Cetuximab plus chemotherapy is a first-line treatment option in metastatic KRAS and NRAS wild-type colorectal cancer (CRC) patients. No data are currently available on continuing anti-epidermal ...growth factor receptor (EGFR) therapy beyond progression.
We did this open-label, 1:1 randomized phase II trial at 25 hospitals in Italy to evaluate the efficacy of cetuximab plus 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX) as second-line treatment of KRAS exon 2 wild-type metastatic CRC patients treated in first line with 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) plus cetuximab. Patients received FOLFOX plus cetuximab (arm A) or FOLFOX (arm B). Primary end point was progression-free survival (PFS). Tumour tissues were assessed by next-generation sequencing (NGS). This report is the final analysis.
Between 1 February 2010 and 28 September 2014, 153 patients were randomized (74 in arm A and 79 in arm B). Median PFS was 6.4 95% confidence interval (CI) 4.7–8.0 versus 4.5 months (95% CI 3.3–5.7); hazard ratio (HR), 0.81; 95% CI 0.58–1.12; P = 0.19, respectively. NGS was performed in 117/153 (76.5%) cases; 66/117 patients (34 in arm A and 32 in arm B) had KRAS, NRAS, BRAF and PIK3CA wild-type tumours. For these patients, PFS was longer in the FOLFOX plus cetuximab arm median 6.9 (95% CI 5.5–8.2) versus 5.3 months (95% CI 3.7–6.9); HR, 0.56 (95% CI 0.33–0.94); P = 0.025. There was a trend in better overall survival: median 23.7 (95% CI 19.4–28.0) versus 19.8 months (95% CI 14.9–24.7); HR, 0.57 (95% CI 0.32–1.02); P = 0.056.
Continuing cetuximab treatment in combination with chemotherapy is of potential therapeutic efficacy in molecularly selected patients and should be validated in randomized phase III trials.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
An 82-year-old Caucasian man presented with initially asymptomatic livid red plaques on the plantar surface of the feet that become confluent and evolved into invasively growing nodules accompanied ...by massive edema. Histology allowed a diagnosis of the classical form of Kaposi's sarcoma; the serology test result for HIV was negative, whereas the associated human herpes virus type 8 was detected by polymerase chain reaction on the skin sample. Over the subsequent 6 months, skin lesions become vegetative and partially necrotic, and extended to the hands and eyelids. Chemotherapy with vinblastine appeared to stabilize the cutaneous disease, but the patient developed a massive gastrointestinal hemorrhage secondary to dissemination to the stomach. Twelve months after the onset of the disease, vegetative and easily bleeding lesions progressively occluded the mouth of the patient: histological features were consistent with a low-grade angiosarcoma distinct from that of Kaposi's sarcoma. The patient could not chew and swallow anymore; he was put on an artificial nutrition but died shortly thereafter. This case illustrates that, even in its classical form, Kaposi's sarcoma may be a malignant, rapidly progressing tumor. Learning Points. a) The extent and rate of spread of initial skin lesions should be considered to be early signs of aggressive dissemination, even in the absence of other variables (i.e., histological pattern, human herpes virus type 8 positive mononuclear cells) associated with progression of the disease. b) An endoscopy may be useful given the high prevalence of gastrointestinal involvement. c) When classical Kaposi's sarcoma displays aggressive behavior a second, primary malignant tumor arising from the vascular tissue should be investigated. Take-Home Message. Even in its classical form, Kaposi's sarcoma may be a malignant, rapidly progressing tumor with visceral involvement; also, a second malignancy may occur in nearly one patient of four. Because localized skin lesions can regress completely with radiotherapy, watchful waiting is probably inappropriate in most cases.
Insulin is a major endocrine hormone also involved in the regulation of energy and lipid metabolism via the activation of an intracellular signaling cascade involving the insulin receptor (INSR), ...insulin receptor substrate (IRS) proteins, phosphoinositol 3-kinase (PI3K) and protein kinase B (AKT). Specifically, insulin regulates several aspects of the development and function of adipose tissue and stimulates the differentiation program of adipose cells. Insulin can activate its responses in adipose tissue through two INSR splicing variants: INSR-A, which is predominantly expressed in mesenchymal and less-differentiated cells and mainly linked to cell proliferation, and INSR-B, which is more expressed in terminally differentiated cells and coupled to metabolic effects. Recent findings have revealed that different distributions of INSR and an altered INSR-A:INSR-B ratio may contribute to metabolic abnormalities during the onset of insulin resistance and the progression to type 2 diabetes. In this review, we discuss the role of insulin and the INSR in the development and endocrine activity of adipose tissue and the pharmacological implications for the management of obesity and type 2 diabetes.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Obesity is a chronic disease caused by an excess of adipose tissue that may impair health by altering the functionality of various organs, including the lungs. Excessive deposition of fat in the ...abdominal area can lead to abnormal positioning of the diaphragm and consequent reduction in lung volume, leading to a heightened demand for ventilation and increased exposure to respiratory diseases, such as chronic obstructive pulmonary disease, asthma, and obstructive sleep apnoea. In addition to mechanical ventilatory constraints, excess fat and ectopic deposition in visceral depots can lead to adipose tissue dysfunction, which promotes metabolic disorders. An altered adipokine-secretion profile from dysfunctional adipose tissue in morbid obesity fosters systemic, low-grade inflammation, impairing pulmonary immune response and promoting airway hyperresponsiveness. A potential target of these adipokines could be the NLRP3 inflammasome, a critical component of the innate immune system, the harmful pro-inflammatory effect of which affects both adipose and lung tissue in obesity. In this review, we will investigate the crosstalk between adipose tissue and the lung in obesity, highlighting the main inflammatory mediators and novel therapeutic targets in preventing pulmonary dysfunction.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Leptin is a principal adipose-derived hormone mostly implicated in the regulation of energy balance through the activation of anorexigenic neuronal pathways. Comprehensive studies have established ...that the maintenance of certain concentrations of circulating leptin is essential to avoid an imbalance in nutrient intake. Indeed, genetic modifications of the leptin/leptin receptor axis and the obesogenic environment may induce changes in leptin levels or action in a manner that accelerates metabolic dysfunctions, resulting in a hyperphagic status and adipose tissue expansion. As a result, a vicious cycle begins wherein hyperleptinaemia and leptin resistance occur, in turn leading to increased food intake and fat enlargement, which is followed by leptin overproduction. In addition, in the context of obesity, a defective thermoregulatory response is associated with impaired leptin signalling overall within the ventromedial nucleus of the hypothalamus. These recent findings highlight the role of leptin in the regulation of adaptive thermogenesis, thus suggesting leptin to be potentially considered as a new thermolipokine. This review provides new insight into the link between obesity, hyperleptinaemia, leptin resistance and leptin deficiency, focusing on the ability to restore leptin sensitiveness by way of enhanced thermogenic responses and highlighting novel anti-obesity therapeutic strategies.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Diabetes and cancer are worldwide chronic diseases with a major impact on the quality and expectancy of life. Metabolic abnormalities observed during the onset and progression of diabetes may have a ...critical role on the initiation and progression of carcinogenesis. To date, there are no conclusive data on the mechanisms underlying the relationship between diabetes and any type of human cancer. However, recent evidence suggests that both hyperglycemia and hyperinsulinemia in diabetes could elicit cell damage responses, such as glucotoxicity, lipotoxicity and oxidative stress, which participate in the cell transformation process raising the risk of cancer development. In addition, clinical trials have revealed that several anti-diabetes therapies may potentially affect the risk of cancer though largely undefined mechanisms. In this review, we highlight epidemiological and pathophysiological aspects of diabetes, which may influence cancer initiation and progression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The histone deacetylases SIRT1 and SIRT2 have been shown to be involved in the differentiation of rodent adipocyte precursors. In light of the differences in gene expression and metabolic function of ...visceral (V) and subcutaneous (S) adipose tissue (AT) and their resident cells, the aim of this study was to investigate the role of SIRT1 and SIRT2 in the differentiation of adipose stem cells (ASCs) isolated from SAT and VAT biopsies of nondiabetic obese and nonobese individuals.
Human ASCs were isolated from paired SAT and VAT biopsies obtained from 83 nonobese and 92 obese subjects and were differentiated in vitro. Adipogenesis was evaluated by analyzing the lipid deposition using an image processing software, and gene expression by RT-qPCR. SIRT1 and SIRT2 protein expression was modified by using recombinant adenoviral vectors.
Visceral but not subcutaneous ASCs from obese subjects showed an intrinsic increase in both adipogenesis and lipid accumulation when compared with ASCs from nonobese subjects, and this was associated with reduced SIRT1 and SIRT2 mRNA and protein levels. Moreover, adipose tissue mRNA levels of SIRT1 and SIRT2 showed an inverse correlation with BMI in the visceral but not subcutaneous depot. Overexpression of SIRT1 or SIRT2 in visceral ASCs from obese subjects resulted in inhibition of adipocyte differentiation, whereas knockdown of SIRT1 or SIRT2 in visceral ASCs from nonobese subjects enhanced this process. Changes in SIRT1 or SIRT2 expression and adipocyte differentiation were paralleled by corresponding changes in PPARG, CEBPA, and other genes marking terminal adipocyte differentiation.
SIRT1 and SIRT2 modulate the differentiation of human ASC. Reduced expression of SIRT1 and SIRT2 may enhance the differentiation capacity of visceral ASC in human obesity, fostering visceral adipose tissue expansion.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Diabetes mellitus is a chronic metabolic disease, the prevalence of which is constantly increasing worldwide. It is often burdened by disabling comorbidities that reduce the quality and expectancy of ...life of the affected individuals. The traditional complications of diabetes are generally described as macrovascular complications (e.g., coronary heart disease, peripheral arterial disease, and stroke), and microvascular complications (e.g., diabetic kidney disease, retinopathy, and neuropathy). Recently, due to advances in diabetes management and the increased life expectancy of diabetic patients, a strong correlation between diabetes and other pathological conditions (such as liver diseases, cancer, neurodegenerative diseases, cognitive impairments, and sleep disorders) has emerged. Therefore, these comorbidities have been proposed as emerging complications of diabetes. P66Shc is a redox protein that plays a role in oxidative stress, apoptosis, glucose metabolism, and cellular aging. It can be regulated by various stressful stimuli typical of the diabetic milieu and is involved in various types of organ and tissue damage under diabetic conditions. Although its role in the pathogenesis of diabetes remains controversial, there is strong evidence regarding the involvement of p66Shc in the traditional complications of diabetes. In this review, we will summarize the evidence supporting the role of p66Shc in the pathogenesis of diabetes and its complications, focusing for the first time on the emerging complications of diabetes.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abnormal accumulation of saturated fatty acids in the heart results in insulin resistance, stress kinase activation, and increased cardiovascular risk in humans. The viability of human cardiac ...progenitor cells (CPC) is essential for myocardium homeostasis. This study investigates the ability of palmitate, a saturated fatty acid, to induce apoptosis, autophagy, and stress kinase activation in human CPC isolated from right auricle biopsies of nondiabetic, non-obese subjects, and the potential protective effects of insulin on palmitate-induced abnormalities. Human CPC expressed both IR-A and IR-B, and IR-A was more expressed than IR-B, as assessed by quantitative RT-PCR and immunoblotting. Exposure of human CPC to 100 nM insulin for 15 minutes resulted in increased Akt (S473) and p44/p42 MAPK (T202/Y204) phosphorylation (p<0.05), as evidenced by immunoblotting. Treatment of human CPC with palmitate 0.25 mM for 16 h induced apoptosis (p<0.05), as assessed by caspase-3 cleavage and ELISA assay, and increased S63-phosphorylation of c-Jun (p<0.05), a downstream transcription factor of JNK 1/2, as assessed by immunoblotting. Exposure of human CPC to 0.25 mM palmitate for 16 h resulted also in increased autophagy, evidenced by light chain 3-II immunoblotting (p<0.05). Pretreatment with 20 µM SP600125, a JNK inhibitor, for 1 h inhibited palmitate-induced apoptosis (p<0.05), but not autophagy. Similarly, pretreatment with 10 mM 3-methyladenine, an autophagy inhibitor, for 1 h decreased palmitate-induced apoptosis (p<0.05). Interestingly, palmitate effects on apoptosis, autophagy, and on stress kinase activation, were prevented when human CPC were pretreated with 100 nM insulin for 1 h (p<0.05). In conclusion, insulin prevents palmitate-induced apoptosis by inhibition of JNK signaling and autophagy in human CPC. Hence, preserving insulin signaling in human CPC might protect from lipotoxicity-induced metabolic alterations in the heart.
Disclosure
I. Calderoni: None. R. Doria: None. C. Caccioppoli: None. V. Genchi: None. G. Palma: None. G. Santarpino: None. A.D. Milano: None. A. Leonardini: None. A. Natalicchio: Other Relationship; AstraZeneca, Novo Nordisk, Sanofi, Boehringer-Ingelheim, Lilly. S. Perrini: None. A. Cignarelli: Speaker's Bureau; Eli Lilly and Company, Novo Nordisk, Sanofi. F. Giorgino: Research Support; Lilly, Roche Diabetes Care. Consultant; Novo Nordisk, Lilly. Speaker's Bureau; Abbott, Boehringer-Ingelheim, Lilly. Advisory Panel; Boehringer-Ingelheim, Amarin Corporation, Medtronic, Roche Diabetes Care, Sanofi. Speaker's Bureau; Sanofi. Advisory Panel; Bayer Inc., Novo Nordisk. Research Support; AlfaSigma. Speaker's Bureau; Medscape. L. Laviola: Speaker's Bureau; Abbott. Advisory Panel; A. Menarini Diagnostics, Boehringer Ingelheim Inc., Eli Lilly and Company, Novo Nordisk, Roche Diabetes Care. Speaker's Bureau; Terumo Corporation. Other Relationship; Medtronic. Advisory Panel; Sanofi.
Dapagliflozin (DAPA), an SGLT2 inhibitor, has been shown to counteract heart failure outcomes in subjects with obesity and diabetes. We investigated the mechanisms of the protective action of DAPA in ...human cardiac progenitor cells (hCPC) exposed to the conditioned medium (CM) from abdominal visceral (AV) and epicardial (E) adipose stem cells (ASC) and from AV mature adipocytes from obese subjects. ASC and mature adipocytes were isolated from AV and E adipose tissue biopsies of 15 obese (Ob) and 13 non-Ob subjects (n-Ob), respectively. hCPC were isolated from right auricle biopsies of healthy non-Ob donors. Exposure of hCPC to the CM of adipose cells from Ob, but not from non-Ob subjects, induced apoptosis, c-Jun phosphorylation, and impairment of actin filaments, as assessed by ELISA assay and immunofluorescence, respectively, while these effects were not observed when the hCPC were pretreated with DAPA. The CM of adipose cells from Ob compared to n-Ob subjects displayed a different pattern of pro-inflammatory and anti-inflammatory cytokines. The levels of pro-inflammatory cytokines such as RANTES and MIP1β were increased in the CM from AV-ASC with higher BMI (p<0.05), while the levels of anti-inflammatory factors such as GCSF in the CM of E-ASC were inversely correlated with BMI (p<0.05). SGLT2 was found to be expressed as both mRNA and protein in the hCPC, and silencing of SGLT2 with a specific siRNA attenuated the capacity of DAPA to counteract the pro-apoptotic effects of the CM. In conclusion, we show that: i) in human obesity, the CM of both AV- and E-ASC and mature adipocytes is characterized by pro-inflammatory cytokines that induce stress kinase activation and apoptosis in the hCPC; ii) hCPC express SGLT2 mRNA and protein; iii) DAPA prevents the hCPC damage induced by the CM through an SGLT2-dependent mechanism.
Disclosure
G.Palma: None. A.Natalicchio: Other Relationship; AstraZeneca, Novo Nordisk, Sanofi, Boehringer-Ingelheim, Lilly. L.Laviola: Advisory Panel; A. Menarini Diagnostics, Boehringer Ingelheim Inc., Eli Lilly and Company, Novo Nordisk, Roche Diabetes Care, Sanofi, Other Relationship; Medtronic, Speaker's Bureau; Abbott, Terumo Corporation. A.Pezzolla: None. F.Giorgino: Advisory Panel; Boehringer-Ingelheim, Amarin Corporation, Medtronic, Roche Diabetes Care, Sanofi, Bayer Inc., Novo Nordisk, Consultant; Novo Nordisk, Lilly, Research Support; Lilly, Roche Diabetes Care, AlfaSigma, Speaker's Bureau; Abbott, Boehringer-Ingelheim, Lilly, Sanofi, Medscape. S.Perrini: None. C.Caccioppoli: None. R.Doria: None. V.Genchi: None. I.Calderoni: None. A.Braun: None. G.Santarpino: None. A.D.Milano: None. A.Cignarelli: Speaker's Bureau; Eli Lilly and Company, Novo Nordisk, Sanofi.
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