Acute generalized exanthematous pustulosis (AGEP) is a rare acute reaction that is drug induced in 90% of the cases and characterized by a widespread, sterile pustular rash. Erlotinib, a small-molecule EGFR tyrosine kinase inhibitor, has been approved by the FDA for patients with pancreatic cancer and non-small cell lung cancer. Skin rash is a well-known side effect related with all EGFR blocking agents. It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival. We report a case of rare presentation of AGEP involving an adverse effect of erlotinib. The commonly reported adverse effects of erlotinib are mild skin eruptions. However, our case describes the rare presentation of AGEP induced by erlotinib. The estimated incidence rate of AGEP is approximately 1-5 cases per million/year.
Abstract Utilization of hydrophobic motifs present in auto-inhibited protein kinases has resulted in the identification of a series of 5,6-dihydrobenzo [h]quinazolin-2-amines with activity as fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors. Herein we describe the combination of a proprietary in silico design process, a new screening paradigm using an array of biochemical and biophysical technologies in conjunction with an established parallel chemistry process for the identification and optimization of a series of novel FGFR inhibitors. These potent FGFR inhibitors exhibit a preference for the inactive form of the kinase, are non-ATP competitive, and exhibit robust cellular pharmacodynamic inhibition as well as in vitro anti-proliferative effects in cells dependent on FGFR and significant anti-tumor activity in appropriate xenograft models in vivo. The design strategy, synthesis, structure activity relationships and in vitro and in vivo biology of selected inhibitors will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3905. doi:1538-7445.AM2012-3905
Oral squamous cell carcinoma (OSCC) comprises most of head and neck neoplasms and is one of the highest-ranking and lethal cancers in Pakistan due to prevailing mouth habits. Several types of receptors act as prognostic markers and targets for therapy in some cancers, but their application in OSCC is largely unexplored. This study aimed to evaluate the expression of hormonal receptors and Her-2 in OSCC patients and correlate it with 10-year, overall and disease-free survival. To achieve this objective, immunohistochemistry for Her-2, AR, ER and PR was performed on 100 formalin-fixed paraffin-embedded primary OSCC specimens. Receptor expression was correlated with mouth habits and clinicopathological features and patient survival was analyzed using Kaplan-Meier method and Cox regression univariate analysis. We observed that in 100 patients, there were 57 males and 43 females. Immunopositive Her-2 expression was observed in 21% of patients, AR in 13%, ER in 3% and 0% for PR. Patients with betel quid/areca nut mouth habits had significantly absent Her-2 expression ( P = 0.035). Also, Her-2 negative patients were also negative for AR expression ( P = 0.002). Her-2 positive patients had poor 10-year survival ( P = 0.041). A trend of low survival and high recurrence rate was observed in AR positive patients, but this was not significant ( P = 0.072). No statistically relevant correlations were seen in the case of ER and PR. In conclusion, Her-2 may be a valuable marker for predicting long-term prognosis of OSCC patients.
Aim: TP53 gene mutation and overexpression of its protein is widely recognised as the commonest event in the most malignancies including development of oral cancer. Alteration of TP53 in oral squamous cell carcinoma (OSCC) is believed to be associated with reduced overall survival (OS) and disease-free survival (DFS). The purpose of this study is to determine whether TP53 protein overexpression in OSCC is prognostic indicator of patient survival along with its correlation with smoking, chewing habits, histological variables like grade & stage of the tumour in a high risk population. Material and methods: A total of 140 patients of OSCC were included in this study. TP53 protein overexpression was investigated by means of immunohistochemistry. Clinical and histopathological data was gathered, and correlation with survival and histologic variable was analysed. Results: Overexpression of TP53 protein was observed in 75 patients (54%) using a threshold of 10% stained cell nuclei. In univariate Cox regression analysis, TP53 overexpression was significantly associated with shortened OS (HR = 1.8; P = 0.033). However, Multivariate Cox regression analysis did not reveal independent association of TP53 overexpression with reduced OS and DFS. Multivariate analysis revealed that histological grade (P = 0.046), T (P = 0.045), and N stage (P < 0.001) were significantly independent prognostic variables. Conclusion: Overexpression of TP53 protein was not an independent prognosticator of tumour behaviour in patient with OSCC. However, histological grade and N stage are two common, independent risk factors for reduced overall and DFS.
Abstract Background: In 2013, the ASCO/CAP consensus panel published updated guidelines for HER2 testing in breast cancer that modified the definition of HER2 amplification by in situ hybridization (ISH), creating five new prognostic categories (group 1: classic amplified, group 2: monosomy, group 3: co-amplified (polysomy), group 4: equivocal, and group 5: classic non-amplified). Patients determined to be ISH amplified, were considered eligible for HER2-directed therapy. Concern over whether patients from non-classic groups 2-4 would benefit from treatment has led to the recent publication of the 2018 HER2 focused update. This update has modified the criteria for interpreting these ISH categories, recommending that the final diagnosis take into consideration a combination of HER2 immunohistochemistry (IHC) and ISH results. With increased emphasis on the HER2 protein assessment, it has prompted us to quantitatively examine HER2 protein expression in the ISH categories, using two different novel technologies. Materials & Methods: A cohort of 170 cases (URMC) and 102 cases (PSHMC) of invasive breast cancers, which had previously undergone HER2 IHC and ISH testing, were selected for this study. Cases were sorted and categorized into the HER2 ISH categories defined by ASCO/CAP. HER2 protein expression was quantitatively measured in the URMC and PSHMC cohorts using a novel immunodetection methodology (streptavidin-coated Phosphor-Integrated Dot (PID) fluorescent nanoparticles), and a novel dual-antibody, proximity-binding immunoassay (HERmark® Breast Cancer Assay, Monogram Biosciences, South San Francisco, California), respectively. HER2 protein expression was compared to the HER2 FISH and IHC results by ASCO/CAP category. Results: Cases in group 1 had a significantly (p < 0.01) higher average PID/cell and HERmark compared to cases in groups 2-5 (Table 1). Cases in groups 2-4 showed lower quantitative levels of HER2 protein expression, similar to the classic non-amplified cases (group 5). Group 1 was further divided into three subgroups (Table 2): Group A - ISH high-level amplified (ratio > 2, HER2 > 6, CEP17 < 2.7), Group B - amplified with elevated CEP17 (ratio > 2, CEP17 > 2.7), and Group C - low-level amplified (ratio > 2, HER2 > 4 and < 6). Group A and B had a significantly (p < 0.01) higher average PID/cell and HERmark compared to Group C. Group C was more comparable to cases in groups 2-5 (Table 1). Conclusion: Our results suggest that quantitative assessment of HER2 protein expression may help to further classify cases for HER2 status for targeted therapy, supporting the 2018 ASCO/CAP recommendation that non-classic ISH results might be resolved by evaluating protein expression. Follow up studies with a larger patient cohort and dual quantitative assessment are warranted. Average PID/cell and HERmark in ASCO category groupsASCO category groupN (URMC)PID/cell (URMC)*N (PSHMC)HERmark (PSHMC)*18888.07761.521011.20N/A32016.0213.84238.5315.95296.3208.3*averageTable 2:Average PID/cell and HERmark in subgroups of Group 1SubgroupN (URMC)PID/cell (URMC)*N (PSHMC)HERmark (PSHMC)*A24157.66465.7B34101.61044.1C3016.9329.8*average Citation Format: Buscaglia B, Turner B, Goda H, Huang W, Leitzel K, Natori T, Nakano Y, Okada H, Sperinde J, Ali S, Vasekar M, D'Aguiar M, McMahon L, Henry J, Lipton A, Hicks D. ASCO/CAP human epidermal growth factor receptor-2 (HER2) in situ hybridization (ISH) categories evaluated by quantitative HER2 protein diagnostic methodologies: A comparative analysis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-03-02.
Abstract Objective This study associated Human Papillomavirus (HPV) infection and other clinical parameters with five-year survival of oral squamous cell carcinoma patients at a tertiary care hospital in Karachi, Pakistan. Methods A total of 140 patients diagnosed with oral squamous cell carcinoma were enlisted. HPV status and subtypes were established through polymerase chain reaction performed in a previously published study. Clinical data including five-year survival were obtained through institutional medical records. Results Ninety-five patients (67.9 per cent) were positive for HPV. Of these, 85 patients were HPV 16 positive while 2 patients were HPV 18 positive. The mean survival time for HPV positive patients was 44.3 months, whereas survival time for HPV negative patients was 46.9 months. Univariate analysis showed that HPV status in oral squamous cell carcinoma was not a statistically significant factor in determining five-year survival rate ( p = 0.386). Conclusion There is a high prevalence of HPV positive oral squamous cell carcinoma in Pakistan; however, there is no difference in the five-year survival rate when compared to HPV negative oral squamous cell carcinoma.
Interest in Eg5 as a molecular target for anti-cancer therapy has increased based on recent work showing that over-expression of this member of the kinesin superfamily promotes both genomic instability and tumorigenicity. However, other inhibitors of Eg5 have been associated with bone marrow suppression, raising concerns about mechanism-related toxicity. We have previously described the biological properties of a novel compound with excellent drug-like properties, designated ARQ 621, which inhibits human Eg5 potently and selectively. In proliferation assays, ARQ 621 showed cytotoxicity against a subset of human cancer cell lines, with corresponding cell cycle analysis confirming a G2/M arrest followed by cell death. ARQ 621 induced characteristic monoasters in proliferating cells, the hallmark of aborted bipolar spindle formation, in every cancer cell line tested to date. Sensitivity to the cell-based cytotoxicity of ARQ 621 in cancer cells predicted responsiveness of these tumors in athymic mouse xenograft models. Anti-tumor activity was documented in the MIA PaCa-2 pancreatic cell line, the MDA-MB-231 breast carcinoma cell line, the DU-145 prostate cell line, and the SK-OV-3 ovarian carcinoma cell line following i.p. administration of ARQ 621 (dose ranges: 3.0 to 12.5 mg/kg three times a week). Pharmacodynamically, increases in phospho-histone H3 were documented by both IHC and western blotting. Furthermore, no hematological changes were observed at efficacious doses in xenograft studies with the MIA PaCa-2 and MDA-MB-231 cell lines, suggesting that treatment with ARQ 621 did not result in bone marrow toxicity. Myeloid/erythroid ratios in bone marrow smears were normal after 28 days of dosing in both rats and dogs at 30 mg/kg. In summary, ARQ 621 is a clinical stage anti-cancer drug candidate that shows little toxicity among the rapidly dividing cells of the bone marrow. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4604.
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