Syed Hasan Raza Jafri

Thymoquinone and cisplatin as a therapeutic combination in lung cancer: In vitro and in vivo

BackgroundThymoquinone (TQ) is a compound extracted from Black Caraway seeds of Nigella Sativa and is active against various cancers. Cisplatin (CDDP) is the most active chemotherapeutic agent in Lung Cancer. Here we report activity of TQ against non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cell lines alone and in combination with Cisplatin (CDDP).MethodsFor proliferation MTT assay, cell viability trypan blue assay and for apoptosis Annexin-V FITC assay were used in NCI-H460 and NCI-H146 cell lines. Inhibition of invasion by TQ was assessed using Matrigel assay and its affect on release of various cytokines was determined using RayBio Human Cytokine detection kit. Mouse xenograft model using NCI-H460 was used to determine in vivo activity of TQ and CDDP. Inhibition of LPS induced NF-κB expression by TQ was determined using transgenic mice expressing a luciferase reporter.ResultsTQ was able to inhibit cell proliferation, reduce cell viability and induce apoptosis. TQ at 100 μM and CDDP at 5 μM inhibited cell proliferation by nearly 90% and the combination showed synergism. TQ was able to induced apoptosis in both NCI-H460 and NCI-H146 cell lines. TQ also appears to affect the extracellular environment inhibiting invasion and reducing the production of two cytokines ENA-78 and Gro-alpha which are involved in neo-angiogenesis. Using a mouse xenograft model we were able to demonstrate that combination of TQ and CDDP was well tolerated and significantly reduced tumor volume and tumor weight without additional toxicity to the mice. In the combination arms (TQ5 mg/kg/Cis 2.5 mg/kg) tumor volume was reduced by 59% and (TQ20 mg/kg/Cis 2.5 mg/kg) by 79% as compared to control which is consistent with in vitro data. TQ down regulated NF-κB expression which may explain its various cellular activities and this activity may prove useful in overcoming CDDP resistance from over expression of NF-κB.ConclusionsThus TQ and CDDP appear to be an active therapeutic combination in lung cancer.

Cisplatin, Cetuximab, and Radiation in Locally Advanced Head and Neck Squamous Cell Cancer: A Retrospective Review

Efficacy of cisplatin versus cetuximab with radiation in locally advanced head and neck cancer (LAHNC) was evaluated. A total of 96 patients with newly diagnosed LAHNC treated at our institution between 2006 and 2011 with concurrent radiation and cisplatin (group A, n = 45), cetuximab (group B, n = 24), or started with cisplatin but switched to cetuximab because of toxicity (group C, n = 27) were reviewed. Chi-square test, analysis of variance, and log-rank test were used for analysis. The three groups had similar baseline characteristics, except for median age, T stage, albumin levels, hemoglobin levels, performance status, and comorbidities. A complete response (CR) was seen in 77%, 17%, and 67% of patients (P < 0.001), respectively. There was no significant difference in median overall survival (OS) between groups A and C. The median OS for groups A and C was not reached (>65 months), even though it was significantly longer than median OS for group B (11.6 months; P ≤ 0.001). The 2-year OS in groups A and C is significantly higher than that in group B (70% for groups A and C, 22% for group B). There is no significant difference in progression-free survival (PFS) between groups A and C. The median PFS for these groups was not reached (>62 months), and is significantly longer than that for group B (4.3 months; P ≤ 0.001). The 2-year PFS of group A (67%) and group C (76%) was significantly longer than that of group B (20%). Cisplatin with radiation appears to be more efficacious even in suboptimal dosing than cetuximab with radiation in LAHNC but the two groups were not well matched.

Lifestyle modification in colorectal cancer patients: an integrative oncology approach.

Colorectal cancer (CRC) is predominantly a disease of economically developed countries, with many lifestyle-related risk factors proposed that contribute to a higher incidence. These risk factors include obesity, especially visceral fat, lack of physical activity, high consumption of red and processed meat, alcohol and a low intake of dietary fiber. Many population-based studies suggest that a combination of these lifestyle-related risk factors not only increases the incidence of CRC, but also contributes to an increased risk of CRC recurrence after the initial diagnosis. In this article we have reviewed various scientific studies that link lifestyle risk factors with CRC and we propose lifestyle modification as an adjunct intervention to surgery and chemotherapy in patients with early stage and locally advanced CRC.

Cachexia Index in Advanced Non-Small-Cell Lung Cancer Patients

Introduction Cancer cachexia affects many advanced non-small-cell lung cancer (NSCLC) patients. Cachexia index (CXI) was developed to assess the degree of cachexia in these patients. Methods Patients with metastatic NSCLC diagnosed between January 1, 2000, and June 30, 2011, at our institution were retrospectively studied. Abdominal computed tomography scans done within 1 month of diagnosis were reviewed to estimate skeletal muscle area (SMA) and skeletal muscle index (SMI) at the L3 level. CXI was developed as follows: CXI = SMI × A 1 b NLR where SMI is the skeletal muscle index, Alb is the serum albumin, and NLR is the NLR neutrophil-to-lymphocyte ratio. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. Survival among various factors was calculated using the log-rank test. Multivariate Cox regression was used to perform survival analysis in order to estimate the effects of various factors. Results Patients were divided into two groups around the median into stage I cachexia (CXI ≥35, n = 56) and stage II cachexia (CXI <35, n = 56). Groups did not differ in age, gender, ethnicity, or histology of cancer. Patients with stage II cachexia had significantly worse PFS (2.45 vs 5.43 months, P < 0.0001) and OS (3.45 vs 8.8 months, P = 0.0001) than those with stage I cachexia. On multivariate analysis adjusting for gender, race, and histology, patients with stage II cachexia were found to have worse PFS (hazard ratio [HR] 1.94, 95% confidence interval [CI] 1.27–2.95) and OS (HR 1.53, 95% CI 1.0009–2.34). Conclusion The CXI is a novel index for estimating cachexia that also correlates with prognosis in both men and women with advanced NSCLC.

Current and emerging pharmacotherapies for the treatment of relapsed small cell lung cancer.

Small cell lung cancer (SCLC) is a very aggressive cancer with poor outcome if left untreated, but it is also one of the most chemotherapy responsive cancers. Overall it has a very poor prognosis especially if it is chemotherapy resistant to first line treatment. Second line chemotherapy has not been very beneficial in SCLC as opposed to breast cancer and lymphoma. In the last few years topotecan is the only drug that has been approved by the food and drug administration (FDA) for the second line treatment of SCLC but in Japan another drug, amrubicin is approved. There are many combinations of different chemotherapies available in moderate to high intensity, in this difficult to treat patient to overcome the chemo resistance, but many of these studies are small or phase II trials. In this article we have reviewed single agent and multidrug regimens that were studied in both chemo sensitive and refractory setting, including the most recent clinical trials.

Endobronchial Ultrasound for Nodal Staging of Patients with Non–Small-Cell Lung Cancer with Radiologically Normal Mediastinum. A Meta-Analysis

&NA; Rationale: An accurate assessment of the mediastinal lymph node status is essential in the staging and treatment planning of potentially resectable non‐small‐cell lung cancer. Objectives: We performed this meta‐analysis to evaluate the role of endobronchial ultrasound‐guided transbronchial needle aspiration in detecting occult mediastinal disease in non‐small‐cell lung cancer with no radiologic mediastinal involvement. Methods: The PubMed, Embase, and Cochrane libraries were searched for studies describing the role of endobronchial ultrasound‐guided transbronchial needle aspiration in patients with lung cancer with radiologically negative mediastinum. The individual and pooled sensitivity, prevalence, negative predictive value, and diagnostic odds ratio were calculated using the random effects model. Meta‐regression analysis, heterogeneity, and publication bias were also assessed. Results: A total of 13 studies that met the inclusion criteria were included in the meta‐analysis. The pooled effect sizes of the different diagnostic parameters were estimated as follows: prevalence, 12.8% (95% confidence interval, 10.4‐15.7%); sensitivity, 49.5% (95% confidence interval, 36.4‐62.6%); negative predictive value, 93.0% (95% confidence interval, 90.3‐95.0%); and log diagnostic odds ratio, 5.069 (95% confidence interval, 4.212‐5.925). Significant heterogeneity was noticeable for the sensitivity, disease prevalence, and negative predictive value, but not observed for log diagnostic odds ratio. Publication bias was detected for sensitivity, negative predictive value, and log diagnostic odds ratio but not for prevalence. Bivariate meta‐regression analysis showed no significant association between the pooled calculated parameters and the type of anesthesia, imaging used to define negative mediastinum, rapid on‐site test usage, and presence of bias by Quality Assessment of Diagnostic Accuracy Studies (QUADAS)‐2 tool. Interestingly, we observed a greater sensitivity, negative predictive value, and log diagnostic odds ratio for studies published before 2010 and for prospective multicenter studies. Conclusions: Among patients with non‐small‐cell lung cancer with a radiologically normal mediastinum, the prevalence of mediastinal disease is 12.8% and the sensitivity of endobronchial ultrasound‐guided transbronchial needle aspiration is 49.5%. Despite the low sensitivity, the resulting negative predictive value of 93.0% for endobronchial ultrasound‐guided transbronchial needle aspiration suggests that mediastinal metastasis is uncommon in such patients

Abstract 5261: Prognosis of baseline absolute lymphocyte count (ALC) and neutrophil to lymphocyte ratio (NLR) in patients with pancreatic adenocarcinoma

Introduction There are no established prognostic biomarkers in pancreatic adenocarcinoma (PDAC). ALC and NLR have recently been of considerable interest in a variety of cancers including pancreatic cancer as a potential prognostic biomarker. In this single institution, retrospective study, we evaluated ALC and NLR as prognostic indicators for pancreatic cancer. Methods: We performed a retrospective chart review of patients diagnosed at LSU Health Shreveport with PDAC from Jan 1, 2000 to December 31, 2010. Various clinical, laboratory, imaging and treatment data were recorded. NLR was calculated by dividing the absolute neutrophil count by the absolute lymphocyte count. Results A total of 152 patients had analyzable data. Median overall survival across all patients examined was 5.34 months. Univariate COX analysis showed hazard ratio favorable for patients with early stage pancreatic cancer, better performance status, those who received chemo-radiation and surgery, ALC ≥ 1000 and NLR 10 (P = 0.001). Median OS for subjects with ALC ≤999 = 2.47 months compared to those with ALC >1000 = 6.02 months (P Conclusion: ALC and NLR are routinely performed laboratory tests which are inexpensive and have prognostic value in pancreatic cancers. The biological mechanisms underlying changes in ALC and NLR needs further exploration and could be a potential area for translational research. Citation Format: Kartik Anand, Erkut Borazanci, Sachin Pai, Runhua Shi, Syed H. Jafri, Glenn Mills. Prognosis of baseline absolute lymphocyte count (ALC) and neutrophil to lymphocyte ratio (NLR) in patients with pancreatic adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5261. doi:10.1158/1538-7445.AM2015-5261

Abstract 5385: Thymoquinone(TQ) and cisplatin(CDDP) in a non-small cell lung cancer (NSCLC) xenograft model

Introduction: Lung cancer is the leading cause of cancer related death in United States. The most active chemotherapeutic agent for NSCLC is Cisplatin. Thymoquinone (TQ) is the bioactive constituent of the volatile oil of The Black Caraway seed also known as (Nigella Sativa, Ranunculaceae family) and has been shown to have anti-neoplastic activities. Based on our intvitro data we combined CDDP and TQ in a mouse xenograft model using NSCLC cell line NCI-H460. Materials and Methods: a) Cisplatin at 2.5mg/kg was prepared weekly by dissolving in PBS. Cisplatin was injected i.p. once a week for three weeks. b) TQ was prepared in concentrations 5mg/kg or 20mg/kg and dissolved in solvent of cremophor: alcohol: PBS in a ratio (1:1:4) and injected subcutaneous M, W, F for 3 weeks. These doses were selected based on an earlier Maximum tolerated dose (MTD) study. 5-6 weeks old female SCID mice were obtained from harlan laboratories and were placed under pathogen free conditions in animal care facility according to LSU, Shreveport animal care guidelines. Animal protocol was reviewed and approved by animal care committee. NCI-H460 2×10^6 cells were injected subcutaneous into right flank after shaving that area. Tumors were allowed to grow for one week and when tumor volume reached approximately 20mm 3 mice were randomized to 6 groups with 10 mice in each group. Tumor volume was calculated using the formula V= (LxW 2 ) x 0.5 where V= volume, L= length, W=width. c) Treatment groups: Mice were randomized into following 6 groups (n=60) treated as described above for 3 weeks. 1) Control 2) TQ 5mg/kg s.c. M,W,F 3) TQ 20mg/kg s.c. M,W,F 4) Cisplatin 2.5mg/kg i.p. Monday 5) Combination (1): Cis2.5mg/kg/TQ5mg/kg 6) Combination (2): Cis 2.5mg/kg/TQ20mg/kg. Tumor volume and body weight was measured M, W, F for three weeks during the course of study. At (Day 26) mice were sacrificed and tissue samples were obtained for histological analysis Statistical analysis: For statistical analysis we used factorial analysis of variance (ANOVA) and a p value of Results: Results show that TQ alone at 5mg/kg s.c. M,W, F had no effect on reducing tumor volume in fact mean tumor volume was higher as compared to control but not statistically significant. TQ alone at 20mg/kg was active and reduced tumor volume (p 0.075). Cisplatin alone at 2.5mg/kg reduced tumor volume significantly (p In the combination arm (TQ5mg/kg/Cis 2.5mg/kg) tumor volume was reduced by 59% and (TQ20mg/kg /Cis 2.5mg/kg) tumor volume was reduced T.V by 79% as compared to control. Conclusion: TQ alone and in combination with CDDP significantly reduces tumor volume in a NSCLC mouse xenograft model and should be considered for future clinical development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5385.