Effects of sequential chemotherapy of FOLFIRI/FOLFOX on the endocrine axes of ACTH–cortisol and renin–angiotensin–aldosterone

The chemotherapies of FOLFOX (leucovorin?+?5-fluorouracil?+?oxaliplatin) and FOLFIRI (folinic acid?+?5-fluorouracil?+?irinotecan) are effective for a variety of malignant tumors. In particular, the sequential chemotherapy of FOLFOX/FOLFIRI has become the preferred post-operational treatment approach for gastrointestinal cancer and an important palliative care program for advanced cancer. However, the sequential chemotherapy of FOLFOX/FOLFIRI showed severe side effects due to the fact that the toxicity of the drugs can be enhanced by each other. Here, we report the dynamic changes in the activities of serum ACTH, cortisol, renin, angiotensin, and aldosterone in patients following multiple cycles of FOLFOX/FOLFIRI sequential chemotherapy. We found that the sequential chemotherapy might cause damage to the activities of the endocrine cells and/or the sympathetic nerve, and alter endocrine function, specifically the ACTH-cortisol and renin-angiotensin-aldosterone axes.     

List of reviewers 2009–2010

Acknowledgments

List of reviewers 2009–2010     

List of reviewers 2010–2011

Acknowledgments

List of reviewers 2010–2011     

Acute effects of megestrol on the hypothalamic–pituitary–adrenal axis

Background Clinical observations suggest that prolonged treatment with megestrol can lead to Cushing-like symptoms, while withdrawal of prolonged treatment with megestrol may result in adrenal insufficiency. However, only little is known about the acute effects of megestrol on the hypothalamic–pituitary–adrenal (HPA) axis. As part of an endocrine study, we evaluated the acute effects of megestrol, hydrocortisone and placebo on morning cortisol and ACTH levels.Method Using a balanced double-blind design, ten healthy male subjects were treated at 11:00 p.m. and 8:00 a.m. with megestrol (total dose 320 mg), hydrocortisone (total dose 30 mg) or placebo. After 1 h of rest, blood was drawn at 10:00 a.m. and 10:30 a.m. for determination of cortisol and ACTH levels.Results Compared to placebo, acute administration of megestrol resulted in a significant decrease in morning ACTH and cortisol levels. The suppression of ACTH after pretreatment with megestrol was less pronounced than after pretreatment with hydrocortisone.Conclusions Our results suggest that megestrol exerts glucocorticoid-like effects and has an acute depressing effect on the HPA axis. Therefore alterations in the steroid system should be included in the differential diagnosis of all subjects under treatment with megestrol.     

Management of aromatase inhibitor–induced arthralgia

Aromatase inhibitors (ais) are commonly used as adjuvant treatment in postmenopausal women with hormone receptor–positive early breast cancer. With both steroidal and nonsteroidal ais, ai-induced arthralgia is frequently observed. The mechanism of ai-induced arthralgia remains unknown, and the data available from clinical trails using ais are limited. We review the pertinent information from a clinical perspective, including an algorithm to treat ai-induced arthralgia.     

Toxicity of engineered nanomaterials mediated by nano–bio–eco interactions

Engineered nanomaterials may adversely impact human health and environmental safety by nano–bio–eco interactions not fully understood. Their interaction with biotic and abiotic environments are varied and complicated, ranging from individual species to entire ecosystems. Their behavior, transport, fate, and toxicological profiles in these interactions, addressed in a pioneering study, are subsequently seldom reported. Biological, chemical, and physical dimension properties, the so-called multidimensional characterization, determine interactions. Intermediate species generated in the dynamic process of nanomaterial transformation increase the complexity of assessing nanotoxicity. We review recent progress in understanding these interactions, discuss the challenges of the study, and suggest future research directions.     

Bannayan–Riley–Ruvalcaba syndrome: further delineation of the phenotype and management of PTEN mutation-positive cases

Bannayan–Riley–Ruvalcaba syndrome (BRRS) is characterised by macrocephaly, intestinal hamartomatous polyps, lipomas, pigmented maculae of the glans penis, developmental delay and mental retardation. The syndrome follows an autosomal dominant pattern of inheritance. In 1997 reports on two BRRS patients with a deletion at 10q23.2–q24.1 were published. In the same year, the first two families with BRRS and a mutation of the PTEN gene were reported. Mutations in the PTEN gene have also been demonstrated in patients with Cowden syndrome (CS), which shows partial clinical overlap with BRRS, and in families with cases both of BRRS and CS. PTEN mutation positive BRRS and CS are likely to be different phenotypic presentations of the same syndrome. If BRRS and CS are one single condition, the question arises whether patients with BRRS should be screened for malignant tumours, since patients with Cowden syndrome have an increased risk of breast, endometrial, thyroid and renal cancer. We present two isolated cases and one family and confirm that BRRS and CS are allelic. Furthermore, we review the PTEN mutation positive BRRS cases, to further delineate the phenotype and to compare the cases with a genomic deletion with the cases with a point mutation. We recommend offering BRRS cases with a mutation in PTEN the same surveillance protocol for (malignant) tumours as is currently recommended for CS. In addition, we propose a yearly haemoglobin test from early infancy for the early detection of intestinal hamartomas, which are likely to give severe complications, especially in BRRS cases. This revised version was published online in August 2006 with corrections to the Cover Date.     

Cancer Evolution–Development: experience of hepatitis B virus–induced hepatocarcinogenesis

Here, we present the basic concept and theoretical framework of a scientific hypothesis called Cancer Evolution–Development (“Cancer Evo-Dev”), based on our recent studies of the molecular mechanisms by which chronic infection with the hepatitis B virus induces hepatocarcinogenesis, together with related advances in that field. Several aspects central to our hypothesis are presented:

• ■ Immune imbalance—caused by the interaction of genetic predispositions and environmental exposures such as viral infection—is responsible for the maintenance of chronic non-resolving inflammation. Non-resolving inflammation promotes the occurrence and progression of cancers, characterized by an evolutionary process of “mutation–selection–adaptation” for both viruses and host cells.
• ■ Under a microenvironment of non-resolving inflammation, proinflammatory factors promote mutations in viral or host genomes by transactivation of the expression of cytidine deaminases and their analogues. Most cells with genomic mutations and mutated viruses are eliminated in the competition for survival in the inflammatory microenvironment. Only a small percentage of the mutated cells that alter their survival signal pathways and exhibit the characteristics of “stem-ness” can survive and function as cancer-initiating cells.
• ■ Cancers generally develop with properties of “backward evolution” and “retro-differentiation,” indicating the indispensability of stem-like signal pathways in the evolution and development of cancers.

The hypothesis of Cancer Evo–Dev not only lays the theoretical foundation for understanding the mechanisms by which inflammation promotes the development of cancers, but also plays an important role in specific prophylaxis, prediction, early diagnosis, and targeted treatment of cancers.     

Management of Bcr–Abl-positive leukemias with dasatinib

Dasatinib is a novel, potent, multi-targeted kinase inhibitor that is approved in Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) and Ph+ acute lymphoblastic leukemia following imatinib failure. Clinical trials have demonstrated its activity across all phases of CML. Dasatinib was superior to high-dose imatinib in a randomized, Phase II study of patients with chronic-phase CML who were resistant or intolerant to imatinib. Preliminary data from a Phase II trial in patients with previously untreated CML suggests that dasatinib compares favorably with imatinib in first-line use. Adverse events experienced with dasatinib include myelosuppression and fluid retention (e.g., pleural effusions), which were manageable with dose adjustment or treatment.     

Matrix Metalloproteinase-9 Expression in the Normal Mucosa–Adenoma–Dysplasia–Adenocarcinoma Sequence of the Colon

It has been proposed that matrix metalloproteinases (MMPs) play a role in tumor invasion. We determined protein expression of matrix metalloproteinase-9 (MMP-9) in colorectal cancer (CRC), corresponding normal mucosa and colorectal adenomas. For confirmation of immunohistochemical results MMP-9 TaqMan RT-PCR analysis was performed. Expression of MMP-9 was determined on paraffin embedded biopsy sections by immunohistochemistry in 31 CRC patients (from cancer tissue and corresponding normal mucosa) and in 30 patients with adenoma (nine adenomas with high grade of dysplasia). MMP-9 immunostaining was determined semi-quantitatively. For Taqman RT-PCR analyses normal mucosa (n = 5), adenoma without (n = 6) and with high grade dysplasia (n = 7) and CRC (n = 10) were investigated. Statistical analysis with ANOVA, LSD test and correlation analysis were performed. P value of <0.05 was considered significant. The MMP-9 expression in CRC was significantly higher compared to adenomas or the normal mucosa (P = 0.001). Significantly higher expression of MMP-9 has been observed in adenomas with high grade dysplasia compared to other adenomas or normal colon (P < 0.001). Diffuse strong MMP-9 expression was present in tumor as well as in stromal cells. In adenoma samples, dysplastic epithelial cells showed moderate intensive cytoplasmic MMP-9 expression, with a clear-cut differentiation between dysplastic and non-dysplastic areas. Staining intensity correlated with the grade of CRC. We demonstrate a significantly higher expression of MMP-9 in adenoma with high grade dysplasia-CRC sequence as compared to normal tissue. The over-expression of MMP-9 strongly suggests its association with colorectal carcinogenesis.     

Gene Expression Profiling of Non–Hodgkin Lymphomas

Background: Chromosomal translocations are genetic aberrations associated with specific non–Hodgkinlymphoma (NHL) subtypes. This study investigated the differential gene expression profile of Egyptian NHLcases based on a microarray approach. Materials and Methods: The study included tissue samples from 40 NHLpatients and 20 normal lymph nodes used as controls. Total RNA was extracted and used for cDNA microarrayassays. The quantitative real time polymerase chain reaction was used to identify the aberrantly expressedgenes in cancer. Results: Significant associations of 8 up-regulated and 4 down-regulated genes with NHLwere observed. Aberrant expression of a new group of genes not reported previously was apparent, includingdown-regulated NAG14 protein, 3 beta hydroxy-delta 5-c27 steroid oxi-reductase, oxi-glutarate dehydrogenase(lipo-amide), immunoglobulin lambda like polypeptide 3, protein kinase x linked, Hmt1, and caveolin 2 Tetraprotein. The up-regulated genes were Rb binding protein 5, DKFZP586J1624 protein, protein kinase inhibitorgamma, zinc finger protein 3, choline ethanolamine phospho-transferase CEPT1, protein phosphatase, andhistone deacetylase-3. Conclusions: This study revealed that new differentially expressed genes that may bemarkers for NHL patients and individuals who are at high risk for cancer development.     

Incorporation of perineural invasion of gastric carcinoma into the 7th edition tumor–node–metastasis staging system

The aim of this study was to determine the prognostic value of perineural invasion (PNI) in patients with gastric cancer who underwent curative resection. We retrospectively analyzed 518 patients who had undergone curative gastrectomy. Paraffin sections of surgical specimens from all patients were stained with hematoxylin and eosin. PNI was defined when carcinoma cells infiltrated into the perineurium or neural fascicles. Patients with PNI had a significantly larger tumors (≥5.0 cm), lymphatic venous invasion (positive), deeper tumor invasion (T4), more number of lymph node metastases (N3), and higher tumor stage (III). Regarding survival, multivariate analysis showed that PNI emerged as an independent prognostic factor for survival (hazard ratio (HR)?=?1.901, P?PNI and TNMIII_PNI stage both had lower ?2loglikelihood value (?2loglikelihood?=?3,306.608; ?2loglikelihood?=?2,535.151) and higher HR and 95 % CI (HR?=?1.879, 95 % CI?=?1.720–2.053; HR?=?2.268, 95 % CI?=?1.900–2.707), which represented the optimum prognostic stratification, together with better homogeneity, discriminatory ability. Our results showed that the frequency of PNI was high in patients with gastric cancer who underwent curative gastrectomy and the proportion of PNI positivity increased with progression and clinical stage of disease. PNI may be useful in detecting patients who had poor prognosis after curative resection in gastric cancer and it should be incorporated into TNM staging.     

Microscopic anatomy of the brain–meningioma interface

We analyzed the relation between meningioma and the brain in 50 surgical cases. So-called capsule formation was seen in 20 meningiomas, of which 13 were categorized as thin and 7 as thick. In 21 meningiomas the arachnoid membrane was intact, and 10 meningiomas had no underlying arachnoid membrane. The other 19 tumors showed partial disruption of the arachnoid membrane. The degree of arachnoid disruption correlated with the tumor grade, perifocal edema, pial blood supply on angiography, and tumor size. The existence of brain invasion correlated with the tumor grade and partially with tumor size. In case of invasive tumor, GFAP-positive cells were found deep in the tumor, usually in contact with blood vessels. The axons in gliotic brain often showed degenerative changes such as ballooning or varicose swelling. Meningiomas were usually demarcated by a basement membrane that was collagen type 4 (Col4)-positive. However, atypical and anaplastic meningiomas usually lacked Col4 staining at the interface. In two benign meningiomas that looked like an invasive growth, Col4 staining was seen above the brain. A pia mater-like structure covered the tumor surface in both cases. We could not demonstrate a relation between the expression of matrix metalloproteinase (MMP)-2 or MMP-9 and arachnoid disruption or brain invasion.     

Spontaneous regression of metastatic melanoma after inoculation with tetanus–diphtheria–pertussis vaccine

Spontaneous regression of metastatic melanoma is an exceedingly rare event, with only 76 well-documented cases in the literature since 1866. Here, we present the case of a patient who developed metastatic melanoma despite interferon therapy and who then achieved spontaneous regression shortly after a reaction to tetanus–diphtheria–pertussis vaccination. A common theme among these cases is the development of febrile illness before remission of the malignant disease. A brief overview of proposed mechanisms for these miraculous recoveries is presented, including a highlight on the potential role of the herv-k-mel viral marker, a nona- or decapeptide that appears in most melanomas, with homologies to peptides in pathogenic microorganisms.     

The Role of Anti–Epidermal Growth Factor Receptor and Anti–Vascular Endothelial Growth Factor Therapies in the Treatment of Non–Small-Cell Lung Cancer

Standard first-line therapy for non–small-cell lung cancer (NSCLC) with platinum-based agents, given in combination with cytotoxic compounds, has reached a relative plateau in its therapeutic efficacy. Novel molecular targeted agents acting on specific pathways have emerged as effective agents for treating NSCLC; some have already produced positive results in phase III trials. Notably, inhibition of the vascular endothelial growth factor (VEGF) pathway with an anti-VEGF antibody, bevacizumab, and targeting the epidermal growth factor receptor (EGFR) pathway with a small-molecule EGFR tyrosine kinase inhibitor erlotinib or a monoclonal antibody (cetuximab) have demonstrated prolonged survival in patients with advanced disease in both the first- and second-line settings. The heterogeneity of signaling processes leading to tumor cell survival and proliferation supports the targeting of multiple signaling pathways as an effective anticancer treatment strategy. Consequently, rational combinations of molecular targeted agents might offer superior clinical efficacy and an alternative treatment option to patients refractory to, or unable to tolerate, standard chemotherapy. The challenge lies in determining which molecular entities should be pursued and the best approach to combine them. This review discusses the potential clinical utility of combining bevacizumab and erlotinib to inhibit both angiogenesis and EGFR signaling as a valid nonchemotherapeutic approach for the treatment of NSCLC. Other combinations of novel therapies that block EGFR and angiogenic pathways, as well as complementary signaling pathways, with unique modes of action and low toxicity profiles could offer an increased repertoire of individualized treatment options for patients with advanced NSCLC.     

Importance of Quality of Life in Patients with Non–Small-Cell Lung Cancer

The therapeutic options for patients with advanced non–small-cell lung cancer (NSCLC) are palliative. Therefore, the quality of life in oncology is considered as an endpoint in clinical trials, and several scales have been accepted for its measurement in parallel with other clinical determinations. However, its use in clinical practice is hindered by various obstacles that need to be overcome. In this article we examine the concept of the quality of life in patients with NSCLC, as well as giving an evaluation and interpretation of the results of various clinical trials. We describe the new technological methods used in daily clinical practice to measure the quality of life.