Showing papers in "Cancer management and research in 2013"

The role of epithelial-mesenchymal transition programming in invasion and metastasis: a clinical perspective.

Abstract: Epithelial-mesenchymal transition (EMT) is involved in normal developmental cellular processes, but it may also be co-opted by a subset of cancer cells, to enable them to invade and form metastases at distant sites. Several gene transcription factors regulate EMT, including Snail1, Snail2, Zeb1, Zeb2, and Twist; ongoing studies continue to identify and elucidate other drivers. Specific micro ribonucleic acids (RNAs) have also been found to regulate EMT, including the microRNA-200 (miR-200) family, which targets Zeb1/Zeb2. Cancer "stem cells" - with the ability to self-renew and to regenerate all the cell types within the tumor - have been found to express EMT markers, further implicating both cancer stem cells and EMT with metastasis. Microenvironmental cues, including transforming growth factor-β, can direct EMT tumor metastasis, such as by regulating miR-200 expression. In human tumors, EMT markers and regulators may be expressed in a subset of tumor cells, such as in cells at the invasive front or tumor-microenvironment interface, though certain subtypes of cancer can show widespread mesenchymal-like features. In terms of therapeutic targeting of EMT in patients, potential areas of exploration could include targeting the cancer stem cell subpopulation, as well as microRNA-based therapeutics that reintroduce miR-200. This review will examine evidence for a role of EMT in invasion and metastasis, with the focus being on studies in lung and breast cancers. We also carry out analyses of publicly-available gene expression profiling datasets in order to show how EMT-associated genes appear coordinately expressed across human tumor specimens.

The claudin family of proteins in human malignancy: A clinical perspective

Abstract: Tight junctions, or zonula occludens, are the most apical component of the junctional complex and provide one form of cell–cell adhesion in epithelial and endothelial cells. Nearly 90% of malignant tumors are derived from the epithelium. Loss of cell–cell adhesion is one of the steps in the progression of cancer to metastasis. At least three main tight junction family proteins have been discovered: occludin, claudin, and junctional adhesion molecule (JAM). Claudins are the most important structural and functional components of tight junction integral membrane proteins, with at least 24 members in mammals. They are crucial for the paracellular flux of ions and small molecules. Overexpression or downregulation of claudins is frequently observed in epithelial-derived cancers. However, molecular mechanisms by which claudins affect tumorigenesis remain largely unknown. As the pivotal proteins in epithelial cells, altered expression and distribution of different claudins have been reported in a wide variety of human malignancies, including pancreatic, colonic, lung, ovarian, thyroid, prostate, esophageal, and breast cancers. In this review, we will give the readers an overall picture of the changes in claudin expression observed in various cancers and their mechanisms of regulation. Downregulation of claudins contributes to epithelial transformation by increasing the paracellular permeability of nutrients and growth factors to cancerous cells. In the cases of upregulation of claudin expression, the barrier function of the cancerous epithelia changes, as they often display a disorganized arrangement of tight junction strands with increased permeability to paracellular markers. Finally, we will summarize the literature suggesting that claudins may become useful biomarkers for cancer detection and diagnosis as well as possible therapeutic targets for cancer treatment.

Radium-223 chloride: a potential new treatment for castration-resistant prostate cancer patients with metastatic bone disease.

Abstract: Background Radium-223 chloride ((223)Ra; Alpharadin) is an alpha-emitting radioisotope that targets areas of osteoblastic metastasis and is excreted by the small intestine. When compared with beta-emitters (eg, strontium-89, samarium-153), (223)Ra delivers a high quantity of energy per track length with short tissue penetration. Objective This review describes the mechanism, radiobiology, and preclinical development of (223)Ra and discusses the clinical data currently available regarding its safety and efficacy profile. Methods Data from clinical trials including abstracts were collected and reviewed using the PubMed Database, as well as the American Society of Clinical Oncology abstract database. Conclusion Current bone-targeted therapies fall into two main categories: antiresorptive agents (eg, zoledronic acid, denosumab), which have been shown to delay skeletal-related events, and radiopharmaceuticals (eg, samarium-153), which may have a role in pain palliation. Historically, neither antiresorptive agents nor radiopharmaceuticals have shown definitive evidence of improved overall survival or other antitumor effects in metastatic castrate-resistant prostate cancer (mCRPC). Radiopharmaceuticals are limited by myelosuppresion, thrombocytopenia, and renal excretion. In a recently reported randomized Phase III trial in men with symptomatic bone-metastatic CRPC who had received or were ineligible for docetaxel chemotherapy, (223)Ra treatment resulted in improved overall survival and delayed skeletal-related events. Toxicity consisted of minor gastrointestinal side effects and mild neutropenia and thrombocytopenia that were rarely severe. Pending regulatory approval, (223)Ra may represent a unique and distinct option for an important subgroup of patients with mCRPC; future trials should address its use in combination or in sequence with existing and novel agents.

Treatment challenges in the management of relapsed or refractory non-Hodgkin's lymphoma - novel and emerging therapies.

Abstract: Over the last few decades, advances in immunochemotherapy have led to dramatic improvement in the prognosis of non-Hodgkin’s lymphoma (NHL). Despite these advances, relapsed and refractory disease represents a major treatment challenge. For both aggressive and indolent subtypes of NHL, there is no standard of care for salvage regimens, with prognosis after relapse remaining relatively poor. Nevertheless, there are multiple emerging classes of targeted therapies for relapsed/refractory disease, including monoclonal antibodies, antibody– drug conjugates, radioimmunotherapy, small-molecule inhibitors of cell-growth pathways, and novel chemotherapy agents. This review will discuss treatment challenges of NHL, current available salvage regimens for relapsed/refractory NHL, and the safety and efficacy of novel emerging therapies.

Nedaplatin: a cisplatin derivative in cancer chemotherapy.

Abstract: Nedaplatin, a cisplatin analog, has been developed to decrease the toxicities induced by cisplatin, such as nephrotoxicity and gastrointestinal toxicity. The dose of nedaplatin is determined by body surface area, not by the area under the curve (AUC). The recommended therapeutic dose is 80–100 mg/m2, although the pharmacokinetic profile of nedaplatin is similar to that of carboplatin. In our preliminary study, there was a favorable correlation between AUC and creatinine clearance (CL), suggesting that renal function should be considered when nedaplatin is administered. Ishibashi’s formula, ie, DoseNDP = AUC × CLNDP, where CLNDP = 0.0738 × creatinine clearance + 4.47, would be predictable and useful for estimating the individual dose of nedaplatin. Several Phase II studies have suggested that nedaplatin might be a useful second analog, especially for patients with non-small cell lung cancer, esophageal cancer, uterine cervical cancer, head and neck cancer, or urothelial cancer. Further, nedaplatin was reported to be a useful chemotherapeutic agent with radiosensitizing properties; however, there is no Phase III study of nedaplatin, neither with chemotherapy nor with concurrent chemoradiotherapy, because nedaplatin is not commonly used throughout the world. Further evaluation in a randomized controlled trial is warranted to demonstrate definitively the activity of nedaplatin.

AKT-independent PI3-K signaling in cancer - emerging role for SGK3.

Abstract: The phosphoinositide 3-kinase (PI3-K) signaling pathway plays an important role in a wide variety of fundamental cellular processes, largely mediated via protein kinase B/v-akt murine thymoma viral oncogene homolog (PKB/AKT) signaling. Given the crucial role of PI3-K/AKT signaling in regulating processes such as cell growth, proliferation, and survival, it is not surprising that components of this pathway are frequently dysregulated in cancer, making the AKT kinase family members important therapeutic targets. The large number of clinical trials currently evaluating PI3-K pathway inhibitors as a therapeutic strategy further emphasizes this. The serum- and glucocorticoid-inducible protein kinase (SGK) family is made up of three isoforms, SGK1, 2, and 3, that are PI3-K-dependent, serine/threonine kinases, with similar substrate specificity to AKT. Consequently, the SGK family also regulates similar cell processes to the AKT kinases, including cell proliferation and survival. Importantly, there is emerging evidence demonstrating that SGK3 plays a critical role in AKT-independent oncogenic signaling. This review will focus on the role of SGK3 as a key effector of AKT-independent PI3-K oncogenic signaling.

Critical appraisal of the potential use of cannabinoids in cancer management.

Abstract: Cannabinoids have been attracting a great deal of interest as potential anticancer agents. Originally derived from the plant Cannabis sativa, there are now a number of endo-, phyto- and synthetic cannabinoids available. This review summarizes the key literature to date around the actions, antitumor activity, and mechanisms of action for this broad range of compounds. Cannabinoids are largely defined by an ability to activate the cannabinoid receptors - CB1 or CB2. The action of the cannabinoids is very dependent on the exact ligand tested, the dose, and the duration of exposure. Some cannabinoids, synthetic or plant-derived, show potential as therapeutic agents, and evidence across a range of cancers and evidence in vitro and in vivo is starting to be accumulated. Studies have now been conducted in a wide range of cell lines, including glioma, breast, prostate, endothelial, liver, and lung. This work is complemented by an increasing body of evidence from in vivo models. However, many of these results remain contradictory, an issue that is not currently able to be resolved through current knowledge of mechanisms of action. While there is a developing understanding of potential mechanisms of action, with the extracellular signal-regulated kinase pathway emerging as a critical signaling juncture in combination with an important role for ceramide and lipid signaling, the relative importance of each pathway is yet to be determined. The interplay between the intracellular pathways of autophagy versus apoptosis is a recent development that is discussed. Overall, there is still a great deal of conflicting evidence around the future utility of the cannabinoids, natural or synthetic, as therapeutic agents.

Daily baseline skin care in the prevention, treatment, and supportive care of skin toxicity in oncology patients: recommendations from a multinational expert panel.

Abstract: Skin reactions due to radiotherapy and chemotherapy are a significant problem for an important number of cancer patients. While effective for treating cancer, they disturb cutaneous barrier function, causing a reaction soon after initiation of treatment that impacts patient quality of life. Managing these symptoms with cosmetics and nonpharmaceutical skin care products for camouflage or personal hygiene may be important for increasing patient self-esteem. However, inappropriate product choice or use could worsen side effects. Although recommendations exist for the pharmaceutical treatment of skin reactions, there are no recommendations for the choice or use of dermatologic skin care products for oncology patients. The present guidelines were developed by a board of European experts in dermatology and oncology to provide cancer care professionals with guidance for the appropriate use of non-pharmaceutical, dermocosmetic skin care management of cutaneous toxicities associated with radiotherapy and systemic chemotherapy, including epidermal growth factor inhibitors and monoclonal antibodies. The experts hope that these recommendations will improve the management of cutaneous side effects and hence quality of life for oncology patients.

Gastric cancer in young people under 30 years of age: worse prognosis, or delay in diagnosis?

Abstract: BACKGROUND: Gastric cancer is an aggressive disease with nonspecific early symptoms. Its incidence and prognosis in young patients has shown considerable variability. PURPOSE OF THE STUDY: Our objective was to retrospectively study patients from our institution aged <30 years with gastric carcinoma. The study was undertaken to describe the experience of gastric cancer in this population, and to demonstrate its specific clinical and pathological characteristics. MATERIALS AND METHODS: We reviewed the cases of histologically confirmed gastric cancer between 1985 and 2006 at the Instituto Nacional de Cancerologia of Mexico (INCan); emphasis in our review was placed on clinical presentation, diagnostic and therapeutic intervention, pathology, and the results. RESULTS: Thirty cases of gastric carcinoma were reviewed. The patients' median age was 27 years (range, 18-30 years) and the male:female ratio was 1:1. CONCLUSION: Gastric cancer exhibits different behavior in patients aged, 30 years, but delay in diagnosis and the tumor's behavior appear to be the most important factors in prognosis of the disease.

Anti-VEGF agents in metastatic colorectal cancer (mCRC): are they all alike?

Abstract: Bevacizumab is a monoclonal antibody that binds and neutralizes vascular endothelial growth factor (VEGF)-A, a key player in the angiogenesis pathway. Despite benefits of bevacizumab in cancer therapy, it is clear that the VEGF pathway is complex, involving multiple isoforms, receptors, and alternative ligands such as VEGF-B, and placental growth factor, which could enable escape from VEGF-A-targeted angiogenesis inhibition. Recently developed therapies have targeted other ligands in the VEGF pathway (eg, aflibercept, known as ziv-aflibercept in the United States), VEGF receptors (eg, ramucirumab), and their tyrosine kinase signaling (ie, tyrosine kinase inhibitors). The goal of the current review was to identify comparative preclinical data for the currently available VEGF-targeted therapies. Sources were compiled using PubMed searches (2007 to 2012), using search terms including, but not limited to: “bevacizumab,” “aflibercept,” “ramucirumab,” and “IMC-18F1.” Two preclinical studies were identified that compared bevacizumab and the newer agent, aflibercept. These studies identified some important differences in binding and pharmacodynamic activity, although the potential clinical relevance of these findings is not known. Newer antiangiogenesis therapies should help further expand treatment options for colorectal and other cancers. Comparative preclinical data on these agents is currently lacking.

3-Phosphoinositide-dependent protein kinase-1 as an emerging target in the management of breast cancer.

Abstract: It should be noted that 3-phosphoinositide-dependent protein kinase-1 (PDK1) is a protein encoded by the PDPK1 gene, which plays a key role in the signaling pathways activated by several growth factors and hormones. PDK1 is a crucial kinase that functions downstream of phosphoinositide 3-kinase activation and activates members of the AGC family of protein kinases, such as protein kinase B (Akt), protein kinase C (PKC), p70 ribosomal protein S6 kinases, and serum glucocorticoid-dependent kinase, by phosphorylating serine/threonine residues in the activation loop. AGC kinases are known to play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation, and survival. Changes in the expression and activity of PDK1 and several AGC kinases have been linked to human diseases including cancer. Recent data have revealed that the alteration of PDK1 is a critical component of oncogenic phosphoinositide 3-kinase signaling in breast cancer, suggesting that inhibition of PDK1 can inhibit breast cancer progression. Indeed, PDK1 is highly expressed in a majority of human breast cancer cell lines and both PDK1 protein and messenger ribonucleic acid are overexpressed in a majority of human breast cancers. Furthermore, overexpression of PDK1 is sufficient to transform mammary epithelial cells. PDK1 plays an essential role in regulating cell migration, especially in the context of phosphatase and tensin homologue deficiency. More importantly, downregulation of PDK1 levels inhibits migration and experimental metastasis of human breast cancer cells. Thus, targeting PDK1 may be a valuable anticancer strategy that may improve the efficacy of chemotherapeutic strategies in breast cancer patients. In this review, we summarize the evidence that has been reported to support the idea that PDK1 may be a key target in breast cancer management.

Orphan G protein receptor GPR55 as an emerging target in cancer therapy and management

Abstract: G protein-coupled receptors (GPCRs) modulate a vast array of cellular processes. The current review gives an overview of the general characteristics of GPCRs and their role in physiological conditions. In addition, it describes the current knowledge of the physiological and pathophysiological functions of GPR55, an orphan GPCR, and how it can be exploited as a therapeutic target to combat various cancers.

Cancer-associated thrombosis: clinical presentation and survival.

Abstract: Background Thromboembolic events are important causes of morbidity and mortality in cancer patients. Clinical presentation in a community-based setting has not been fully clarified. The purpose of this study was to evaluate the incidence, risk factors, role of thrombophilia, and subsequent survival following thrombosis in cancer patients.

Benefit risk assessment and update on the use of docetaxel in the management of breast cancer

Abstract: The objective of this paper is to review the data supporting the use of docetaxel in the treatment of breast cancer, focusing on pharmacokinetics, efficacy in adjuvant and metastatic trials alone and in combination with chemotherapeutic and targeted agents, and the toxicity of docetaxel in comparison to paclitaxel. Docetaxel is a semisynthetic product derived from the European yew tree Taxus baccata L. It promotes the assembly of microtubules, stabilizes them, and thereby prevents their depolymerization. Docetaxel has been incorporated into neo-adjuvant chemotherapy regimens, both with and without anthracyclines. The inclusion of taxanes such as docetaxel in polychemotherapy regimens in early breast cancer is associated with a statistically significant reduction in mortality. As a single agent, docetaxel is highly active in the treatment of metastatic breast cancer. In first-line treatment of metastatic breast cancer, the combination of docetaxel and capecitabine was associated with an improvement in overall survival; however, toxicity was higher. The toxicity profile of docetaxel has been well documented and is predictable; the most frequent adverse effects are neutropenia and febrile neutropenia. Taxane-specific adverse effects, such as peripheral neuropathy, are also expected but are manageable with appropriate dosing and scheduling.

New and emerging combination therapies for esophageal cancer

Abstract: Esophageal cancer comprises two different histological forms - squamous cell carcinoma (SCC) and adenocarcinoma (AC). While the incidence of AC has increased steeply in Western countries during the last few years, the incidence of SCC is fairly stable. Both forms differ in pathogenesis and response to chemotherapy and radiation therapy. Plenty of studies have evaluated new chemotherapy combination regimens in the neoadjuvant, adjuvant, and palliative setting. In addition, new radiation and chemoradiation protocols have been investigated. Finally, molecular-targeted therapy has been included in several new randomized prospective trials. Therefore, this review presents new data on this topic and critically discusses promising approaches towards a more effective treatment in a disease with a grim prognosis.

Endoscopic endonasal approach for the treatment of a large clival giant cell tumor complicated by an intraoperative internal carotid artery rupture

Abstract: Giant cell tumors (GCTs) are primary bone neoplasms that rarely involve the skull base. These lesions are usually locally aggressive and require complete removal, including the surrounding apparently healthy bone, to provide the best chance of cure. GCTs, as well as other lesions located in the clivus, can nowadays be treated by a minimally invasive fully endoscopic extended endonasal approach. This approach ensures a more direct route to the craniovertebral junction than other possible approaches (transfacial, extended lateral, and posterolateral approaches). The case reported is a clival GCT operated on by an extended endonasal approach that provides another contribution on how to address one of the most feared complications attributed to this approach: a massive bleed due to an internal carotid artery injury.

Marked radiographic response of a HER-2-overexpressing biliary cancer to trastuzumab

Abstract: Trastuzumab is a monoclonal antibody targeting HER-2 HER-2 overexpression has been described in gallbladder cancer and in cholangiocarcinoma This report describes the first case of a patient with HER-2 overexpressing metastatic gallbladder adenocarcinoma and responding radiographically and biochemically to trastuzumab alone

Targeting CD19 in B-cell lymphoma: emerging role of SAR3419

Abstract: Non-Hodgkin lymphoma symbolizes a heterogeneous group of diseases resulting from malignant transformation of lymphocytes with differing patterns of behavior and responses to treatment. The potential curability of non-Hodgkin lymphoma differs among the various histologic subtypes and is associated in part with the stage at presentation. CD19 antigen is a type I transmembrane glycoprotein belonging to the immunoglobulin Ig superfamily. CD19 is specifically expressed in normal and neoplastic B-cells. Recent study showed that in a mouse model, CD19 and c-Myc synergize functionally to accelerate B-cell lymphomagenesis, which is associated with increased disease severity. Specificity is the most important challenge in cancer therapeutics. Antibody–drug conjugates have the prospect of enhancing the therapeutic efficacy over unconjugated monoclonal antibodies through the selective delivery of cytotoxic agents to cancer cells. The ubiquitous expression of CD19 in these tumors, especially at an earlier stage and the property of efficient internalization, makes CD19 an attractive and affective target for antibody–drug conjugate therapy as compared to CD20. SAR3419 (huB4-DM4) is a novel antibody–drug conjugate that is composed of a humanized monoclonal IgG1 anti-CD19 antibody (huB4) attached to the potent cytotoxic drug, a maytansine derivative (DM4), through a cleavable disulfide cross-linking agent N-Succinimidyl-4-2-pyridyldithio butanoic acid (SPDB). The preclinical efficacy of maytansine derivative–anti-CD19 conjugate was demonstrated in our laboratory, and SAR3419 was found to be more effective than CHOP in a xenograft model. Phase I trials have also been conducted on the basis of preclinical studies that demonstrated promising antitumor activity with acceptable safety results in human B-cell lymphoma models. Additional trials are ongoing and will provide additional insight into the full potential of this novel drug.

Cost-effectiveness of an aprepitant regimen for prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer in the UK

Abstract: Purpose Prevention of chemotherapy-induced nausea and vomiting (CINV) remains an important goal for patients receiving chemotherapy. The objective of this study was to define, from the UK payer perspective, the cost-effectiveness of an antiemetic regimen using aprepitant, a selective neurokinin-1 receptor antagonist, for patients receiving chemotherapy for breast cancer. Methods A decision-analytic model was developed to compare an aprepitant regimen (aprepitant, ondansetron, and dexamethasone) with a standard UK antiemetic regimen (ondansetron, dexamethasone, and metoclopramide) for expected costs and health outcomes after single-day adjuvant chemotherapy for breast cancer. The model was populated with results from patients with breast cancer participating in a randomized trial of CINV preventative therapy for cycle 1 of single-day chemotherapy. Results During 5 days after chemotherapy, 64% of patients receiving the aprepitant regimen and 47% of those receiving the UK comparator regimen had a complete response to antiemetic therapy (no emesis and no rescue antiemetic therapy). A mean of £37.11 (78%) of the cost of aprepitant was offset by reduced health care resource utilization costs. The predicted gain in quality-adjusted lifeyears (QALYs) with the aprepitant regimen was 0.0048. The incremental cost effectiveness ratio (ICER) with aprepitant, relative to the UK comparator, was £10,847/QALY, which is well below the threshold commonly accepted in the UK of £20,000-£30,000/QALY. Conclusion The results of this study suggest that aprepitant is cost-effective for preventing CINV associated with chemotherapy for patients with breast cancer in the UK health care setting.

Personalized treatment for advanced colorectal cancer: KRAS and beyond

Abstract: Targeted therapies have improved the survival of patients with advanced colorectal cancer (CRC). However, further improvements in patient outcomes may be gained by the development of predictive biomarkers in order to select individuals who are most likely to benefit from treatment, thus personalizing treatment. Using the epidermal growth-factor receptor (EGFR) pathway, we discuss the existing and potential predictive biomarkers in clinical development for use with EGFR-targeted agents in metastatic CRC. The data and technological issues surrounding such biomarkers as expression of EGFR or its family members or ligands, KRAS-, NRAS-, and BRAF-mutation status, PI3K/PTEN expression, and imaging and clinical biomarkers, such as rash and hypomagnesemia, are summarized. Although the discovery of KRAS mutations has improved patient selection for EGFR-targeted treatments, further biomarkers are required, especially for those patients who exhibit KRAS mutations rather than the wild-type gene.

Profile of vismodegib and its potential in the treatment of advanced basal cell carcinoma.

Abstract: Basal cell carcinoma (BCC) is the most common human malignancy. Recent advances in our understanding of the critical biologic pathways implicated in the development and progression of BCC have led to the development of the first molecular targeted therapy for this disease. The hedgehog pathway is mutated in virtually all patients with BCC and recent trials with vismodegib, an inhibitor of this pathway, have shown significant responses. This review will discuss the importance of the hedgehog pathway in the pathogenesis of BCC and describe in detail the pharmacology of vismodegib in relation to its activity in advanced BCC.

Antiangiogenic treatment in hepatocellular carcinoma: the balance of efficacy and safety.

Abstract: Hepatocellular carcinoma (HCC) is a severe complication of advanced liver disease with a worldwide incidence of more than 600,000 patients per year. Liver function, clinical performance status, and tumor size are considered in the Barcelona Clinic Liver Cancer (BCLC) system. While curative treatment options are available for early stages, most patients present with intermediate- or advanced-stage HCC, burdened with a poor prognosis, substantially influenced by the degree of liver-function impairment. Hypervascularization is a major characteristic of HCC, and antiangiogenic treatments are the basis of treatment in noncurative stages, including interventional and pharmacological treatments. Currently, the tyrosine-kinase inhibitor sorafenib is still the only approved drug for HCC. Further improvements in survival in patients with intermediate- and advanced-stage HCC may be anticipated by both multimodal approaches, such as combination of interventional and systemic treatments, and new systemic treatment options. Until now, the Phase III development of other tyrosine-kinase inhibitors in patients with advanced HCC has failed due to minor efficacy and/or increased toxicity compared to sorafenib. However, promising Phase II data have been reported with MET inhibitors in this hard-to-treat population. This review gives a critical overview of antiangiogenic drugs and strategies in intermediate- and advanced-stage HCC, with a special focus on safety.

The association of race with timeliness of care and survival among Veterans Affairs health care system patients with late-stage non-small cell lung cancer.

Abstract: Background Non-small cell lung cancer is the leading cause of cancer-related mortality in the United States. Patients with late-stage disease (stage 3/4) have five-year survival rates of 2%–15%. Care quality may be measured as time to receiving recommended care and, ultimately, survival. This study examined the association between race and receipt of timely non-small cell lung cancer care and survival among Veterans Affairs health care system patients.

Long-term use of dasatinib in patients with metastatic castration-resistant prostate cancer after receiving the combination of dasatinib and docetaxel.

Abstract: Dasatinib is a potent oral tyrosine kinase inhibitor which targets several kinases, including the SRC family kinases. SRC family kinases have been implicated in androgen therapy resistance that often develops in metastatic castration-resistant prostate cancer (mCRPC), which drives the need for non-androgen targeting therapies. This article describes the preclinical rationale for the use of combination dasatinib and docetaxel therapy in mCRPC, and highlights the results of a phase I–II trial in which 46 patients with mCRPC, treated with a regimen of dasatinib and docetaxel, demonstrated improvements in bone scans, high rates of soft tissue responses, and modulation of markers of bone turnover. This brief report discusses in detail follow-up data on two patients who remain alive after >2.5 years on dasatinib single-agent therapy after discontinuing docetaxel treatment.

Advanced medullary thyroid cancer: pathophysiology and management.

Abstract: Medullary thyroid carcinoma (MTC) is a rare malignant tumor originating from thyroid parafollicular C cells. This tumor accounts for 3%-4% of thyroid gland neoplasias. MTC may occur sporadically or be inherited. Hereditary MTC appears as part of the multiple endocrine neoplasia syndrome type 2A or 2B, or familial medullary thyroid cancer. Germ-line mutations of the RET proto-oncogene cause hereditary forms of cancer, whereas somatic mutations can be present in sporadic forms of the disease. The RET gene encodes a receptor tyrosine kinase involved in the activation of intracellular signaling pathways leading to proliferation, growth, differentiation, migration, and survival. Nowadays, early diagnosis of MTC followed by total thyroidectomy offers the only possibility of cure. Based on the knowledge of the pathogenic mechanisms of MTC, new drugs have been developed in an attempt to control metastatic disease. Of these, small-molecule tyrosine kinase inhibitors represent one of the most promising agents for MTC treatment, and clinical trials have shown encouraging results. Hopefully, the cumulative knowledge about the targets of action of these drugs and about the tyrosine kinase inhibitor-associated side effects will help in choosing the best therapeutic approach to enhance their benefits.

Molecularly targeted approaches herald a new era of non-small-cell lung cancer treatment.

Abstract: The discovery of activating mutations in the epidermal growth-factor receptor (EGFR) gene in 2004 opened a new era of personalized treatment for non-small-cell lung cancer (NSCLC). EGFR mutations are associated with a high sensitivity to EGFR tyrosine kinase inhibitors, such as gefitinib and erlotinib. Treatment with these agents in EGFR-mutant NSCLC patients results in dramatically high response rates and prolonged progression-free survival compared with conventional standard chemotherapy. Subsequently, echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK), a novel driver oncogene, has been found in 2007. Crizotinib, the first clinically available ALK tyrosine kinase inhibitor, appeared more effective compared with standard chemotherapy in NSCLC patients harboring EML4-ALK. The identification of EGFR mutations and ALK rearrangement in NSCLC has further accelerated the shift to personalized treatment based on the appropriate patient selection according to detailed molecular genetic characterization. This review summarizes these genetic biomarker-based approaches to NSCLC, which allow the instigation of individualized therapy to provide the desired clinical outcome.

The prognostic value of ERCC1 and RRM1 gene expression in completely resected non-small cell lung cancer: tumor recurrence and overall survival

Abstract: BACKGROUND The roles of excision repair cross-complementing group 1 gene (ERCC1) expression and ribonucleotide reductase subunit M1 gene (RRM1) expression in completely resected non-small cell lung cancer (NSCLC) are still debatable. Previous studies have shown that both genes affected the overall survival and outcomes of patients who received platinum-based chemotherapy; however, some studies did not show this correlation. The aim of this study was to evaluate the prognostic values of ERCC1 and RRM1 gene expression in predicting tumor recurrence and overall survival in patients with completely resected NSCLC who received adjuvant chemotherapy and in those who did not. PATIENTS AND METHODS A retrospective cohort study was conducted in 247 patients with completely resected NSCLC. All patients had been treated with anatomic resection (lobectomy or pneumonectomy) with systematic mediastinal lymphadenectomy between January 2002 and December 2011 at Chiang Mai University Hospital, Chiang Mai, Thailand. They were divided into two groups: recurrence and no recurrence. Protein expression of ERCC1 and RRM1 was determined by immunohistochemistry. Correlations between clinicopathologic variables, including ERCC1 and RRM1 expression and tumor recurrence, were analyzed. Univariate and multivariate Cox proportional hazards regression analysis stratified by nodal involvement, tumor staging, intratumoral blood vessel invasion, intratumoral lymphatic invasion, and tumor necrosis was used to identify the prognostic roles of ERCC1 and RRM1. RESULTS ERCC1 and RRM1 expression did not demonstrate prognostic value for tumor recurrence and overall survival in patients with completely resected NSCLC. In patients who did not receive adjuvant chemotherapy treatment, those with high ERCC1 and high RRM1 expression seemed to have greater potential for tumor recurrence and shorter overall survival than did those who had low ERCC1 and low RRM1 (hazard ratio [HR] =1.7, 95% confidence interval [CI] =0.6-4.3, P=0.292 and HR =1.6, 95% CI =0.5-4.5, P=0.411, respectively). In contrast, in patients who received adjuvant chemotherapy treatment, those with high ERCC1 and high RRM1 expression seemed to have benefited from adjuvant chemotherapy and showed good overall survival compared with those who had low ERCC1 and low RRM1 (HR =0.8, 95% CI = 0.4-1.8, P=0.612 and HR = 0.4, 95% CI = 0.1-2.4, P=0.325, respectively). Subgroup analysis in patients whose first-line metastatic chemotherapy failed demonstrated that ERCC1 expression and RRM1 expression were not prognostic factors for tumor recurrence and overall survival; however, patients who had high ERCC1 and high RRM1 expression seemed to have benefited from first-line chemotherapy treatment (HR =0.7, 95% CI =0.3-1.8, P=0.458). CONCLUSION ERCC1 expression and RRM1 expression were not prognostic of tumor recurrence and overall survival in patients with completely resected NSCLC, either with or without adjuvant chemotherapy. Prospective studies that include a larger number of patients are needed for definite conclusions.

Economic evaluation of therapies for patients suffering from relapsed-refractory multiple myeloma in Greece.

Abstract: Background Multiple myeloma is a hematologic malignancy that incurs a substantial economic burden in care management. Since most patients with multiple myeloma eventually relapse or become refractory to current therapies (rrMM), the aim of this study was to assess the cost-effectiveness of the combination of lenalidomide–dexamethasone, relative to bortezomib alone, in patients suffering from rrMM in Greece.

Serous endometrial intraepithelial carcinoma: a case series and literature review.

Abstract: Background Minimal uterine serous cancer (MUSC) or serous endometrial intraepithelial carcinoma (EIC) has been described by many different names since 1998. There have been very few cases reported in literature since EIC/MUSC was recognized as a separate entity. The World health Organization (WHO) Classification favors the term serous EIC. Although serous EIC is confined to the uterine endometrium at initial histology diagnosis, a significant number of patients could have distal metastasis at diagnosis, without symptoms. Serous EIC is considered as being the precursor of uterine serous cancer (USC), but pure serous EIC also has an aggressive behavior similar to USC. It is therefore prudent to have an accurate diagnosis and appropriate surgical staging. There are very few published articles in literature that discuss the pure form of serous EIC. The aim of this series is to share our experience and review evidence for optimum management of serous EIC. Patients and methods We report a series of five women treated in our institute in the last 3 years. We reviewed the relevant literature on serous EIC and various management strategies, to recommend best clinical practice. Conclusion Pure serous EIC is a difficult histopathological diagnosis, which requires ancillary immunohistochemical staining. It can have an aggressive clinical behavior with early recurrence and poor survival. Optimum surgical staging, with appropriate adjuvant treatment, should be discussed when treating these patients.

Perspectives on the immunologic microenvironment of astrocytomas.

Abstract: Background The microenvironment of astrocytomas includes infiltrative inflammatory cells that are dynamic in nature, possibly reflecting tumor biology. We evaluated the inflammatory cell infiltrate in astrocytic tumors aiming for a better understanding of their immunobiology. Methods Immunohistochemical expression of CD68, CD3, and CD20 was investigated in 21 glioblastomas, 21 anaplastic astrocytomas, 13 diffuse astrocytomas, and 18 pilocytic astrocytomas. The inflammatory infiltrate was classified based on microanatomic location as perivascular and intratumoral, and subsequently graded semiquantitatively. Results Perivascularly, CD68-positive infiltrate was noted in 71.4% of glioblastomas compared with 14.3% of anaplastic astrocytomas (P = 0.0001), 7.7% of diffuse astrocytomas (P = 0.0001), and 33.3% of pilocytic astrocytomas (P = 0.017). Intratumorally, 85.7% of glioblastomas exhibited CD68-positive infiltrate compared with 42.9% of anaplastic astrocytomas (P = 0.004), 38.5% of diffuse astrocytomas (P = 0.008), and 33.3% of pilocytic astrocytomas (P = 0.001). Among diffusely infiltrating astrocytomas, intratumoral CD3-positive infiltrate was only associated with glioblastoma. A CD20-positive infiltrate was only detected in the perivascular space of a single case of diffuse astrocytoma. Conclusion These data indicate a distinct immune profile in the glioblastoma microenvironment primarily related to the prevalence of macrophages. Thus, novel glioblastoma therapies should address this key CD68-positive population and its possible role in generating an antitumor immune response.