This study aims to make an indirect comparison between enzalutamide and abiraterone acetate for mCRPC post-docetaxel.
A search for published phase 3 trials was performed with PubMed. Indirect comparisons of enzalutamide (AFFIRM) to abiraterone acetate (COU-AA-301) on outcomes overall survival (OS), time to prostate-specific-antigen (PSA) progression, radiographic progression-free survival (PFS), and PSA response were constructed in the context of log-linear regression models.
There was no statistically significant difference in OS (hazard ratio (HR) 0.85, 95% CI 0.68–1.07). However, there was some evidence that enzalutamide may outperform abiraterone acetate with respect to secondary outcomes: time to PSA progression (HR 0.40, 95% CI 0.30–0.53), radiographic PFS (HR 0.61, 95% CI 0.50–0.74), and PSA response rates (RRs) (OR 10.69, 95% CI 3.92–29.20).
While there was no statistically significant difference in OS, enzalutamide may be advantageous for secondary endpoints. Findings of this indirect comparison serve to be hypothesis-generating for future head-to-head trials.
enzalutamide; abiraterone acetate; metastatic castration-resistant prostate cancer; mCRPC; post-docetaxel
To investigate the relationship between gender differences in fatty acid-binding protein7 (FABP7) and BRN2 (POU class 3 homeobox 2) expression in renal cell carcinoma (RCC) and the prognosis of patients with RCC.
MATERIALS AND METHODS
immunohistochemical (IHC) staining as well as reverse transcription-polymerase chain reaction (RT-PCR) was performed in renal tissues from 103 patients (83 men, mean age = 63.6 years old; 20 women, mean age = 63.1 years old) underwent radical nephrectomy from January 1, 2001 through December 31, 2010. The probability of overall patient survival was estimated using the Kaplan-Meier method.
FABP7 mRNA expression was more frequent in men (P = 0.07) while BRN2 protein expression was significantly more frequent in women (P = 0.029). In particular, FABP7 was expressed in 100% of G1 renal cell carcinoma both in mRNA and protein levels. In women, FABP7 (−) and BRN2 (+) groups had a worse prognosis both in mRNA level (P = 0.038) and protein level (P = 0.058). BRN2 was expressed 100% of papillary RCC both in mRNA and protein levels.
Our results demonstrated that gender was a key factor in FABP7 and BRN2 expression in RCC, and the combination with FABP7 and BRN2 stratified by gender could be a new potential prognostic factor in patients with RCC.
BRN2; FABP7; gender; overall survival; renal cell carcinoma
The aim of the study was to explore and describe the effect of polymorphisms in folate-associated genes regarding the levels of different folate forms and their distribution in tumors and mucosa in patients with colorectal cancer.
MATERIALS AND METHODS
Tumor and mucosa tissues from 53 patients with colorectal cancer were analyzed. The concentrations of tetrahydrofolate (THF), 5-methylTHF, and 5,10-methyleneTHF were measured by liquid chromatography—mass spectrometry. Genotyping of polymorphisms in the folate-associated genes methylenetetrahydrofolate reductase (MTHFR, C677T), methionine synthase (MTR, A2756G), and thymidylate synthase (TS, 5′-TSER 28 bp tandem repeat and 3′-TSUTR 6 bp deletion/insertion), were done by real-time polymerase chain reaction. Folate levels and distributions were determined in the total patient cohort and after subgrouping by genotypes.
The total folate level, as well as the THF and 5,10-methyleneTHF levels, were significantly higher in the tumor compared with mucosa tissue (P = 0.030, 0.031, and 0.015, respectively). The individual variation in folate levels in both tumor and mucosa were larger than the variation found when the patients were subgrouped by the gene polymorphisms. No significant differences in the mean concentration of any folate in the mucosa or tumor tissue were found in relation to the analyzed polymorphisms. The percentage level of 5,10-methyleneTHF in tumors was highest in patients with the MTHFR 677 CC genotype, and lowest in patients with the TT genotype (P = 0.033). A significantly lower percentage level of the 5,10-methyleneTHF level was found in tumors of patients with the 5′-TSER 3R/3R genotype (P = 0.0031).
A significant difference was found between the percentage level of 5,10-methyleneTHF in tumor tissues in relation to the MTHFR C677T and 5′-TSER 28 bp repeat polymorphisms. However, no differences were found in the actual tissue folate levels, or in their distribution, in relation to the polymorphisms in the MTHFR, MTR, or TS genes. These findings could be of importance for further research in the field by explaining some of the difficulties of obtaining reproducible and uniform results when using a few selected polymorphisms as predictive markers.
colorectal cancer; folate levels; gene polymorphisms
The cancer prevalence in the Malwa region of Punjab (1089/million/year) is much higher than the national average cancer prevalence in India (800/million/year). The participants in the present study were 50 healthy individuals and 49 cancer patients all living in the Malwa region of Punjab, with the healthy people being selected from the same household as the cancer patients. High concentrations of several potentially toxic elements were found in hair samples from people living in Punjab. Compared to standard reference ranges, the metals in excess in both the control and patient groups were aluminium (Al), barium (Ba), manganese (Mn), strontium (Sr) and uranium (U). The most significant findings were high lead (Pb), U and Ba concentrations. The maximum values for Ba, Mn, Pb and U were found in hair from breast cancer patients. The mean concentration of U in hair from the breast cancer patients was 0.63 μg U/g, which is more than double the value found in the control group and over six times higher than the reference range of 0.1 μg U/g. Water, soil, and phosphate fertilizers all seem to play a potential role, causing an increased metal burden in Punjabi people living in the Malwa region. The present study indicates that metals, and especially U, may be a factor in the development of breast cancer among Punjabi women.
Punjab; Malwa region; cancer; breast cancer; hair analysis; barium; lead; strontium; uranium
Early and accurate diagnosis of oral potentially malignant lesions (OPML) is of critical importance in preventing malignant transformation. Although histopathological interpretation of the degree of epithelial dysplasia is considered the gold standard for diagnosis, this method is subjective and lacks sensitivity. Therefore, many attempts have been made to identify objective molecular biomarkers to improve diagnosis. Microarray technology has the advantage of screening the expression of the whole genome making it one of the best tools for searching for novel biomarkers. However, microarray studies of OPMLs are limited, and no review has been published to highlight and compare their findings. In this paper, we systematically review all studies that have incorporated microarray analyses in the investigation of gene profile alterations in OPMLs and suggest a set of commonly dysregulated genes across multiple gene expression profile studies. This list of common genes may help focus selection of markers for further analysis regarding their importance in the diagnosis and prognosis of OPMLs.
oral cancer; oral potentially malignant lesion; biomarker; microarray; systematic review
Over the last seven years, seven targeted agents have been approved in the treatment of advanced or metastatic renal cell cancer, changing the therapeutic approach and prognosis of the disease dramatically. The latest agent with demonstrated efficacy is axitinib (Inlyta®). This new generation of tyrosine kinase agent differs from previously existing agents by its greater activity potency of inhibition of vascular endothelial growth factor-receptor (VEGFR1-3). This efficacy has been tested in phase II and III clinical trials. Axitinib is the only targeted agent that benefits from recommended titration, with intra-patient dose escalation. The toxicity profile of the drug is tolerable. This paper reviews the mechanism of action of axitinib, its metabolism, and its pharmacokinetic profile. Clinical data of efficacy and safety is also detailed. The agent has been integrated in the international therapeutic guidelines, as a standard in treatment of renal cell cancer patients, previously treated through antiangiogenic therapy.
axitinib; safety; efficacy; renal cell cancer
Leiomyosarcomas arising from the wall of blood vessels are rare and aggressive neoplasm. We report a case of a previously healthy 66-year-old woman who presented with intermittent abdominal pain, progressive constipation, and weight loss. Abdominal computed tomography showed a 12 cm solid heterogeneous tumor in the tail of the pancreas. The patient subsequently underwent surgical resection of the pancreatic mass. Surprisingly, histological and immunohistochemical analyses revealed leiomyosarcoma arising from the smooth muscle of the splenic vein. After surgery, she received adjuvant chemotherapy. One year later, there was no evidence of local recurrence. In this paper, we discuss the available information about leiomyosarcomas of splenic vein and its management.
sarcomas of the great vessels; leiomyosarcoma; splenic vein
Primary synovial sarcoma (SS) of the kidney is a rare neoplasm and its presenting features are similar to other common renal tumors, making early diagnosis difficult. To date, few cases have been reported in the literature. Primary renal SSs can exist in either a monophasic or a biphasic pattern, the former being more common and tending to have a better prognosis than the biphasic variant. Herein we describe a case of primary renal SS that was diagnosed based on histopathology and immunohistochemistry after radical nephrectomy. Fusion gene product analysis was also done by FISH and RT-PCR. Patient follow-up and literature review are presented, focused on systemic therapy. We highlight that these tumors should be correctly diagnosed as clinical results and specific treatment are distinct from primary epithelial renal cell carcinoma. Adjuvant chemotherapy should be tailored for each patient in the management of disease, although its role still remains unclear.
synovial sarcoma; kidney neoplasms; SYT-SSX fusion protein; chemotherapy
Both PCR and Hybrid Capture II (HCII) have been used for identifying cervical dysplasia; however, comparisons on the performance between these two tests show inconsistent results. We evaluated the performance of HCII and PCR MY09/11 in both screening and diagnostic populations in sub-sample of 1,675 non-pregnant women from a cohort in three clinical centers in the United States and Canada.
Sensitivity, specificity, positive predictive value, negative predictive value, and concordance between the two tests were calculated.
Specificity of HCII in detecting low-grade squamous intraepithelial lesion (LSIL) was higher in the screening group (88.7%; 95% CI: 86.2%–90.8%) compared to the diagnostic group (46.3%; 95% CI: 42.1%–50.6%); however, specificity of PCR was low in both the screening (32.8%; 95% CI: 29.6%–36.2%) and diagnostic (14.4%; 95% CI: 11.6%–17.6%) groups. There was comparable sensitivity by both tests in both groups to detect high-grade squamous intraepithelial lesion (HSIL); however, HCII was more specific (89.1%; 95% CI: 86.8%–91.0%; 66.2%; 95% CI: 62.0%–70.1%) than PCR (33.3%; 95% CI: 30.2%–36.5%; 17.9%; 95% CI: 14.8%–21.6%) in the screening and diagnostic groups, respectively. Overall agreement for HPV positivity was approximately 50% between HCII and PCR MY09/11; with more positive results coming from the PCR MY09/11.
In the current study, PCR MY09/11 was more sensitive but less specific than HCII in detecting LSIL, and HCII was more sensitive and specific in detecting HSIL than PCR in both screening and diagnostic groups.
comparison; test accuracy; hybrid capture II (HC II); polymerase chain reaction (PCR); cervical dysplasia
Enzalutamide, previously known as MDV300, is an oral, second-generation androgen receptor (AR) signaling inhibitor or antagonist that was approved by the Food and Drug Administration in 2012 for the treatment of metastatic castrate-resistant prostate cancer (mCRPC) postdocetaxel. Preclinical studies have demonstrated impressive affinity to the AR compared to the first-generation AR inhibitors. The landmark Phase III AFFIRM trial demonstrated improved overall survival benefit compared to placebo in addition to improvement in all tested parameters. Enzalutamide is currently being studied in several trials prechemotherapy and in earlier settings of prostate cancer. This review will discuss the mechanism of action of enzalutamide, its pharmacokinetics, the preclinical and clinical trials that led to its approval, the ongoing clinical trials, its safety and efficacy, as well as patterns of resistance, and discusses its place in therapy within the context of several recently approved agents for mCRPC.
enzalutamide; androgen receptor; metastatic castrate resistant prostate cancer; MDV30
Lung cancer is one of the leading causes of death in industrialized and developing countries. Approximately 80% of patients are diagnosed with non-small cell histology. Although a multidisciplinary approach is necessary for the treatment of patients at early or locally-advanced stages of the disease, further successes in the treatment of patients with advanced disease will largely rely on improved systemic tumor control. Although therapies directed against the epidermal growth factor receptor (EGFR) have been incorporated into daily clinical practice, the value of other treatments remains to be elucidated. The current review highlights the most important driver mutations in non-small cell lung cancer (NSCLC) and describes recent study results and the status of EGFR-directed therapy, anaplastic lymphoma kinase (ALK)-directed agents, antiangiogenic therapy, and mesenchymal-epithelial transition factor (MET) inhibitors. However, many other agents with different modes of action are being examined in clinical research.
lung cancer; NSCLC; chemotherapy; targeted therapy
Multiple myeloma (MM) is a neoplastic disorder. It results from proliferation of clonal plasma cells in bone marrow with production of monoclonal proteins, which are detectable in serum or urine. MM is clinically characterized by destructive bone lesions, anemia, hypercalcemia and renal insufficiency. Its prognosis is severe, with a median survival after diagnosis of approximately 3 years due to frequent relapses. Treatments for patients with relapsed/refractory MM include hematopoietic cell transplantation, a rechallenge using a previous chemotherapy regimen or a trial of a new regimen. The introduction of new drugs such as thalidomide, lenalidomide and bortezomib has markedly improved MM outcomes. When relapse occurs, the clinician’s challenge is to select the optimal treatment for each patient while balancing efficacy and toxicity. Patients with indolent relapse can be first treated with a 2-drug or a 3-drug combination. Patients with more aggressive relapse often require therapy with a combination of multiple active agents. Autologous stem cell transplantation should be considered as salvage therapy at first relapse for patients who have cryopreserved stem cells early in the disease course. The aim of this review is to provide an overview on the pharmacological and molecular action of treatments used for patients with relapsed/refractory multiple myeloma.
relapsed/refractory multiple myeloma; proteasome inhibitors; immunomodulatory drugs (IMIDs); chemotherapy
Although osteosarcoma represents the second most common primary bone tumor, spinal involvement is rare, accounting for 3%–5% of all osteosarcomas. The most frequent symptom of osteosarcoma is pain, which appears in almost all patients, whereas more than 70% exhibit neurologic deficit. At a molecular level, it is a tumor of great genetic complexity and several genetic disorders have been associated with its appearance. Early diagnosis and careful surgical staging are the most important factors in accomplishing sufficient management. Even though overall prognosis remains poor, en-block tumor removal combined with adjuvant radiotherapy and chemotherapy is currently the treatment of choice. This paper outlines histopathological classification, epidemiology, diagnostic procedures, and current concepts of management of spinal osteosarcoma.
spine; primary tumors; osteosarcoma; imaging/diagnosis
Acute myeloid leukemia (AML) represents a malignant accumulation of immature myeloid cells in the marrow, presenting with impaired hematopoiesis and its attendant complications, including bleeding, infection, and organ infiltration. Chromosomal abnormalities remain the most powerful predictors of AML prognosis and help to identify a subgroup with favorable prognosis. However, the majority of AML patients who are not in the favorable category succumb to the disease. Therefore, better efforts to identify those patients who may benefit from more aggressive and investigational therapeutic approaches are needed. Newer molecular markers aim at better characterizing the large group of intermediate-risk patients and to identify newer targets for therapy. A group that has seen little improvement over the years is the older AML group, usually defined as age ≥ 60. Efforts to develop less intensive but equally efficacious therapy for this vulnerable population are underway.
AML; management; prognosis
The purpose of the present retrospective study was to review outcome and patterns of failure of patients who were treated with radiotherapy for cervical lymph node metastases from an unknown primary site (CUP).
Patients and Methods
Between 2000 and 2009, 34 patients diagnosed with squamous cell CUP were admitted to radiotherapy in curative intent. In 26 of 34 patients (76%) neck dissection was performed prior to radiotherapy, extracapsular extension (ECE) was seen in 20 of 34 patients (59%). Target volumes included the bilateral neck and panpharyngeal mucosa. Concomitant chemotherapy was applied in 14 of 34 patients (41%).
After a median follow-up of 45 months for the entire group, 2 of 34 patients (6%) presented with an isolated regional recurrence, another 2 of 34 patients (6%) developed both local and distant recurrence, and 6 of 34 patients (18%) had distant failure only. Estimated overall survival after 2- and 5 -years was 78% and 63%. All patients with N1 or N2a disease (n=6) were disease free after 5 years. ECE, concomitant chemotherapy and involvement of neck levels 4 and 5 were associated with worse overall survival on univariate analysis.
Radiotherapy of the panpharynx and bilateral neck leads to excellent local control while distant metastases are the most frequent site of failure and prognostically limiting. Therefore intensified concomitant or sequential systemic therapies should be evaluated in future trials.
radiotherapy; CUP; unknown primary site; patterns of failure
The objective of this study was to evaluate some of the mechanisms involved in the activation of the immune system in patients with advanced-stage cancer (n = 7) who received an autologous dendritic cell vaccine. We examined the immune response mediated by macrophages (CD14+), natural killer cells (CD56+), and B lymphocytes (CD19+) by flow cytometry and assessed the expression of Th1 (IFN-γ, TNF-α, IL-2, and IL-12), Th2 (IL-4), and Treg (TGF-β) cytokines by flow cytometry and an enzyme-linked immunosorbent assay. The CD14+ TNF-α+ population was significantly increased (P < 0.04) when patients received the vaccine; IL-2 expression in both NK cells and in B lymphocytes was increased after a transient initial increase showed a nearly significant decrease (P < 0.07 and P < 0.06 respectively), whereas the CD19+ and CD56+ populations did not show significant changes. Dendritic cell-based immunotherapy led to increased secretion of IFN-γ and IL-12 and reduced secretion of TGF-β. In conclusion, it is likely that the autologous dendritic cell vaccine stimulated the immune cells from the peripheral blood of patients with cancer and generally increased the production of Th1 cytokines, which are related to immunomodulatory responses against cancer.
immune response; cancer; dendritic cells; immunotherapy
Primary malignant lymphoma of the breast is a rare tumor, defined as a tumor localized in the breast with or without axillary lymph-node metastases. Such a tumor is mainly found in female patients and located more frequently in the right breast. It is difficult to make primary breast lymphoma (PBL) diagnosis before operation, and PBL diagnosis is mainly based on pathological biopsy and immunohistochemical staining. In this paper, the cases of three patients who had PBL, and who were treated for it at the Institute for Oncology and Radiology of Serbia between 2008 and 2012, are reviewed and discussed. These cases of PBL had no recorded reoccurrence of the disease and were originally treated by surgery, radiotherapy R-CHOP, and/or chemotherapy. While there is no consensus to the question of how to best treat PBL (ie, with chemotherapy, radiotherapy, or combined therapy), it is hoped that this review will offer insight into successful treatment procedures for tumors of this category.
breast lymphoma; extranodal non-hodgkin lymphoma; breast cancer
Cervical cancer is still a major contributor to cancer-related mortality amongst women living in poor, rural communities of developing countries. The objective of this study is to establish the clinical presentation of cervical cancer and the management challenges encountered in Abakaliki, southeast Nigeria, with a view to finding intervention strategies. This study is a retrospective descriptive assessment of cases of clinically diagnosed cervical cancer managed at a state teaching hospital over six years. Of 76 cases managed, 61 (80.3%) cases notes were available for study. The mean age and parity of patients were 53.8 years and 6.8 years, respectively. The majority (75.4%) were illiterate. All had been married, but 42.6% were widowed. The main occupations were farming or petty trading. One patient (1.6%) had had a single Pap smear in her life. The major presenting complaints were abnormal vaginal bleeding (86.9%), offensive vaginal discharge (41.0%), and weight loss. Twenty patients (32.8%) were lost to follow-up prior to staging. Of the remaining 41 patients, 16 (39.0%) had stage III disease and 17.1% stage IV. Fifteen patients (24.6%) with late stage disease accepted referral, and were referred for radiotherapy. Those who declined were discharged home on request, though 4 (9.8%) died in the hospital. There was no feedback from referred patients confirming that they went and benefitted from the referral. The presentation followed known trends. Illiteracy, poverty, early marriages, high parity, widowhood, non-use of screening methods, late presentation, non-acceptance of referral, and lack of communication after referral were some of the major challenges encountered. These underscore the needs for health education and awareness creation, women educational and economic empowerment, legislation against early marriages and in protection of widows, and creation of a well-staffed and well-equipped dedicated gynecologic oncology unit to forestall further referral.
cervical cancer; late presentation; cancer-related deaths; management challenges; referral
Metastatic melanoma remains a difficult disease to treat, and long term survivors are rare. Over the past few years, however, breakthroughs in both immunotherapy as well as targeted agents have had a tremendous impact on patients diagnosed with this disease. This review summarizes recent advances in systemic therapies for melanoma, including immune modulators directed against cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and programmed death-1 (PD-1), as well as a number of targeted agents. These approaches hold great promise as the landscape of therapeutic options for advanced melanoma continues to evolve.
metastatic melanoma; therapy; ipilimumab; PD-1; BRAF; MEK; KIT
Glioblastoma (GBM) or grade IV glioma is the most common primary brain tumor in adults. Standard treatment median overall survival (OS) is only 14–15 months and less than 10% of patients will survive 5 years after diagnosis. There is no standard treatment in recurrent GBM and OS ranges from 3 to 9 months. GBM is 1 of the most vascularized human tumors and GBM cells produce vascular endothelial growth factor (VEGF). Bevacizumab, a humanized monoclonal antibody against VEGF, has demonstrated activity in vitro and in phase II trials in relapse, as well as in 1 phase III trial as first line therapy. Bevacizumab also improves quality of life for patients suffering GBM. This paper reviews the mechanism of action of bevacizumab, its metabolism and pharmacokinetic profile. It summarizes the clinical studies in recurrent and newly diagnosed GBM, its potential side effects and complications and its place in therapy.
glioblastoma; bevacizumab; VGEF; chemotherapy; antiangiogenesis
Gain-of-function mutations in oncogenes and loss-of-function mutations in tumor suppressor genes (TSG) lead to cancer. In most human cancers, these mutations occur in somatic tissues. However, hereditary forms of cancer exist for which individuals are heterozygous for a germline mutation in a TSG locus at birth. The second allele is frequently inactivated by gene deletion, point mutation, or promoter methylation in classical TSGs that meet Knudson’s two-hit hypothesis. Conversely, the second allele remains as wild-type, even in tumors in which the gene is haplo-insufficient for tumor suppression. This article highlights the importance of PTEN, APC, and other tumor suppressors for counteracting aberrant PI3K, β-catenin, and other oncogenic signaling pathways. We discuss the use of gene-engineered mouse models (GEMM) of human cancer focusing on Pten and Apc knockout mice that recapitulate key genetic events involved in initiation and progression of human neoplasia. Finally, the therapeutic potential of targeting these tumor suppressor and oncogene signaling networks is discussed.
tumor suppressor gene; mouse model; PTEN; AKT; APC; ATM; CHK2; VHL
Hepatocellular carcinoma (HCC) is the most common liver cancer and the third leading cause of cancer death. It has been a major worldwide health problem with more new cases being diagnosed each year. The current available therapies for patients with advanced HCC are extremely limited. Therefore, it is of great clinical interests to develop more effective therapies for systemic treatment of advanced HCC. Several promising target-based drugs have been tested in a number of clinical trials. One breakthrough of these efforts is the approved clinical use of sorafenib in patients with advanced HCC. Targeted therapies are becoming an attractive option for the treatment of advanced HCC. In this review, we summarize the most recent progress in clinical targeted treatments of advanced HCC.
targeted therapy; hepatocellular carcinoma (HCC); sorafenib; tumor inhibitor; signaling pathway