Aims
Cancer patients with reduced dihydropyrimidine dehydrogenase (DPD) activity are at increased risk of severe fluoropyrimidine (FP)‐related adverse events (AE). Guidelines recommend FP dosing ...adjusted to genotype‐predicted DPD activity based on four DPYD variants (rs3918290, rs55886062, rs67376798 and rs56038477). We evaluated the relationship between three further DPYD polymorphisms: c.496A>G (rs2297595), *6 c.2194G>A (rs1801160) and *9A c.85T>C (rs1801265) and the risk of severe AEs.
Methods
Consecutive FP‐treated adult patients were genotyped for “standard” and tested DPYD variants, and for UGT1A1*28 if irinotecan was included, and were monitored for the occurrence of grade ≥3 (National Cancer Institute Common Terminology Criteria) vs. grade 0–2 AEs. For each of the tested polymorphisms, variant allele carriers were matched to respective wild type controls (optimal full matching combined with exact matching, in respect to: age, sex, type of cancer, type of FP, DPYD activity score, use of irinotecan/UGT1A1, adjuvant therapy, radiotherapy, biological therapy and genotype on the remaining two tested polymorphisms).
Results
Of the 503 included patients (82.3% colorectal cancer), 283 (56.3%) developed grade ≥3 AEs, mostly diarrhoea and neutropenia. Odds of grade ≥3 AEs were higher in c.496A>G variant carriers (n = 127) than in controls (n = 376) OR = 5.20 (95% CI 1.88–14.3), Bayesian OR = 5.24 (95% CrI 3.06–9.12). Odds tended to be higher in c.2194G>A variant carriers (n = 58) than in controls (n = 432) OR = 1.88 (0.95–3.73), Bayesian OR = 1.90 (1.03–3.56). c.85T>C did not appear associated with grade ≥3 AEs (206 variant carriers vs. 284 controls).
Conclusion
DPYD c.496A>G and possibly c.2194G>A variants might need to be considered for inclusion in the DPYD genotyping panel.
Fluoropyrimidines (FPs) are antineoplastic drugs widely used in the treatment of various solid tumors. Nearly 30% of patients treated with FP chemotherapy experience severe FP-related toxicity, and ...in some cases, toxicity can be fatal. Patients with reduced activity of DPD, the main enzyme responsible for the breakdown of FP, are at an increased risk of experiencing severe FP-related toxicity. While European regulatory agencies and clinical societies recommend pre-treatment DPD deficiency screening for patients starting treatment with FPs, this is not the case with American ones. Pharmacogenomic guidelines issued by several pharmacogenetic organizations worldwide recommend testing four DPD gene (
) risk variants, but these can predict only a proportion of toxicity cases. New evidence on additional common
polymorphisms, as well as identification and functional characterization of rare
variants, could partially address the missing heritability of DPD deficiency and FP-related toxicity.
Obesity and cancer BILIĆ, IVAN
Periodicum biologorum,
12/2014, Letnik:
116, Številka:
4
Journal Article
Odprti dostop
Epidemiologic evidence associating obesity and cancer accumulated over
last two decades pointing to potentially preventable forms of cancer disease. Observational prospective analyses point to breast ...and colon cancer as most influenced by obesity-linked lifestyle habits. Other tumor-types can comprise to this group as well (endometrium, esophagus, liver, stomach, thyroid, pancreas, and prostate cancer), according to epidemiological data, but with lesser level of certainty. Randomized studies of lifestyle interventions are still scarce in this area of research, despite being urgently needed. Different pathophysiological mechanisms for obesity-cancer link are proposed in literature. Endocrine factors, deregulated signaling cascades, oxidative stress, and chronic inflammation are implicated as obesity-related carcinogenic processes. Considering
growing prevalence of obesity, expert recommendations for lifestyle
change (healthy nutrition, physical activity) are widely suggested as a main
strategy in primary and secondary prevention of adiposity-related cancers.
Purpose
We investigated the impact of anthracycline-based chemotherapy on methylation status of RB1 gene in peripheral blood leukocytes together with parameters of oxidative stress and inflammation ...in sarcoma patients.
Patients/methods
Blood samples were collected from 51 consecutive newly diagnosed sarcoma patients admitted to University Hospital Center Zagreb (Zagreb, Croatia) for first-line chemotherapy before the first cycle and post-chemotherapy. Methylation and copy number variation (CNV) of leukocyte RB1 gene were assessed using MS-MLPA probes. In addition, in blood samples, parameters of oxidative stress (ROS, MDA, SOD, and GSH) and inflammation (CRP, WBC, and NBC) were followed.
Results
In pre-chemotherapy samples, no CNVs and aberrant methylation of CpG106 promoter region of RB1 gene were detected; however, one patient had hypermethylation (by approximately 10%) of imprinted locus CpG85 in intron 2 of RB1 gene. In addition, a very good correlation of the tumor burden and CRP and tumor burden and GSH was found. The anthracycline-based chemotherapy reverts methylation of RB1 gene-imprinted locus CpG85 to normal level. Moreover, inflammation and oxidative stress parameters such as CRP, WBC, ROS, and MDA were significantly decreased in post-chemotherapy samples.
Conclusion
This single-centered study on a cohort of consecutive sarcoma patients indicates that sarcoma patients can have aberrant germline DNA methylation and confirms the relationship of tumor burden with inflammation and oxidative stress. The applied chemotherapy protocols reverted RB1 gene methylation to normal level and decreased the level of inflammation and oxidative damage, thus indicating chemotherapy benefit to the patient’s health status.
Metastatic involvement of the breast is far less common than primary breast carcinoma, comprising 0.5%‐6.6% of all breast malignancies. Malignant pleural mesothelioma (MPM) is a rare and aggressive ...tumor with higher incidence among men, particularly smokers, strongly associated with asbestos exposure. The epithelioid type of MPM can represent a diagnostic pitfall in this setting, as it shows similar histologic features to primary breast carcinoma as well as other metastatic epithelioid malignancies. We report a rare case of breast metastasis of malignant pleural mesothelioma in a 61‐year‐old female.
Interindividual variability in drug metabolism is an important cause of adverse drug reactions and variability in drug efficiency. Polymorphisms of cytochrome P450 (CYPs) genes have a significant ...effect on drug metabolism and toxicity. This review brings an update about how genetic polymorphisms of CYP2C8 and CYP2C9 enzymes affect the disposition and clinical outcomes of ibuprofen and diclofenac, two of the most common pain relievers. The most common side effects associated with the influence of CYP2C8*3 and CYP2C9*2*3 variants on ibuprofen and diclofenac pharmacokinetics are hepatotoxicity and gastrointestinal bleeding. CYP genotyping may therefore identify patients at increased risk of these adverse reactions, and these patients could have their doses adjusted or start receiving another NSAID that does not share the same metabolic pathways with ibuprofen or diclofenac. However, before genotyping is introduced into regular clinical practice, more research is needed to evaluate the effectiveness of this strategy in improving treatment with ibuprofen and diclofenac.
Interindividual variability in drug metabolism is an important cause of adverse drug reactions and variability in drug efficiency. Polymorphisms of cytochrome P450 (CYPs) genes have a significant ...effect on drug metabolism and toxicity. This review brings an update about how genetic polymorphisms of CYP2C8 and CYP2C9 enzymes affect the disposition and clinical outcomes of ibuprofen and diclofenac, two of the most common pain relievers. The most common side effects associated with the influence of CYP2C8*3 and CYP2C9*2*3 variants on ibuprofen and diclofenac pharmacokinetics are hepatotoxicity and gastrointestinal bleeding. CYP genotyping may therefore identify patients at increased risk of these adverse reactions, and these patients could have their doses adjusted or start receiving another NSAID that does not share the same metabolic pathways with ibuprofen or diclofenac. However, before genotyping is introduced into regular clinical practice, more research is needed to evaluate the effectiveness of this strategy in improving treatment with ibuprofen and diclofenac.
Dear Editor, Inhibition of the epidermal growth factor receptor (EGFR) is a new strategy in treatment of a variety of solid tumors, such as colorectal carcinoma, non-small cell lung cancer, squamous ...cell carcinoma of the head and neck, and pancreatic cancer (1). Cetuximab is a chimeric human-murine monoclonal antibody against EGFR. Cutaneous side effects are the most common adverse reactions occurring during epidermal growth factor receptor inhibitors (EGFRI) therapy. Papulopustular rash (acne like rash) develop with 80-86% patients receiving cetuximab, while xerosis, eczema, fissures, teleangiectasiae, hyperpigmentations, and nail and hair changes occur less frequently (2). The mechanism underlying these skin changes has not been established and understood. It seems EGFRI alter cell growth and differentiation, leading to impaired stratum corneum and cell apoptosis (3-5). An abdominoperineal resection of the rectal adenocarcinoma (Dukes C) was performed on a 43-year-old female patient. Following surgery, adjuvant chemo-radiotherapy was applied. After two years, the patient suffered a metastatic relapse. Abdominal lymphadenopathy was detected on multi-slice computer tomography (MSCT) images, with an increased value of the carcinoembryonic antigen (CEA) tumor marker (maximal value 57 ng/mL). Hematological and biochemical tests were within normal limits, so first-line chemotherapy with oxaliplatin and a 5-fluorouracil (FOLFOX4) protocol was introduced. A wild type of the KRAS gene was confirmed in tumor tissue (diagnostic prerequisite for the introduction of EGFRI) and cetuximab (250 mg per m2 of body surface) was added to the treatment protocol. The patient responded well to the treatment with confirmed partial regression of the tumor formations. Three months after the patient started using cetuximab, an anti-EGFR monoclonal antibody, the patient presented with a papulopustular eruption in the seborrhoeic areas (Figure 1) and eczematoid reactions on the extremities with dry, scaly, itchy skin (Figure 2). Furthermore, hair and nail changes gradually developed, culminating with trichomegaly (Figure 3) and paronychia (Figure 4). The patient was treated with oral antibiotics (tetracycline) and a combination of topical steroids with moisturizing emollients due to xerosis, without reduction of EGFRI therapy and with a very good response. Trichomegaly was regularly sniped with scissors. Nail fungal infection was ruled out by native examination and cultivation, so antiseptics and corticosteroid ointments were introduced for paronychia treatment. During the above-mentioned therapy, apart from skin manifestations, iatrogenic neutropenia grade IV occurred, with one febrile episode, and because of this, the dose of cytostatic drugs was reduced. After 10 months of therapy, progression of the disease occurred with lung metastases, so EGFRI therapy was discontinued and the patient was given second-line chemotherapy for metastatic colorectal carcinoma. This led to gradual resolution of all aforementioned cutaneous manifestations. Since the pathogenesis of skin side-effects due to EGFRI is not yet fully understood, there are no strict therapy protocols. Therapy is mainly based on clinical experience and follows the standard treatments for acne, rosacea, xerosis, paronychia, and effluvium. The therapeutic approach for papulopustular exanthema includes topical and systemic antibiotics for their antimicrobial as well as anti-inflammatory effect, sometimes in combination with topical steroids. Topical application of urea cream with K1 vitamin yielded positive results in skin-changes prevention during EGFRI therapy, especially with xerosis, eczema, and pruritus (6). Hair alterations in the form of effluvium are usually tolerable, and if needed a 2% minoxidil solution may be applied. Trichomegaly or abnormal eyelash growth can lead to serious complications, so ophthalmologic examination is needed. At the beginning of the growth, regular lash clipping may reduce possibility of corneal abrasion (7,8). Nail changes can just be a cosmetic problem (pigmentary changes, brittle nails), and in the occurrence of paronychia or onycholysis (of several or all nails) they result in high morbidity and impair daily activities. Nail management should be started as soon as possible because of slow nail growth and the relatively long half-life of EGFRI. Combination of topical iodide, corticosteroids, antibiotics, and antifungals with avoidance of nail traumatization will yield the best results (9). EGFRI are potentially life prolonging therapies, and our goal as dermatovenereologists is to provide optimal patient care and improve their quality of life in a multidisciplinary collaboration with oncologists, radiotherapists, and ophthalmologists.
Autonomous manipulation systems operating in domains where human intervention is difficult or impossible (e.g., underwater, extraterrestrial or hazardous environments) require a high degree of ...robustness to sensing and communication failures. Crucially, motion planning and control algorithms require a stream of accurate joint angle data provided by joint encoders, the failure of which may result in an unrecoverable loss of functionality. In this paper, we present a novel method for retrieving the joint angles of a robot manipulator using only a single RGB image of its current configuration, opening up an avenue for recovering system functionality when conventional proprioceptive sensing is unavailable. Our approach, based on a distance-geometric representation of the configuration space, exploits the knowledge of a robot's kinematic model with the goal of training a shallow neural network that performs a 2D-to-3D regression of distances associated with detected structural keypoints. It is shown that the resulting Euclidean distance matrix uniquely corresponds to the observed configuration, where joint angles can be recovered via multidimensional scaling and a simple inverse kinematics procedure. We evaluate the performance of our approach on real RGB images of a Franka Emika Panda manipulator, showing that the proposed method is efficient and exhibits solid generalization ability. Furthermore, we show that our method can be easily combined with a dense refinement technique to obtain superior results.
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