Ahmed El Bastawisy

Mistletoe preparation (Viscum Fraxini-2) as palliative treatment for malignant pleural effusion: a feasibility study with comparison to bleomycin

Background Malignant pleural effusion is a common problem in patients with solid tumours. It has a significant impact on quality of life, and, hence, there is a substantial need to investigate new agents to treat it. Patients and methods This is a prospective randomised controlled study, including patients with symptomatic recurrent malignant pleural effusion of different primaries. Patients were randomised into two groups: the first group received five ampoules of mistletoe preparation with defined lectin content (Viscum Fraxini-2, ATOS Pharma) diluted in 10 cc glucose 5% solution. Re-instillation was repeated every week until complete dryness of the pleural fluid was achieved (the maximum duration of the therapy was eight weeks). The second group received 60 units of bleomycin once intrapleurally. Aims The primary aim of this paper was to evaluate the efficacy of mistletoe preparation as a palliative treatment for malignant pleural effusions in comparison with bleomycin. The secondary aim was to evaluate the tolerability of the mistletoe preparation. Results A total of 23 patients were included and followed up during the study from December 2007 to January 2012: 13 patients received mistletoe preparation, and ten patients received bleomycin. Overall clinical response was reported in 61.5% of the mistletoe preparation arm versus 30% in bleomycin arm (p = 0.2138), 95% CI = (–0.1203, 0.6325). The toxicity of both arms was mild and manageable; the mistletoe preparation arm included fever, chills, headache, malaise, and, in two cases, allergic reaction, which was controlled by discontinuation of the drug and steroid injection. Conclusion Mistletoe preparation is an efficient and well tolerated sclerosant agent which needs further investigation.

Serum cytokeratin 19 fragment in advanced lung cancer: could we eventually have a serum tumor marker?

Introduction: Lung cancer is one of the most lethal malignancies; however, no serum marker has been routinely recommended until now. Methods: This is a prospective case control study including two groups of patients: Group I—patients with advanced lung cancer and Group II—patients with benign lung disease as control. Serum cytokeratin 19 (CK19) fragment levels were measured at baseline by real-time polymerase chain reaction before first-line chemotherapy. The CK19 cut-off taken was 15-cycle threshold. The primary end point was the comparison of high CK19 in cases and controls. The secondary end point was the correlation between high CK19 and progressive disease (PD), progression-free survival, and overall survival (OS) in advanced lung cancer patients. Results: A total of 30 patients with advanced lung cancer (16 non-small and 14 small cell lung cancer) and 15 patients with benign lung disease were included and followed up during the period from October 2008 to October 2011 with median follow-up of one and half years. High CK19 was found in 90% of lung cancer cases as compared with 7% in controls (p < 0.001). High CK19 was found in all cases showing PD (p = 0.04). One-year OS in high CK was 61% as compared with 33% in normal CK (p = 0.1). Conclusion: Serum CK19 fragment is a potential diagnostic and prognostic marker for advanced lung cancer.

Plasma vascular endothelial growth factor 165 in advanced non-small cell lung cancer.

Currently, there is no serum marker that is routinely recommended for lung cancer. Therefore, the aim of the present study was to demonstrate that plasma vascular endothelial growth factor 165 (VEGF 165) may be a potential marker for advanced lung cancer. Lung cancer is the leading cause of cancer-related mortality worldwide, therefore, it is important to develop novel diagnostic techniques. The present prospective case control study included two groups of patients; a control group of healthy volunteers and a second group of patients with advanced non-small cell lung cancer (NSCLC). The plasma VEGF 165 levels were measured at baseline by ELISA prior to the first-line gemcitabine-cisplatin regimen. The high VEGF 165 expression level cut-off was >703 pg/ml, and the primary endpoint was used to compare the plasma VEGF 165 levels between the NSCLC patients and the control group subjects. The secondary endpoint was used to identify the correlations between high VEGF 165 levels and; clinical response (CR), progression-free survival (PFS) and overall survival (OS) in the advanced NSCLC patients. In total, patients with advanced NSCLC (n=35) were compared with a control group of age- and gender-matched healthy subjects (n=34). The follow-up period was between Oct 2009 and Oct 2012, with a median follow-up time of 10.5 months. The median plasma VEGF 165 level was 707 pg/ml in the NSCLC patients versus 48 pg/ml in the healthy control subjects (P<0.001). However, no significant correlation was found between the plasma VEGF 165 levels and CR (P<0.5), median PFS (P=1.00) or OS (P=0.70). Therefore, it was concluded that plasma VEGF 165 may serve as a potential diagnostic marker for advanced NSCLC.

BRCA1-IRIS overexpression promotes and maintains the tumor initiating phenotype: implications for triple negative breast cancer early lesions

Tumor-initiating cells (TICs) are cancer cells endowed with self-renewal, multi-lineage differentiation, increased chemo-resistance, and in breast cancers the CD44+/CD24-/ALDH1+ phenotype. Triple negative breast cancers show lack of BRCA1 expression in addition to enhanced basal, epithelial-to-mesenchymal transition (EMT), and TIC phenotypes. BRCA1-IRIS (hereafter IRIS) is an oncogene produced by the alternative usage of the BRCA1 locus. IRIS is involved in induction of replication, transcription of selected oncogenes, and promoting breast cancer cells aggressiveness. Here, we demonstrate that IRIS overexpression (IRISOE) promotes TNBCs through suppressing BRCA1 expression, enhancing basal-biomarkers, EMT-inducers, and stemness-enforcers expression. IRISOE also activates the TIC phenotype in TNBC cells through elevating CD44 and ALDH1 expression/activity and preventing CD24 surface presentation by activating the internalization pathway EGFR→c-Src→cortactin. We show that the intrinsic sensitivity to an anti-CD24 cross-linking antibody-induced cell death in membranous CD24 expressing/luminal A cells could be acquired in cytoplasmic CD24 expressing IRISOE TNBC/TIC cells through IRIS silencing or inactivation. We show that fewer IRISOE TNBC/TICs cells form large tumors composed of TICs, resembling TNBCs early lesions in patients that contain metastatic precursors capable of disseminating and metastasizing at an early stage of the disease. IRIS-inhibitory peptide killed these IRISOE TNBC/TICs, in vivo and prevented their dissemination and metastasis. We propose IRIS inactivation could be pursued to prevent dissemination and metastasis from early TNBC tumor lesions in patients.

Inflammatory breast cancer: is it really a separate entity?

Background Inflammatory breast cancer (IBC) is the most aggressive form of primary breast carcinoma and is associated with a dismal outcome despite the availability of multi-modality treatment options. Patients and methods This is a prospective case control study comparing two groups of newly diagnosed patients; the first with inflammatory breast cancer (IBC) and the second with locally advanced non inflammatory breast cancer (LABC). In both groups MIB1, ER, PR, Her2neu were assessed. Neo-adjuvant chemotherapy consisted of four cycles of FEC100 followed by modified radical mastectomy according to clinical response, postoperative chemotherapy with two courses of the same regimen followed by radiotherapy. Tamoxifen 20 mg po daily for 5 years in ER and/or PR positive tumours, starting after the completion of radiotherapy. Primary end points were a) comparison of MIB-1 score in both groups, b) comparison of clinical and pathological responses in both groups. Secondary endpoints were comparison of progression free survival and overall survival. Results From a total of 42 patients, 21 were stage III B (T4d, N0-2 M0) IBC and 21 were stage III B (T4a-c, N0-2, M0) LABC. Patients in the age range from 28 to 68 were included and followed from November 2007 until February 2010 with a median follow-up period of 22.5 months. Toxicity of both arms, mainly haematologic, nausea and vomiting, was in general acceptable with no treatment-related deaths. Of the patients with IBC 81.3% had a high MIB-1 score as compared with 43.8% of patients with LABC (P-value = 0.028). Objective clinical response to neo-adjuvant chemotherapy in the IBC arm was 57.1% (4.8% complete response (CR)) as compared with 81% (9.5% CR) in LABC (P-value = 0.09). Overall pathological response (complete pathological response (pCR)+partial pathological response (pPR)) was 35.3% in the IBC arm compared with 40% in LABC arm (P-value = 0.618). One year, 2 year and median progression free survival (PFS) were 55.87%, 37.71% and 21.7 months, respectively in the IBC arm compared with 85.71%, 66.67% in LABC (median PFS was not reached) (P-value = 0.072). One and 2 year overall survival (OS) were 69.82% and 51.20%, respectively in the IBC arm compared with 95.24% and 95.24% in LABC arm (P-value = 0.0038). Conclusions IBC should be considered as a separate entity. A high MIB-1 score is a potential molecular marker for IBC.

BAP1 gene mutations in Egyptian patients with advanced sporadic malignant Pleural mesothelioma (MPM): Relation with clinical outcomes and survival

BACKGROUND Malignant Pleural Mesothelioma (MPM) is a lethal cancer with few therapeutic options. Patients with MPM have a poor prognosis, with estimated 1 year median survival and currently no treatment is curative. The BRCA associated protein 1 (BAP1) has the highest prevalence of protein-altering mutations identified in MPM. AIMS Assessment of the frequency and pattern of BAP1 gene mutations in Egyptian patients with advanced sporadic MPM in relation to disease progression and survival rates in order to identify a novel therapeutic target for MPM. METHODS This prospective, cohort study included 122 patients who were diagnosed and treated as advanced MPM. BAP1 gene mutations were assessed from circulating tumor cells (CTCs) by polymerase chain reaction (PCR) and sequencing and these mutations have been confirmed using the tumor tissue. BAP1 immunohistochemistry was performed using the Dako Envision visualization system. The relationship between BAP1 gene mutations, PFS and OS rates was assessed using the log rank test. The relationship between BAP1 gene mutations, clinical response and patients clinicopathological characteristics was assessed using chi-square test. RESULTS Forty seven (38.5%) MPM cases showed one or more mutations in BAP1 gene. The presence of BAP1 mutations associated significantly with BAP1 protein expression (p < 0.001), the incidence of organ metastasis (p = 0.04), PFS after second line treatment (p = 0.04) and clinical response after second line treatment (p = 0.01) only. CONCLUSION BAP1 gene mutations are relatively common in Egyptian patients with advanced sporadic MPM. BAP1 mutations are associated with disease progression especially after second line therapy and the incidence of organ metastasis.