patients who received chemotherapy between 1995 and 2012 was conducted. Demographics, histology and site(s) of metastases of patients were reviewed. Time interval between the date of diagnosis and the date of starting chemotherapy was calculated in days. Patients were divided in two groups based on median time interval: Group A \u3c 46 days and group B \u3e 46 days. The primary end point was the difference in overall survival between the two groups. Results: A total of 172 patients were reviewed. Each group had 86 patients. Median age for both groups was 61 years. The most common histology was adenocarcinoma in A and B (43% vs. 45%, respectively). The sites of metastases in A and B were: brain (25% vs. 28%), liver (20% vs. 9%), bone (30% vs. 30%), respectively. Performance status of ECOG (Eastern Cooperative Oncology Group) :( 0-1) was 82% vs. 76% in A and B, respectively. The median overall survival for A was 7 months vs.12 months for B (p=0.04). Conclusion: In this single institution review, delayed chemotherapy for stage IV NSCLC more than 46 days did not have a detrimental effect on overall survival and even suggested a better outcome. Further larger and prospective studies are warranted to validate these findings

A unique case of chronic myeloid leukemia presenting as monocular vision loss with unilateral retinopathy

Purpose: To report a case of unilateral leukemic retinopathy secondary to chronic myeloid leukemia (CML). Observations: Patient presented to clinic with a visual acuity (VA) of 20/200 in the right eye (OD) after several months of progressive monocular vision loss and was found to have dense pre-retinal hemorrhage. Patient underwent 23-gauge pars plana vitrectomy to clear the preretinal hemorrhage along with a complex macula-off retinal detachment repair to address retinal tear and multilayer retinal hemorrhage. The patient was subsequently diagnosed with CML as she was found to be positive for the fusion protein of break point cluster gene (BCR) with Abelson tyrosine kinase (ABL1), BCR-ABL1, upon systemic work-up. Imatinib therapy resulted in complete hematologic and cytogenetic resolution after one month, however, the patient's vision remained unchanged six months after surgery. Conclusion and importance: To the authors' knowledge, this is the first reported case of unilateral leukemic retinopathy secondary to low risk CML, as determined by the Sokal and Hasford prognostic scoring systems. CML should be included in the differential diagnosis of patients with progressive monocular vision loss with suspicious multi-layer retinal compromise. Keywords: BCR-ABL1, Chronic myeloid leukemia, Hasford, Imatinib, Monocular vision loss, Sokal, Unilateral retinopath

Fatty acid synthase is a key enabler for endocrine resistance in heregulin-overexpressing luminal b-like breast cancer

HER2 transactivation by the HER3 ligand heregulin (HRG) promotes an endocrine-resistant phenotype in the estrogen receptor-positive (ER+) luminal-B subtype of breast cancer. The underlying biological mechanisms that link them are, however, incompletely understood. Here, we evaluated the putative role of the lipogenic enzyme fatty acid synthase (FASN) as a major cause of HRG-driven endocrine resistance in ER+/HER2-negative breast cancer cells. MCF-7 cells engineered to stably overexpress HRG (MCF-7/HRG), an in vitro model of tamoxifen/fulvestrant-resistant luminal B-like breast cancer, showed a pronounced up-regulation of FASN gene/FASN protein expression. Autocrine HRG up-regulated FASN expression via HER2 transactivation and downstream activation of PI-3K/AKT and MAPK-ERK1/2 signaling pathways. The HRG-driven FASN-overexpressing phenotype was fully prevented in MCF-7 cells expressing a structural deletion mutant of HRG that is sequestered in a cellular compartment and lacks the ability to promote endocrine-resistance in an autocrine manner. Pharmacological inhibition of FASN activity blocked the estradiol-independent and tamoxifen/fulvestrant-refractory ability of MCF-7/HRG cells to anchorage-independently grow in soft-agar. In vivo treatment with a FASN inhibitor restored the anti-tumor activity of tamoxifen and fulvestrant against fast-growing, hormone-resistant MCF-7/HRG xenograft tumors in mice. Overall, these findings implicate FASN as a key enabler for endocrine resistance in HRG+/HER2-breast cancer and highlight the therapeutic potential of FASN inhibitors for the treatment of endocrine therapy-resistant luminal-B breast cancer.Fil: Menendez, Javier A.. Institut D'investigació Biomèdica de Girona Dr. Josep Trueta; España. Institut Català d'Oncologia ; EspañaFil: Mehmi, Inderjit. The Angeles Clinic And Research Institute; Estados UnidosFil: Papadimitropoulou, Adriana. Academy of Athens; GreciaFil: Steen, Travis Vander. Mayo Clinic; Estados UnidosFil: Cuyàs, Elisabet. Institut D'investigació Biomèdica de Girona Dr. Josep Trueta; España. Institut Català d'Oncologia ; EspañaFil: Verdura, Sara. Institut Català d'Oncologia ; España. Institut D'investigació Biomèdica de Girona Dr. Josep Trueta; EspañaFil: Espinoza, Ingrid. University of Mississippi; Estados UnidosFil: Vellón, Luciano. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Atlas, Ella. University of Ottawa; CanadáFil: Lupu, Ruth. Mayo Clinic Cancer Center; Estados Unidos. Mayo Clinic; Estados Unidos. Academy of Athens; Greci

Inhibition of heregulin expression blocks tumorigenicity and metastasis of breast cancer

The growth factor Heregulin (HRG) is expressed in 30% of breast cancer tumors. HRG induces tumorigenicity and metastasis of breast cancer cells. Our investigation into whether blockage of HRG reduces the aggressiveness of breast cancer cells demonstrated that transfection of MDA-MB-231 with an HRG antisense cDNA suppressed proliferation, tumorigenicity, and metastasis. Blockage of the aggressive phenotype is mediated possibly through inactivation of the erbB signaling pathways and a decrease in MMP-9 activity. Our study is the first to report that HRG is a key promoter of breast cancer progression and should be deemed as a potential target in developing therapies for the treatment of breast carcinomas