Chemotherapy Research and Practice The latest articles from Hindawi Publishing Corporation © 2014 , Hindawi Publishing Corporation . All rights reserved. A Postauthorization Survey to Document the Therapeutic Management of Oxaliplatin as a First-Line Chemotherapy Regimen in South Africa in Patients with Metastatic Colorectal Cancer Thu, 10 Apr 2014 10:24:10 +0000 Oxaliplatin is a standard first-line treatment for metastatic colorectal cancer. The objectives were to document the therapeutic management of oxaliplatin in South Africa, determine the incidence and severity of sensory neuropathy, and record the 2-year survival rate. Meccelox was a prospective, noncontrolled, open label, multicentre, observational survey of adult patients with stage IV metastatic colorectal cancer treated with oxaliplatin-based chemotherapeutic regimens. The study was conducted from August 2007 to November 2011 in 29 sites in South Africa by 66 participating treating physicians. Among the 195 enrolled patients, 61% were treated with FOLFOX regimen (5-fluorouracil/folinic acid plus oxaliplatin) for an average of 12 cycles and 32% patients were treated with XELOX (capecitabine plus oxaliplatin) for an average of 6–8 cycles, with the main reason for discontinuation being completion of the preplanned prescribed regimen. In Meccelox survey, 80% of patients were treated with intent of palliation. Overall 64% of patients reported symptoms of sensory neuropathy. The 2-year survival rate was 30%. Conclusions. Patients received a specified preplanned number of chemotherapy cycles rather than being treated until disease progression or toxicity. Both the incidence of neuropathy and the 2-year survival rate were less than previous reports. Lydia M. Dreosti, Alicia McMaster, and Rashem Mothilal Copyright © 2014 Lydia M. Dreosti et al. All rights reserved. Neurological Adverse Effects in Patients of Advanced Colorectal Carcinoma Treated with Different Schedules of FOLFOX Sun, 29 Sep 2013 09:01:31 +0000 The study is designed to assess the frequency and severity of few dose limiting neurological adverse effects of four different schedules of FOLFOX. Patients with histologically confirmed advanced colorectal carcinoma (CRC) were included in the study. Toxicity was graded according to CTC v 2.0. The frequency of grade 3 and 4 adverse effects was comparatively assessed in each treatment arm. The difference in the pattern of toxicity between the treatment schedule was evaluated. The most frequent adverse symptom of neurological adverse effect was grade 1 paresthesia in the patients treated with FOLFOX4 schedule. Grade 4 peripheral neuropathy was reported in few patients of FOLFOX7 treatment arm. Frequency and onset of neurological adverse effects like paresthesia, dizziness, and hypoesthesia were significantly different (), whereas frequency and onset of peripheral neuropathy were highly significant () in each treatment arm of FOLFOX. Peripheral neuropathy was associated with electrolyte imbalance and diabetes in few patients. Frequency of symptoms, for example, paresthesia, is associated with increased number of recurrent exposure to oxaliplatin (increased number of cycles) even at low doses (85 mg/m2), whereas severity of symptoms, for example, peripheral neuropathy, is associated with higher dose (130 mg/m2) after few treatment cycles. Nusrat Bano, Rahila Najam, and Ahmed Mateen Copyright © 2013 Nusrat Bano et al. All rights reserved. Self-Management of Oxaliplatin-Related Peripheral Neuropathy in Colorectal Cancer Survivors Sun, 25 Aug 2013 09:26:15 +0000 Purpose. The purpose of this study was to evaluate medications that cancer survivors with oxaliplatin-induced peripheral neuropathy take to control neuropathic symptom, and to explore self-management techniques used at home to provide temporary relief of painful neuropathy. This was a mixed methods, descriptive, cross-sectional study using self-reported data from colorectal cancer survivors previously treated with oxaliplatin. We analyzed demographic and medication data obtained from participants, along with written comments from an open-ended question regarding methods participants had tried to self-manage symptoms of neuropathy. Results. Twenty-nine percent of the sample reported taking some type of nutritional supplement with potential neuroprotective qualities. Opioids were being taken by 10% of the sample, and nonsteroidal anti-inflammatory and over-the-counter medications were taken by 15% of participants. Twelve percent of participants were taking antidepressants and 10% were taking anticonvulsants, primarily gabapentin. Recurrent themes for nonpharmacologic treatment included avoiding the cold/keeping warm, keeping moving, massaging or rubbing the affected area, and living with it. Conclusions. Patients treated with oxaliplatin for colorectal cancer utilize a variety of traditional pharmacologic agents and nutritional supplements in an effort to self-manage neuropathic symptoms. Patients also employ a variety of home-based therapies to provide temporary relief of peripheral neuropathy symptoms. Cindy Tofthagen, Laura Gonzalez, Constance Visovsky, and Alex Akers Copyright © 2013 Cindy Tofthagen et al. All rights reserved. Identification of Functional Regulatory Residues of the β-Lactam Inducible Penicillin Binding Protein in Methicillin-Resistant Staphylococcus aureus Mon, 29 Jul 2013 12:04:30 +0000 Resistance to methicillin by Staphylococcus aureus is a persistent clinical problem worldwide. A mechanism for resistance has been proposed in which methicillin resistant Staphylococcus aureus (MRSA) isolates acquired a new protein called β-lactam inducible penicillin binding protein (PBP-2′). The PBP-2′ functions by substituting other penicillin binding proteins which have been inhibited by β-lactam antibiotics. Presently, there is no structural and regulatory information on PBP-2′ protein. We conducted a complete structural and functional regulatory analysis of PBP-2′ protein. Our analysis revealed that the PBP-2′ is very stable with more hydrophilic amino acids expressing antigenic sites. PBP-2′ has three striking regulatory points constituted by first penicillin binding site at Ser25, second penicillin binding site at Ser405, and finally a single metallic ligand binding site at Glu657 which binds to ions. This report highlights structural features of PBP-2′ that can serve as targets for developing new chemotherapeutic agents and conducting site direct mutagenesis experiments. Andreas N. Mbah and Raphael D. Isokpehi Copyright © 2013 Andreas N. Mbah and Raphael D. Isokpehi. All rights reserved. High-Dose Interleukin-2 (HD IL-2) Therapy Should Be Considered for Treatment of Patients with Melanoma Brain Metastases Mon, 13 May 2013 08:25:10 +0000 A retrospective review was performed on patients with stable melanoma brain metastases treated with HD IL-2 therapy (720,000 IU/kg per dose intravenously; 14 doses, 2 cycles per course, maximum 2 courses) from January 1999 to June 2011 at Saint Louis University. There were 5 men and 3 women; median age was 52.2 years (26.8–61.1 years). One patient started treatment with lung lesions only (after resection of melanoma brain disease) and experienced partial response. Seven patients had brain metastases at treatment initiation. Median overall survival (mOS) for entire cohort () was 8.7 months (2.1 to 19.0 months). All patients with brain metastases at first dose () showed progressive disease; mOS was 6.7 months (range 2.1–18.2 months) for this group. Patients received radiosurgery and whole brain radiation before and after HD IL-2 therapy. One patient had symptoms suggestive of neurotoxicity. A history of alcohol abuse was revealed during admission. The patient's symptoms improved with initiation of an alcohol withdrawal protocol. In this analysis, patients with melanoma brain metastases received HD IL-2 without treatment-related mortality. We think that HD IL-2 should be considered as a treatment option in patients with melanoma brain metastases who are otherwise eligible for therapy. Melinda B. Chu, Mark J. Fesler, Eric S. Armbrecht, Scott W. Fosko, Eddy Hsueh, and John M. Richart Copyright © 2013 Melinda B. Chu et al. All rights reserved. Lomustine Analogous Drug Structures for Intervention of Brain and Spinal Cord Tumors: The Benefit of In Silico Substructure Search and Analysis Tue, 16 Apr 2013 11:28:13 +0000 Lomustine is a nitrosourea anticancer agent shown to be effective for treatment of childhood medulloblastoma. In silico substructure searches produced 17 novel nitrosourea agents analogous to lumustine and retaining activity for DNA alkylation and cytotoxic activity. The mean values for Log P, polar surface area, formula weight, number of oxygens & nitrogens, and rotatable bonds were 2.524, 62.89 Anstroms2, 232.8, 5, and 2, respectively. All 17 agents have formula weight less than 450 and Log P less than 5, two criteria preferred for blood-brain barrier penetration. These agents have a polar surface area less than 90 Angstroms2. Each show zero violations of the Rule of five indicating favorable drug likeness and oral drug activity. Hierarchical cluster analysis indicated that 16 of the novel agents were highly similar to lomustine, save for agent 12 which bears a hydroxylated branched carbon substituent. A total of 17 novel anticancer agents were elucidated having molecular properties very effective for penetrating through the BBB and into the central nervous system. This study shows the effectiveness of in silico search and recognition of anticancer agents that are suitable for the clinical treatment of brain tumors. Ronald Bartzatt Copyright © 2013 Ronald Bartzatt. All rights reserved. Neoadjuvant Chemotherapy prior to Radical Prostatectomy for Patients with High-Risk Prostate Cancer: A Systematic Review Thu, 21 Feb 2013 13:51:29 +0000 High-risk prostate cancer represents a pretentious clinical problem since a significant number of its patients will relapse and progress after radical prostatectomy. Neoadjuvant chemotherapy may be valuable since its efficacy in hormone-resistant prostate cancer has been established. In this paper, we report studies of neoadjuvant chemotherapies that have been used in high-risk patients prior to radical prostatectomy. Even though the results regarding the prognostic surrogates are not significant, the effects on clinical and pathological outcomes are promising, while toxicity in most of the studies is in the expected field. Stavros Sfoungaristos, Vasileios Kourmpetis, Eleftherios Fokaefs, and Petros Perimenis Copyright © 2013 Stavros Sfoungaristos et al. All rights reserved. Inhibition of NF-κB by Dehydroxymethylepoxyquinomicin Suppresses Invasion and Synergistically Potentiates Temozolomide and γ-Radiation Cytotoxicity in Glioblastoma Cells Thu, 21 Feb 2013 10:25:47 +0000 Despite advances in neurosurgery and aggressive treatment with temozolomide (TMZ) and radiation, the overall survival of patients with glioblastoma (GBM) remains poor. Vast evidence has indicated that the nuclear factor NF-κB is constitutively activated in cancer cells, playing key roles in growth and survival. Recently, Dehydroxymethylepoxyquinomicin (DHMEQ) has shown to be a selective NF-κB inhibitor with antiproliferative properties in GBM. In the present study, the ability of DHMEQ to surmount tumor's invasive nature and therapy resistance were further explored. Corroborating results showed that DHMEQ impaired cell growth in dose- and time-dependent manners with G2/M arrest when compared with control. Clonogenicity was also significantly diminished with increased apoptosis, though necrotic cell death was also observed at comparable levels. Notably, migration and invasion were inhibited accordingly with lowered expression of invasion-related genes. Moreover, concurrent combination with TMZ synergistically inhibited cell growth in all cell lines, as determined by proliferation and caspase-3 activation assays, though in those that express O6-methylguanine-DNA methyltransferase, the synergistic effects were schedule dependent. Pretreatment with DHMEQ equally sensitized cells to ionizing radiation. Taken together, our results strengthen the potential usefulness of DHMEQ in future therapeutic strategies for tumors that do not respond to conventional approaches. M. S. Brassesco, G. M. Roberto, A. G. Morales, J. C. Oliveira, L. E. A. Delsin, J. A. Pezuk, E. T. Valera, C. G. Carlotti Jr., E. M. Rego, H. F. de Oliveira, C. A. Scrideli, K. Umezawa, and L. G. Tone Copyright © 2013 M. S. Brassesco et al. All rights reserved. Monoclonal Antibodies against Epidermal Growth Factor Receptor in Solid Tumors Mon, 24 Dec 2012 10:54:25 +0000 Nabil F. Saba, Sue S. Yom, Missak Haigentz, and Bassel El-Rayes Copyright © 2012 Nabil F. Saba et al. All rights reserved. The HER2 Receptor in Breast Cancer: Pathophysiology, Clinical Use, and New Advances in Therapy Thu, 20 Dec 2012 17:35:50 +0000 Human epidermal growth factor receptor 2 (HER2) is overexpressed in around 20–30% of breast cancer tumors. It is associated with a more aggressive disease, higher recurrence rate, and increased mortality. Trastuzumab is a HER2 receptor blocker that has become the standard of care for the treatment of HER2 positive breast cancer. The effectiveness of Trastuzumab has been well validated in research as well as in clinical practice. The addition of Trastuzumab to standard of care chemotherapy in clinical trials has been shown to improve outcomes for early stage as well as metastatic HER2 positive breast cancer. The most clinically significant side effect of Trastuzumab is the risk of cardiac myocyte injury, leading to the development of congestive heart failure. The emergence of patterns of resistance to Trastuzumab has led to the discovery of new monoclonal antibodies and other targeted agents aimed at overcoming Trastuzumab resistance and improving survival in patients diagnosed with HER2 positive breast cancers. Zahi Mitri, Tina Constantine, and Ruth O'Regan Copyright © 2012 Zahi Mitri et al. All rights reserved. Chemotherapy and Dietary Phytochemical Agents Thu, 20 Dec 2012 14:07:29 +0000 Chemotherapy has been used for cancer treatment already for almost 70 years by targeting the proliferation potential and metastasising ability of tumour cells. Despite the progress made in the development of potent chemotherapy drugs, their toxicity to normal tissues and adverse side effects in multiple organ systems as well as drug resistance have remained the major obstacles for the successful clinical use. Cytotoxic agents decrease considerably the quality of life of cancer patients manifesting as acute complaints and impacting the life of survivors also for years after the treatment. Toxicity often limits the usefulness of anticancer agents being also the reason why many patients discontinue the treatment. The nutritional approach may be the means of helping to raise cancer therapy to a new level of success as supplementing or supporting the body with natural phytochemicals cannot only reduce adverse side effects but improve also the effectiveness of chemotherapeutics. Various plant-derived compounds improve the efficiency of cytotoxic agents, decrease their resistance, lower and alleviate toxic side effects, reduce the risk of tumour lysis syndrome, and detoxify the body of chemotherapeutics. The personalised approach using various phytochemicals provides thus a new dimension to the standard cancer therapy for improving its outcome in a complex and complementary way. Katrin Sak Copyright © 2012 Katrin Sak. All rights reserved. Advances in Targeting HER3 as an Anticancer Therapy Wed, 07 Nov 2012 16:16:50 +0000 HER3 (ErbB3) is a unique member of the human epidermal growth factor receptor (EGFR) family (ErbB family). It functions only through dimerization with other members of the ErbB family and modulates activity and sensitivity to targeted cancer therapies. This paper briefly describes the mechanism of HER3 in signal transduction and its potential role in acquired resistance to EGFR- and HER2-targeted therapies. We also consider recent developments in HER3-targeting therapeutics and their combination with inhibitors of other ErbB members in clinical applications. Ning Jiang, Nabil F. Saba, and Zhuo Georgia Chen Copyright © 2012 Ning Jiang et al. All rights reserved. Novel Drugs Targeting the Epidermal Growth Factor Receptor and Its Downstream Pathways in the Treatment of Colorectal Cancer: A Systematic Review Sun, 14 Oct 2012 16:45:18 +0000 Colorectal cancer is the second most common malignancy among men and women in the United States, and the 5-year survival rate remains poor despite recent advances in chemotherapy and targeted agents. The mainstay of therapy for advanced disease remains the cytotoxic chemotherapy including 5-FU, irinotecan, and oxaliplatin. The USFDA approval and introduction of targeted therapies, including cetuximab and panitumumab (monoclonal antibodies targeting the epidermal growth factor receptor (EGFR)) and bevacizumab (monoclonal antibody targeting the vascular epithelial growth factor (VEGF)), has improved the median survival of patients with metastatic colorectal cancer to around 24 months. Clearly, better and more efficacious drugs are needed, and target-specific agents remain the future of cancer treatment. On this front, rapid advances are being made, which are likely to change the future of the management of metastatic colorectal cancer. However, absence of specific biomarkers for the use of targeted agents, in the subset of population who will benefit from the treatment, remains a major drawback. In this paper, we review agents that are in phases 1 and 2 clinical development, specifically targeting the EGFR and its subsequent downstream pathways. Amartej Merla and Sanjay Goel Copyright © 2012 Amartej Merla and Sanjay Goel. All rights reserved. Antiepidermal Growth Factor Receptor Monoclonal Antibodies: Applications in Colorectal Cancer Mon, 08 Oct 2012 11:18:21 +0000 Patients with metastatic colorectal cancer have a poor prognosis and present a challenge to clinicians. The role of the antiepidermal growth factor receptor (EGFR) pathway in tumorogenesis and tumor progression has been well defined. This paper will review the use of anti-EGFR monoclonal antibodies in the treatment of operable, as well as metastatic colorectal cancer both in the setting of KRAS mutation unselected patients and later in KRAS wild-type patients. Active investigations designed to further identify predictive biomarkers that may be potentially druggable are reviewed as well. Efat Azizi, Adam Kittai, and Peter Kozuch Copyright © 2012 Efat Azizi et al. All rights reserved. The Use of Epidermal Growth Factor Receptor Monoclonal Antibodies in Squamous Cell Carcinoma of the Head and Neck Tue, 02 Oct 2012 14:09:11 +0000 Targeting of the EGF receptor (EGFR) has become a standard of care in several tumor types. In squamous cell carcinoma of the head and neck, monoclonal antibodies directed against EGFR have become a regular component of therapy for curative as well as palliative treatment strategies. These agents have anti-tumor efficacy as a single modality and have demonstrated synergistic tumor killing when combined with radiation and/or chemotherapy. While cetuximab has been the primary anti-EGFR monoclonal antibody used in the US, variant anti-EGFR monoclonal antibodies have been used in several clinical studies and shown benefit with improved toxicity profiles. Next generation anti-EGFR monoclonal antibodies may demonstrate multi-target epitope recognition, enhanced immune cell stimulation, or conjugation with radioisotopes in order to improve clinical outcomes. Identification of the specific patient subset that would optimally benefit from anti-EGFR monoclonal antibodies remains an elusive goal. Jeffery S. Russell and A. Dimitrios Colevas Copyright © 2012 Jeffery S. Russell and A. Dimitrios Colevas. All rights reserved. Neoadjuvant Chemoradiation in Squamous Cell Carcinoma of the Maxillary Sinus: A 26-Year Experience Sat, 29 Sep 2012 05:43:17 +0000 Background. The aim of our study was to evaluate the effects of neoadjuvant platinum-based radiochemotherapy (RCT) in patients with maxillary sinus squamous cell carcinoma and to compare the results with other multimodality treatment concepts for advanced-stage maxillary sinus carcinoma in the literature. Methods. In total, 53 patients with squamous cell carcinoma of the maxillary sinus were reviewed retrospectively. All patients received a neoadjuvant RCT containing either cisplatin or carboplatin followed by radical surgery. Overall survival and locoregional control were plotted by Kaplan-Meier analysis. Prognostic factors were identified through univariate and multivariate analysis. Results. Five-year overall survival for all patients was 35%. Eleven patients achieved a complete response after radiochemotherapy. The complete response rate was significantly higher for patients treated with cisplatin (); however the 5-year overall survival rates did not differ significantly () for patients treated with cisplatin (37%) and carboplatin (32%). Orbital invasion () and complete response to radiochemotherapy () had a significant impact on overall survival in univariate analysis. Conclusions. Neoadjuvant radiochemotherapy followed by radical surgery is an effective treatment for patients with advanced maxillary sinus squamous cell carcinoma. In terms of treatment response cisplatin seems to be more effective than carboplatin. Matthias Kreppel, Sarah Danscheid, Martin Scheer, Jan Christoffer Lüers, Hans Theodor Eich, Joachim E. Zöller, Orlando Guntinas-Lichius, and Dirk Beutner Copyright © 2012 Matthias Kreppel et al. All rights reserved. EGFR Monoclonal Antibodies in the Treatment of Squamous Cell Carcinoma of the Head and Neck: A View beyond Cetuximab Thu, 27 Sep 2012 08:10:53 +0000 Squamous cell carcinoma of the head and neck (SCCHN) is a prevalent disease both in the United States and worldwide with an overall poor prognosis, in part due to limited activity of existing therapy. Primary therapy is largely dictated by the anatomical origin of the cancer and whether distant disease is present. Many patients with localized disease are treated with chemoradiotherapy, either in the definitive or adjuvant setting, and those with metastatic disease are treated with palliative chemotherapy. The chemotherapy used in SCCHN can be toxic, whether given with radiation or alone. The epidermal growth factor receptor (EGFR) is highly expressed in SCCHN and serves as a logical therapeutic target. EGFR-directed monoclonal antibodies (MoAbs) have higher activity in SCCHN than small molecule tyrosine kinase inhibitors. Cetuximab, a widely studied EGFR MoAb, is FDA approved in the metastatic setting, as well as with radiation for locally advanced disease. Despite improvements in survival when cetuximab is incorporated with chemotherapy for metastatic disease, the prognosis of patients remains poor. Novel EGFR MoAbs are being developed with the goal of improving efficacy and tolerability. This paper will summarize the use of EGFR-directed MoAbs in treating SCCHN with a focus on novel agents being tested. Scott A. Kono, Missak Haigentz Jr., Sue S. Yom, and Nabil Saba Copyright © 2012 Scott A. Kono et al. All rights reserved. Dermatologic Toxicities from Monoclonal Antibodies and Tyrosine Kinase Inhibitors against EGFR: Pathophysiology and Management Tue, 11 Sep 2012 15:25:00 +0000 Epidermal growth factor receptor (EGFR) inhibition has now been well established as an effective treatment for various cancers. The EGFR belongs to the ErbB family of tyrosine kinase receptors which regulate tumor cell differentiation, survival and proliferation. Activation of EGFR drives tumorigenesis in lung, head and neck, colorectal and pancreatic cancers. Irrespective of the type of cancer being treated and the mechanism by which tumor EGFR drives tumorigenesis, the major side effect of EGFR inhibition is a papulopustular (also described as maculopapular or acneiform) rash which occurs in about two thirds of treated patients. Interestingly, this rash has been commonly correlated with better clinical outcomes (objective tumor response and patient survival). The pathophysiology of dermatological toxicity from EGFR inhibitors is an important area of clinical research, and the proper management of the rash is essential to increase the therapeutic index from this class of drugs. In this paper, we review the dermatologic toxicities associated with EGFR inhibitors with an emphasis on its pathophysiology and clinical management. Shaad E. Abdullah, Missak Haigentz Jr., and Bilal Piperdi Copyright © 2012 Shaad E. Abdullah et al. All rights reserved. Anti-Inflammatory Cytokines: Important Immunoregulatory Factors Contributing to Chemotherapy-Induced Gastrointestinal Mucositis Sun, 02 Sep 2012 08:19:49 +0000 “Mucositis” is the clinical term used to describe ulceration and damage of the mucous membranes of the entire gastrointestinal tract (GIT) following cytotoxic cancer chemotherapy and radiation therapy common symptoms include abdominal pain, bloating, diarrhoea, vomiting, and constipation resulting in both a significant clinical and financial burden. Chemotherapeutic drugs cause upregulation of stress response genes including NFκB, that in turn upregulate the production of proinflammatory cytokines such as interleukin-1β (IL-1β), Interleukin-6 (IL-6), and tumour necrosis factor-α (TNF-α). These proinflammatory cytokines are responsible for initiating inflammation in response to tissue injury. Anti-inflammatory cytokines and specific cytokine inhibitors are also released to limit the sustained or excessive inflammatory reactions. In the past decade, intensive research has determined the role of proinflammatory cytokines in development of mucositis. However, a large gap remains in the knowledge of the role of anti-inflammatory cytokines in the setting of chemotherapy-induced mucositis. This critical paper will highlight current literature available relating to what is known regarding the development of mucositis, including the molecular mechanisms involved in inducing inflammation particularly with respect to the role of proinflammatory cytokines, as well as provide a detailed discussion of why it is essential to consider extensive research in the role of anti-inflammatory cytokines in chemotherapy-induced mucositis so that effective targeted treatment strategies can be developed. Masooma Sultani, Andrea M. Stringer, Joanne M. Bowen, and Rachel J. Gibson Copyright © 2012 Masooma Sultani et al. All rights reserved. Mechanisms of Resistance to Epidermal Growth Factor Receptor Inhibitors and Novel Therapeutic Strategies to Overcome Resistance in NSCLC Patients Wed, 29 Aug 2012 08:06:44 +0000 The epidermal growth factor receptor (EGFR) is a well-characterized oncogene that is frequently activated by somatic kinase domain mutations in non-small cell lung cancer (NSCLC). EGFR TKIs are effective therapies for NSCLC patients whose tumors harbor an EGFR activating mutation. However, EGFR TKI treatment is not curative in patients because of both primary and secondary treatment resistance. Studies over the last decade have identified mechanisms that drive primary and secondary resistance to EGFR TKI treatment. The elucidation of mechanisms of resistance to EGFR TKI treatment provides a basis for the development of therapeutic strategies to overcome resistance and enhance outcomes in NSCLC patients. In this paper, we summarize the mechanisms of resistance to EGFR TKIs that have been identified to date and discusses potential therapeutic strategies to overcome EGFR TKI resistance in NSCLC patients. Luping Lin and Trever G. Bivona Copyright © 2012 Luping Lin and Trever G. Bivona. All rights reserved. Erratum to “Methodology for Anti-Gene Anti-IGF-I Therapy of Malignant Tumours” Mon, 13 Aug 2012 08:33:19 +0000 Jerzy Trojan, Yuexin X. Pan, Ming X. Wei, Adama Ly, Alexander Shevelev, Maciej Bierwagen, Marie-Yvonne Ardourel, Ladislas A. Trojan, Alvaro Alvarez, Christian Andres, Maria C. Noguera, Ignacio Briceno, Beatriz H. Aristizabal, Heliodor Kasprzak, Huynh T. Duc, and Donald D. Anthony Copyright © 2012 Jerzy Trojan et al. All rights reserved. Induction Chemotherapy in Locally Advanced Pharyngolaryngeal Cancers with Stridor: Is It Feasible and Safe? Sun, 12 Aug 2012 08:11:57 +0000 Background. The standard initial management of patients with locally advanced pharyngolaryngeal presenting with stridor is tracheostomy. Tracheostomy has been shown to negatively impact cancer-related outcomes. Methods. Retrospective analysis of prospectively collected data of 9 patients, who underwent induction chemotherapy with the aim of prevention of tracheostomy. Presenting features, time to resolution of stridor, and further management are reported. Results. Eight out of 9 patient received chemotherapy within 12 hours of presentation with stridor. There were 4 patients each with primary hypopharynx and larynx. The stage was IVA in 6 patients and IVB in 2 patients. In all patients receiving immediate chemotherapy, clinical stridor resolved within 48 hours. The radiological response rate was 62.5%. The median reduction in size of tumor was 37%. Conclusion. Immediate neoadjuvant chemotherapy is a feasible and safe option for patients presenting with early stridor and helps in resolution of stridor and avoiding tracheostomy. Vijay Maruti Patil, Vanita Noronha, Amit Joshi, Vamshi Muddu, Bhavesh Poladia, Bharat Chauhan, Kumar Prabhash, Devendra Arvind Chaukar, Pankaj Chatturvedi, Gouri Pantvaidya, Shashikant Juvekar, and Anil D'cruz Copyright © 2012 Vijay Maruti Patil et al. All rights reserved. Preparation and In Vivo Evaluation of Dichloro(1,2-Diaminocyclohexane)platinum(II)-Loaded Core Cross-Linked Polymer Micelles Sun, 15 Jul 2012 15:37:53 +0000 The therapeutic performance of oxaliplatin can be improved by incorporating the central cis-dichloro(1,2-diaminocyclohexane)platinum(II) (DACHPt) motif into the core cross-linked block copolymer micelles. We describe here the preparation, cellular uptake, and in vivo evaluation of core cross-linked micelles loaded with DACHPt. Stable drug-loaded micelles were prepared at high drug loading (~25 w/w%) and displayed a considerably increased in vitro cytotoxicity compared to free oxaliplatin against A2780 ovarian cancer cells. The DACHPt-loaded micelle formulation was well tolerated in mice and exhibited improved antitumor activity than oxaliplatin alone in an ovarian tumor xenograft model. Hardeep S. Oberoi, Natalia V. Nukolova, Yi Zhao, Samuel M. Cohen, Alexander V. Kabanov, and Tatiana K. Bronich Copyright © 2012 Hardeep S. Oberoi et al. All rights reserved. Deciphering the Role of Insulin-Like Growth Factor-I Receptor in Trastuzumab Resistance Mon, 09 Jul 2012 09:22:52 +0000 Resistance to the HER2-targeted antibody trastuzumab is a major clinical concern in the treatment of HER2-overexpressing metastatic breast cancer. Increased expression or signaling of the insulin-like growth factor-I receptor (IGF-IR) has been reported in a subset of cell lines and clinical samples derived from trastuzumab-resistant breast cancers. Genetic and pharmacologic inhibition of IGF-IR signaling has been shown to improve response to trastuzumab in trastuzumab-naïve and trastuzumab-resistant models. In this paper, we will discuss the role of IGF-IR signaling in trastuzumab resistance. Further, we will discuss cotargeting IGF-IR and HER2 as a potential therapeutic strategy for HER2-over-expressing breast cancers that have progressed on trastuzumab treatment. Rita Nahta Copyright © 2012 Rita Nahta. All rights reserved. Extracellular Matrix Proteins Modulate Antimigratory and Apoptotic Effects of Doxorubicin Sun, 01 Jul 2012 10:30:17 +0000 Anticancer drug resistance is a multifactorial process that includes acquired and de novo drug resistances. Acquired resistance develops during treatment, while de novo resistance is the primary way for tumor cells to escape chemotherapy. Tumor microenvironment has been recently shown to be one of the important factors contributing to de novo resistance and called environment-mediated drug resistance (EMDR). Two forms of EMDR have been described: soluble factor-mediated drug resistance (SFM-DR) and cell adhesion-mediated drug resistance (CAM-DR). Anthracyclines, among the most potent chemotherapeutic agents, are widely used in clinics against hematopoietic and solid tumors. Their main mechanism of action relies on the inhibition of topoisomerase I and/or II and the induction of apoptosis. Beyond this well-known antitumor activity, it has been recently demonstrated that anthracyclines may display potent anti-invasive effects when used at subtoxic concentrations. In this paper, we will describe two particular modes of EMDR by which microenvironment may influence tumor-cell response to one of these anthracyclines, doxorubicin. The first one considers the influence of type I collagen on the antimigratory effect of doxorubicin (CAM-DR). The second considers the protection of tumor cells by thrombospondin-I against doxorubicin-induced apoptosis (SFM-DR). Georges Said, Marie Guilbert, Hamid Morjani, Roselyne Garnotel, Pierre Jeannesson, and Hassan El Btaouri Copyright © 2012 Georges Said et al. All rights reserved. CpG Island Methylation, Microsatellite Instability, and BRAF Mutations and Their Clinical Application in the Treatment of Colon Cancer Tue, 26 Jun 2012 09:45:21 +0000 There have been significant developments in colon cancer research over the last few years, enabling us to better characterize tumors individually and classifying them according to certain molecular or genetic features. Currently, we are able to use KRAS mutational status as a guide to therapy with anti-epidermal growth factor receptor antibodies. Other molecular features under research include BRAF mutation, microsatellite instability, and CpG island methylation. These three molecular features are often associated with tumors that have overlapping phenotypes and can be present simultaneously in the same tumor. However, they carry different prognostic and predictive qualities, making analysis of their interaction relatively complex. Much research thus far has examined the clinical relevance of microsatellite instability in helping determine prognosis and the predictive value of adjuvant 5-fluorouracil chemotherapy in stages II and III colon cancers. BRAF mutation appears to be a biomarker for poor prognosis. CpG island methylation is tightly associated with microsatellite instable tumors and BRAF mutation, but its clinical utility remains uncertain. Hereby, we examine preclinical and clinical data that supports the utilization of all three phenotypes in future research applied to clinical practice. Christina Wu and Tanios Bekaii-Saab Copyright © 2012 Christina Wu and Tanios Bekaii-Saab. All rights reserved. Focal Adhesion-Chromatin Linkage Controls Tumor Cell Resistance to Radio- and Chemotherapy Mon, 18 Jun 2012 09:47:54 +0000 Cancer resistance to therapy presents an ongoing and unsolved obstacle, which has clear impact on patient's survival. In order to address this problem, novel in vitro models have been established and are currently developed that enable data generation in a more physiological context. For example, extracellular-matrix- (ECM-) based scaffolds lead to the identification of integrins and integrin-associated signaling molecules as key promoters of cancer cell resistance to radio- and chemotherapy as well as modern molecular agents. In this paper, we discuss the dynamic nature of the interplay between ECM, integrins, cytoskeleton, nuclear matrix, and chromatin organization and how this affects the response of tumor cells to various kinds of cytotoxic anticancer agents. Katja Storch and Nils Cordes Copyright © 2012 Katja Storch and Nils Cordes. All rights reserved. Predictive Molecular Tumour Testing: What Are the Obstacles between Bench and Bedside? Mon, 14 May 2012 14:56:08 +0000 There have been many exciting new breakthroughs in understanding tumour biology. This has opened up the possibility of personalized treatment for people with certain tumours. The epidermal growth factor receptor (EGFR) and K-ras are two such targets that can help classify tumours on a molecular basis and guide treatment decisions. However, there are still questions about how best to implement new molecular tests like these to characterize tumours in clinical practice. Potential obstacles include availability of good quality tissue specimens, access to the right test, and consensus about interpretation, funding, and availability. In this paper, we review these issues, by discussing these two examples in detail and suggest some actions for addressing potential barriers. Linda Mileshkin, Bhaumik Shah, and Michael Michael Copyright © 2012 Linda Mileshkin et al. All rights reserved. Integrin Signaling in Cancer Cell Survival and Chemoresistance Wed, 11 Apr 2012 18:26:59 +0000 Resistance to apoptosis and chemotherapy is a hallmark of cancer cells, and it is a critical factor in cancer recurrence and patient relapse. Extracellular matrix (ECM) via its receptors, the integrins, has emerged as a major pathway contributing to cancer cell survival and resistance to chemotherapy. Several studies over the last decade have demonstrated that ECM/integrin signaling provides a survival advantage to various cancer cell types against numerous chemotherapeutic drugs and against antibody therapy. In this paper, we will discuss the major findings on how ECM/integrin signaling protects tumor cells from drug-induced apoptosis. We will also discuss the potential role of ECM in malignant T-cell survival and in cancer stem cell resistance. Understanding how integrins and their signaling partners promote tumor cell survival and chemoresistance will likely lead to the development of new therapeutic strategies and agents for cancer treatment. Fawzi Aoudjit and Kristiina Vuori Copyright © 2012 Fawzi Aoudjit and Kristiina Vuori. All rights reserved. Bone Loss after Allogeneic Haematopoietic Stem Cell Transplantation: A Pilot Study on the Use of Zoledronic Acid Tue, 10 Apr 2012 12:50:41 +0000 Purpose. Bone loss is a common phenomenon following allogeneic haematopoietic stem cell transplantation (allo-HSCT). The study aimed on tolerance and efficacy of zoledronic acid (ZA) in patients after allo-HSCT. Methods. 40 patients’ with osteoporosis or osteopenia were recruited on this phase II study. ZA was given at a dose of 4 mg IV every 3 months for 2 years (yrs). BMD was determined by dual-energy X-ray absorptiometry (LS lumbar spine, FH femur hip). Patients were evaluated for deoxypyridinoline (Dpd) and calcium excretion by longitudinal measurements. Results. 36 patients who had received at least 3 doses of ZA were evaluable. 26 patients had at least two BMD measurements since baseline (BMD group). Among these patients, BMD increased from 0.97±0.15 to 1.10±0.18 g/cm² (LS baseline—2 yrs, Δ+11.6±6.0%, 𝑃<0.001) and from 0.82±0.10 to 0.91±0.10 g/cm² (FH baseline—2 yrs, Δ+7.5±7.0%, 𝑃<0.001). Factors associated with an increase in BMD were younger age, female donor sex, and immunosuppression with CSA/MTX. Conclusion. ZA was generally well tolerated; it increases BMD and reduces Dpd excretion significantly in patients with bone loss after allo-HSCT. Andreas Hausmann, Wolfgang Hill, Hans Joachim Stemmler, Georg Ledderose, Andrea Baur-Melnyk, Susanne Fritsch, Johanna Ullmann, Hans-Jochem Kolb, Sandra Geiger, and Johanna Tischer Copyright © 2012 Andreas Hausmann et al. All rights reserved.