Etoposide is an agent responsible for bone marrow suppression, defined as grade 4 neutropenia and thrombocytopenia and neutropenic fever, occurring in 20% of the patients treated with BEP regimens.9 A long-term effect of etoposide administration is the increased risk for acute leukemia, especially at doses over 2 g/m2, although the risk is still increased compared with the incidence in the general population, even at a dose lower than 2 g/m2. The cumulative risk of leukemia in patients treated with etoposide regimens is approximately 6%.10 Lastly, cisplatin is considered as one of the most emetogenic agents and nowadays, emesis is successfully managed through the administration of 5HT-antagonists and aprepitant, a neurokinin-1-antagonist. Nephrotoxicity, manifesting as a decrease in glomerular SAHA DRUG rate (GFR), and neurotoxicity as peripheral sensory neuropathy, autonomic neuropathy, Lhermitte sign and encephalopathy are also serious side-effects of cisplatin administration. The most predominant symptom of neurotoxicity is paresthesia, reported in 50% of the treated patients. Ototoxicity is also another cisplatin-induced side-effect, caused by destruction of auditory neurons and Corti’s organ, resulting in high frequency disturbances.11 Angina pectoris and myocardial infarction have also occurred during or shortly after cisplatin administration, as well as thromboembolic phenomena including arterial occlusion, deep venous thrombosis, pulmonary embolism, transient ischemic attack and stroke.12 In addition, patients experience infertility which is a major issue for this group of patients of young age, high cure rate and long-life expectancy.13
EPISPOTDetection Necrostatin 1 viable CTCsNo morphological analysis possible Proteins have to be actively secreted or shed from CTCs CTC-chipVisual confirmation of CTCsSubjective CTC analysis FASTNo enrichment neededSubjective CTC analysis LSCNo enrichment neededSubjective CTC analysis Visual confirmation of CTCsLow specificity due to marker limitations Nucleic-acid basedRT-PCRHigh sensitivityLow specificity Objective assessment of CTC signalInstability of RNA No morphological analysis possible qRT-PCRHigher specificity than regular RT-PCRInstability of RNA Objective assessment of CTC signalNo morphological analysis possible Full-size table Table optionsView in workspaceDownload as CSV Increasing assay sensitivity: enrichment techniques As mentioned before, enrichment can be based on morphologic cell characteristics, such as size or density, or on immunoseparation, using magnetic beads, ferrofluids or rosettes (see Fig. 1 and Fig. 2). Fig. 1. This figure clarifies the various options for enriching CTCs. After blood is drawn from the patient, CTCs can be separated from hematopoietic cells based on size, density or immunological characteristics. ISET (Isolation by Size of Epithelial Tumor cells) filtrates CTCs based on their larger size compared to hematopoietic cells. Ficoll and Percoll are the most commonly used density-gradient based techniques. Immunomagnetic separation techniques separate CTCs from other hematopoietic cells based on marker expression; MACS (Magnetic Activated Cell Sorting) uses microbeads and RARE (RosetteSep-Applied imaging Rare Event) combines magnetic separation with CD45+-cell depletion. CellSearch and the CTC-Chip both enrich based on EpCAM; CellSearch separates cells bound to EpCAM-ferrofluid in a magnetic field, while the CTC-chip does so by binding EpCAM-positive cells to microposts.
The final agent of great interest in the field of minor groove binders is ET-743, (a.k.a. Yondelis? or trabectedin), a member of the Ecteinascidin family and derived from the Caribbean tunicate Ecteinascidia turbinata. 79 Trabectedin is a tetrahydroisoquinoline alkaloid composed of three subunits A, B, and C. 80 While efficacious in a wide variety of solid tumor types tested preclinically, ET-743 also retains its activity in multi-drug-resistant tumors by preventing the transcription of the MDR1 gene. 81 Trabectedin has been shown to bind to the N2 position of GS-1101 in the minor groove of DNA with some sequence specificity. 82 It is believed that subunits A and B of the drug are responsible for DNA recognition and binding. The C subunit of the molecule lies at a tangent to the helical axis of the minor groove. 83 While it was once believed that this subunit was responsible for the cytotoxic effects of the drug, an analogue lacking the C subunit retains biological activity. 84 It is now suggested that the binding of trabectedin causes DNA helix distortion with the DNA bending towards the major groove rather than the site of the drug interaction. Additionally, trabectedin blocks the G2/M phase of the cell-cycle and is a selective inhibitor of activated gene transcription important for maintaining tumor cell viability. 85 It is believed that the lesion formed by the drug is then acted upon by the nucleotide excision repair (NER) pathway. Indeed, while ET-743 retains its activity in mismatch repair-deficient cells, it does appear to require the activity of the nucleotide excision repair pathway for maximum activity. 86
It may be relevant to identify specific signatures of metastases in order to personalized treatment patients. In particular, because the liver is the most frequent site of metastases in CRC, liver metastases represent a research field of great interest, that was less investigated and thus less known biologically. In fact, most studies have analyzed metastatic tissue in comparison with primary tumour to better understand the development process of the tumour as well as to identify gene WEHI-539 patterns predictive of metastatic potential. However little information about its molecular background is available. Many genes codifying for proteins involved in cell adhesion, migration, angiogenesis and proliferation have been linked to the development of colorectal liver metastases, but a real genetic signature for metastatic tissue has still not been defined.66 Varghese et al. found a site-specific segregation of genes between liver and peritoneal metastases, identifying 23 pathways expressed differently.67 Recently we studied gene expression profile of synchronous and metachronous liver metastases using Affymetrix platform and identified two different signatures: EGFr pathway was upregulated in metachronous lesions whereas the pathway mainly related to angiogenesis was upregulated in synchronous lesions.68 These preliminary results, both validated on proteomic assay, suggest that a genetic signature of liver metastases may exist and it can be the basis of treatment choice. Furthermore they sustain that advanced CRC may be a multiform disease, whose medical treatment may be differentiated on the basis of their different molecular features.
Among the most prominent pathways that lhrh antagonist drugs control decisions between life and death at times of cellular stress are members of the PI3K-AKT and mTOR pathways, which channel pro-survival signals to a wide network of downstream target effectors.86 A complex crosstalk connects these pro-survival pathways to the gateways controlling the major types of programmed cell death. The BCL-2 family is centrally involved in a growing number of mechanism regulating cell death, including classical mitochondrial apoptosis,87 and 88 alternative cell death pathways which are dependent on autophagy genes89 and 90 and necroptosis, which represents a type of controlled cell death with necrotic features.91 Finally, members of the Inhibitors of Apoptosis Proteins IAP family, including XIAP and surviving are often abnormally expressed in leukemic cells, resulting in a blockade of caspase-dependent cell death pathways.92 and 93 Because cell wall pathways are deregulated in a context dependent manner in cancer, targeting such central regulatory mechanisms with specific agents could turn out to be very effective, in particular when used as chemosensitizer in combination therapy. A prerequisite for successful application will be to identify practicable biomarkers to predict sensitivity of the leukemia to a given approach.
The possible effect of adjuvant endocrine therapies on cognition is a significant overall quality of life (QoL) concern, particularly in breast cancer patients of 65 years and older.83 Cognitive impairment may occur because of age-related reductions in YO-01027 exposure and the presence of other comorbidities.84 Estrogen deprivation has been found to have effects on cognition in women.85 One study demonstrated that women with low levels of bioavailable estrogen had a greater chance of developing cognitive impairment than women with high levels of estrogen.86 These findings suggest that the reduction of estrogens to near undetectable levels may have an impact on cognition over the long term. A preliminary study found that women who took TAM sought treatment for memory problems more often than women who had never used TAM. and  An analysis of patients in the TEAM trial showed that TAM users scored significantly lower on “mental flexibility” (p = 0.007) and “category fluency” (p < 0.0001) than healthy controls. A significantly higher proportion of both TAM and EXE users reported of memory problems in daily life compared with healthy controls (27.6% and 25.5% vs 6.3%; p = 0.02); however, the reported cognitive complaints did not correlate with cognitive test scores but rather with fatigue and depression. 88 Results from a similar analysis of TEAM patients showed that after 1 year of endocrine therapy, EXE-treated patients did not perform worse than healthy controls on any cognitive domain, whereas TAM-treated patients performed worse than healthy controls on “verbal memory” (p = 0.006) and “executive functioning” (p = 0.004) and worse than EXE-treated patients on “information processing speed” (p = 0.02). 89 Another recent study demonstrated that breast cancer patients in the TEAM trial (N = 205) did not report of higher frequencies of memory, thinking, and language problems in relation to a control group of healthy females (N = 124); cognitive complaints in nerves study did not correlate with age, IQ, general or physical fatigue; however, more persons scoring in the “possible depressive case” range reported of concentration problems compared with non-depressed persons. 90 Finally, one TEAM study found that after 12 months of follow-up, EXE therapy was associated with more impaired word finding compared with TAM. 91
Conclusions Conflict of interest statement The authors have no conflict of interest to declare. Acknowledgment We would like to thank Pippa McKelvie-Sebileau for English medical editorial assistance. Keywords Gastric cancer; Target therapy; Molecularly targeted agents Introduction Gastric cancer is the second leading cause of cancer related-death,1 with approximately 930,000 new cases diagnosed annually (8.6% of all new cancer cases)1 and more than 700,000 deaths recorded in 2006. and  The case fatality ratio for gastric cancer of 0.75 is considerably higher than that CGS-21680 for other common malignancies like colorectal cancer (0.52), breast cancer (0.36) and prostate cancer (0.33).2 Surgical resection is considered the mainstay of curative treatment, though nucleus (atom) can only be performed in a small subgroup of patients.3 Unfortunately, most patients present with an advanced stage of disease that has a dismal outcome. In the metastatic setting, chemotherapy is the gold standard of palliative therapy, achieving objective response rates (ORRs) of only 20–40% and median overall survivals (OS) of 8–10 months. and  Recent investigations have focused on the incorporation of a third chemotherapy agent with two-drug regimens; although a modest improvement in survival was noted, it was not without considerable additional toxicity.4
The optic nerve and optic chiasm transmit visual sensation to the visual cortex. Radiation-related optic nerve and chiasm toxicity results in diminished visual acuity, visual field deficits or vision loss, generally occurring within 3 years after radiation.7 Data on SRS/SRT tolerance of the optic apparatus primarily derives from patients treated for cavernous sinus meningiomas or pituitary adenomas. Data from the 1990s suggest that maximal doses of <8 Gy to the optic Alogliptin Benzoate and chiasm result in low (0–1%) risks of symptomatic optic neuropathy; maximal doses >8–10 Gy, particularly >12 Gy, result in unacceptably higher risks of symptomatic optic neuropathy (Fig. 1)., , ,  and  Patients with pre-existing visual defects maybe at greater risk of further vision loss.11 Weaknesses of these relatively older studies include the use of CT-based planning (as opposed to MRI/CT based planning) and the use of older planning algorithms, in which calculated isodose lines were overlaid onto CT.13 More modern studies have suggested that maximal doses of 10–12 Gy to the optic apparatus are well-tolerated, with low (0–3%) risk of symptomatic optic neuropathy (decreased visual acuity, anopsia or vision loss); maximal doses >12–15 Gy result in unacceptably higher risks of toxicity (Fig. 1) in most series,, ,  and  though not all.17 Similarly, after doses <10–12 Gy, at least 2 studies have shown no detectable decline in visual field testing. and  While the indications for and relative risks from fractionated SRT (versus SRS) are not fully understood, it has been suggested that maximal optic apparatus doses of 12 Gy in 2 fractions or 15 Gy in 3 fractions result in negligible risks of symptomatic optic neuropathy.,  and  Maximal optic apparatus doses of 5 Gy per fraction over 3–5 fractions were used in 2 preliminary studies in which the target was within 2 mm of the optic apparatus. and  In one study,21 only 1 of 34 patients (with a median follow-up of 29 months) experienced visual loss (without evidence of tumor progression), which occurred 6 months after a third SRS (and after multiple transsphenoidal resections, and fractionated radiotherapy). Suggested indications for using hypofractionated SRT instead of single fraction SRS include a radiation target encompassing the optic apparatus and/or targets with relatively high radiobiologic alpha:beta ratios.20 However, the rationale to use hypofractionated SRT versus conventionally fractionated radiation in these situations is not clear. The effect of prior conventionally fractionated radiation (i.e. whole brain radiation) on optic nerve/chiasm tolerance to SRS, in terms of prior dose and duration since treatment, is poorly understood.
NAC: 12× Vin + 12× Trast N, number of patients with evaluable histology of core needle biopsy and resection material; Pts, patients; NAC, neoadjuvant chemotherapy; NS, non-significant; Cut off value, percentage of positive tumor gsk 3 beta used as a cut off point for a positive or negative status; HER2, Human Epidermal growth factor Receptor 2; IHC, immunohistochemistry; FISH, Fluorescent In Situ Hybridization; Pos, positive; Neg, negative; ER, Estrogen; Pac, paclitaxel; Tras, trastuzumab; Cis, cisplatinum; Vin, Vinorelbine. Full-size table Table optionsView in workspaceDownload as CSV Discussion With NAC becoming more common as primary treatment for breast cancer patients, questions about the stability of the ER, PR and HER2 receptors status after NAC need to be addressed to optimize future tailored adjuvant therapy. This paper reviews 32 trials that investigated the influence of NAC with or without trastuzumab on the ER, PR and HER2 receptors in breast cancer. Concordance of ER, PR and HER2 without NAC
Fig. 1. VEGF plays Amyloid beta-Peptide 1-42 central role in tumour vasculature development and maintenance.1 DC, dendritic cell; tPA, tissue-type plaminogen activator; uPA, urokinase-type plasminogen activator; uPAr, urokinase-type plasminogen activator receptor; eNOS, endothelial nitric oxide syntase; COX-2, cyclooxygenase-2. Republished from Ferrara N. Oncologist 2004;9(Suppl. 1):2–10. The Oncologist, Copyright 2011, by Alphamed Press, Inc. Reproduced with permission of Alphamed Press, Inc. Figure optionsDownload full-size imageDownload high-quality image (275 K)Download as PowerPoint slide VEGF is expressed in most tumours, often at significantly increased levels.18 Expression of VEGF has been associated with tumour growth, angiogenesis and metastasis, and increased VEGF levels have been linked to a poor prognosis in breast cancer, and  colon cancer,  and  and non-small cell lung cancer (NSCLC).24 VEGF expression is stimulated by a number of factors (for example, oncogene expression and ); however, arguably the most important regulator is hypoxia., ,  and