Major adverse cardiovascular events associated with VEGF-targeted anticancer tyrosine kinase inhibitors: a real-life study and proposed algorithm for proactive management.

BACKGROUND: Vascular endothelial growth factor receptor (VEGFR)-targeted tyrosine kinase inhibitors (TKIs) are widely used in cancer treatment and burdened by cardiovascular toxicity. The majority of data come from clinical trials, thus in selected populations. The aim of our study is to evaluate the cardiotoxicity profile of VEGFR-targeted TKIs and the impact of cardiovascular risk factors in a real-life population. PATIENTS AND METHODS: In this cohort, population-based study, patients treated with VEGFR-targeted TKIs, bevacizumab and trastuzumab between 2009 and 2014 were analyzed. A multi-source strategy for data retrieval through hospital, pharmaceutical and administrative databases of the Lombardy region, Italy, has been adopted. The primary endpoint was to determine the incidence and type of major adverse cardiovascular events (MACEs) along with their temporal trend. The secondary endpoint was to define the impact of cardiovascular risk factors in the occurrence of MACEs. RESULTS: A total of 829 patients were treated with VEGFR-targeted TKIs. Eighty-one MACEs occurred in the first year of follow-up [crude cumulative incidence (CCI): 9.79%] mainly consisting of arterial thrombotic events (ATEs, 31 events, CCI: 3.99%), followed by rhythm disorders (22 events, CCI: 2.66%), pulmonary embolisms and heart failures (13 events each, CCI: 1.57%). While the incidence of most MACEs showed a plateau after 6 months, ATEs kept increasing along the year of follow-up. Hypertension and dyslipidemia were associated with an increase in risk of ATEs [relative risk difference (RRD) +209.8% and +156.2%, respectively], while the presence of previous MACEs correlated with a higher risk of all MACEs in multivariate analysis (RRD 151.1%, 95% confidence interval 53.6% to 310.3%, P < 0.001). CONCLUSIONS: MACEs occur in a clinically significant proportion of patients treated with VEGFR-targeted TKIs, with ATEs being predominant, mainly associated with hypertension and dyslipidemia. A clinical algorithm for effective proactive management of these patients is warranted.

Strategies to tackle RAS-mutated metastatic colorectal cancer.

The RAS oncogene is among the most commonly mutated in cancer. RAS mutations are identified in about half of patients diagnosed with metastatic colorectal cancer (mCRC), conferring poor prognosis and lack of response to anti-epidermal growth factor receptor (EGFR) antibodies. In the last decades, several investigational attempts failed in directly targeting RAS mutations, thus RAS was historically regarded as 'undruggable'. Recently, novel specific KRASG12C inhibitors showed promising results in different solid tumors, including mCRC, renewing interest in this biomarker as a target. In this review, we discuss different strategies of RAS targeting in mCRC, according to literature data in both clinical and preclinical settings. We recognized five main strategies focusing on those more promising: direct RAS targeting, targeting the mitogen-activated protein kinase (MAPK) pathway, harnessing RAS through immunotherapy combinations, RAS targeting through metabolic pathways, and finally other miscellaneous approaches. Direct KRASG12C inhibition is emerging as the most promising strategy in mCRC as well as in other solid malignancies. However, despite good disease control rates, tumor response and duration of response are still limited in mCRC. At this regard, combinational approaches with anti-epidermal growth factor receptor drugs or checkpoint inhibitors have been proposed to enhance treatment efficacy, based on encouraging results achieved in preclinical studies. Besides, concomitant therapies increasing metabolic stress are currently under evaluation and expected to also provide remarkable results in RAS codon mutations apart from KRASG12C. In conclusion, based on hereby reported efforts of translational research, RAS mutations should no longer be regarded as 'undruggable' and future avenues are now opening for translation in the clinic in mCRC.

Role of FKBP51 in the modulation of the expression of the corticosteroid receptors in bovine thymus following glucocorticoid administration.

The aim of this work was to study the transcriptional effects of glucocorticoids on corticosteroid hormone receptors, prereceptors (11ß-hydroxysteroid dehydrogenase 1 and 2, 11ß-HSD1 and 2), and chaperones molecules regulating intracellular trafficking of the receptors (FKBP51 and FKBP52) in thymus of veal calves. Moreover, the expression of FKBP51 and FKBP52 gene were investigated in beef cattle thymus. In the cervical thymus of veal calves, dexamethasone administration in combination with estradiol decreased FKBP51 expression (P < 0.01). The same treatment increased mineralocorticoid receptor (MR) (P < 0.01) and 11ß-HSD1 expression (P < 0.05) compared to control group in the cervical thymus of veal calves. The thoracic thymus of veal calves treated with dexamethasone and estradiol showed a decrease of FKBP51 (P < 0.05), FKBP52 (P < 0.05), glucocorticoid receptor (P < 0.05), and MR expression (P < 0.05) compared to control group in the thoracic thymus of veal calves. The gene expression of FKBP51 decreased both in cervical (P < 0.01) and thoracic thymus (P < 0.01) of beef cattle treated with dexamethasone and estradiol. In addition, also prednisolone administration reduced FKBP51 expression in the cervical thymus (P < 0.01) and in the thoracic thymus of beef cattle (P < 0.01). The gene expression of FKBP52 increased only in the cervical thymus following dexamethasone administration (P < 0.01). The decrease of FKBP51 gene expression in thymus could be a possible biomarker of illicit dexamethasone administration in bovine husbandry. Moreover, so far, an effective biomarker of prednisolone administration is not identified. In this context, the decrease of FKBP51 gene expression in thymus of beef cattle following prednisolone administration could play an important role in the indirect identification of animals illegally treated with prednisolone.

Ameloblastic fibroma in an alpine chamois (Rupicapra rupicapra).

Spontaneous odontogenic tumors are neoplasms characterized by a mixed odontogenic ectomesenchymal and odontogenic epithelial origin; they are rare in both humans and animals. A 3-year-old male Alpine Chamois (Rupicapra rupicapra) was found dead in north-west Italy, and was referred for the necropsy to the Department of Veterinary Sciences of the University of Turin (Italy). At the external examination a 10 × 8 cm, exophytic, red-pink, smooth, firm and ulcerated mass was observed on the inferior lip. Histologically the tumor was characterized by spindle shaped cells arranged in bundles in an abundant hyaline matrix. Multifocal and rare chords of odontogenic epithelium mixed with rare melanocytes that penetrate the neoplasia were visible. Immunohistochemistry showed a clear cytokeratin positivity of epithelial clusters. Macroscopical, histological and immunohistochemical findings were consistent with a diagnosis of locally infiltrative ameloblastic fibroma. To our best knowledge, this is the first report of this tumor in a wild ungulate and in Alpine Chamois.

Systemic AL amyloidosis in a Beech Marten (Martes foina).

A wild Beech Marten (Martes foina), was referred for necropsy to the Department of Animal Pathology of the University of Turin (Italy). At gross examination, whitish and firm masses, 10-mm in diameter, were found on the heart and in the kidney. Spleen showed lighter color and greater consistency, and the cut surface of the liver appeared scattered with whitish-yellow coalescing foci homogeneously distributed. Amyloid deposits were present in the perivascular and intercellular spaces of the visceral organs, such as the heart, liver, and kidneys. Amyloid stained positively with Congo red with and without 5% potassium permanganate pretreatment and showed green birefringence observable under polarized light. A diagnosis of systemic AL amyloidosis was made. This is the first description of systemic AL amyloidosis in a wild Stone Marten.

Comparison of the potency of 10 different brands of Serenoa repens extracts.

BACKGROUND: The extract of Serenoa repens is the phytopharmaceutical product most often used for the treatment of urological symptoms associated with benign prostatic hyperplasia (BPH). Several extracts are commercially available but extraction processes vary between manufacturers and thus not all these products are equivalent in terms of active ingredient content and composition of preparations. AIM: As there is a paucity of comparative studies, we compared the activity of different extracts of Serenoa repens widely available on the world market. MATERIALS AND METHODS: Beltrax Uno, Permicaps, Permixon, Prostadyn, Prostagutt, Prostamen, Prostamol Uno, ProstaX, Urocaps and Urogutt were assayed for 5-alpha-reductase activity on 10 day fibroblasts and epithelial cells cocultures. Human fibroblast growth factor (hFGF)-induced-proliferation inhibition was also assayed. RESULTS: As to extract activity, differences were observed between the tested extracts, but all were able to inhibit 5-a-reductase types I and II isoenzymes (5alphaR-I and 5alphaR-II) as well as fibroblast proliferation. CONCLUSIONS: Extract potency differs between products and so does proliferation inhibition potency. Quantitative and qualitative variations in the active ingredient are likely to account for these differences.

Diffuse multicentric large B-cell lymphoma invading the central nervous system in a European wild boar (Sus scrofa).

We describe a diffuse, multicentric, large B-cell lymphoma in a wild boar (Sus scrofa) involving the abdomen, head, and nose and invading the frontal leptomeninges. The tumor was predominantly composed of dense, basophilic, round-to-polygonal cells. Immunohistochemistry for CD79 and Ki-67 was positive in all masses.

Malignant pleural mesothelioma in a female lion (Panthera leo).

An 18-year-old female lion (Panthera leo) was referred to the Department of Animal Pathology of the University of Turin (Italy). At necropsy, multiple nodular, 4-20-mm, confluent white firm nodules were scattered throughout the pleural surfaces of the thoracic wall and of the lungs. Histological lesions were represented by proliferations of papillary structures lined by cuboidal basophilic mesothelial cells with large, oval nuclei and abundant granular eosinophilic cytoplasm. Immunohistochemistry revealed immunoreactivity for pancytokeratin and vimentin. None of the cells expressed calretinin antigen. Asbestos fibers and asbestos bodies were not detected respectively by light microscopy and by Scanning Electron Microscope-Energy Dispersive Spectrometer investigations. On the contrary, chrysotile asbestos were identified in samples from shelter material. Histological and immunohistochemical findings were consistent with the diagnosis of an epithelial malignant mesothelioma. To our best knowledge, this is the first report of a pleural mesothelioma in a lion.

Penetration of amphotericin B in human lung tissue after single liposomal amphotericin B (AmBisome) infusion.

The distribution of amphotericin B in lung tissue was studied in 18 patients with primary or secondary lung cancer who underwent thoracotomy and pulmonary resection. At different times before surgery the patients were treated with liposomal amphotericin B 1.5 mg/kg by i.v. infusion over 1h. Blood and lung tissue samples were collected during surgery (one subject for each collecting time) and assayed for amphotericin B levels by HPLC. Due to surgical requirements, it was possible to obtain data from the 10th to the 25th h after the end of infusion. Plasma amphotericin B concentrations progressively decreased from 3.4 microg/ml at the 10th h to 1 microg/ml at the 25th h after the end of intravenous infusion. In lung tissue samples the lowest amphotericin B concentration (about 1 microg/g) was observed at the 10th h, then a progressive increase was observed with the highest value (2.5 microg/g) determined at the 25th h.

Effect of multiple doses of clarithromycin and amoxicillin on IL-6, IFNgamma and IL-10 plasma levels in patients with community acquired pneumonia.

Inflammation is crucial for the pathogenesis of both infectious and chronic obstructive pulmonary diseases. It is therefore important to modulate pulmonary inflammation in patients with these lung disorders. Macrolide antibiotics modulate inflammation in vitro and in in vivo by inhibiting the production of proinflammatory cytokines and prostaglandin E2, neutrophil chemotactic activity and elastase activity. This study evaluates the effect of clarithromycin (500 mg b.i.d. x 7 days) in comparison to amoxicillin (1 g t.i.d. x 7 days) in patients with community acquired pneumonia by testing plasma levels of IL-6, IFNgamma and IL-10 before starting therapy and at the 3rd and 7th days of therapy. Clarithromycin significantly decreased plasma levels of IL-6 and significantly increased those of IFNgamma and IL-10 at the 3rd and 7th day in comparison to basal levels. In patients treated with amoxicillin a significant decrease in IL-6 plasma levels was observed at the 7th day of therapy, probably in relation to the resolution of inflammatory symptoms. In the same patients IFNgamma plasma levels decreased during treatment while IL-10 plasma levels were unaffected.

Long-term inhibition of glioma growth by systemic administration of human PEX.

AIM: The growth of gliomas depends on the balance of factors stimulating or inhibiting angiogenesis, tumor cell invasion and proliferation. The administration of endogenous inhibitors to experimental human gliomas in animal models resulted in a significant inhibition of tumor growth. It is becoming apparent that resistance can develop over time to many types of endogenous inhibitors and seems to be influenced by the tumor type and system of delivery. METHODS: We recently isolated a potent endogenous inhibitor, called human PEX, from human glioma cells in culture. Human PEX is a potent inhibitor of angiogenesis, tumor and endothelial cell proliferation and migration. In this paper, we investigated the ability of human PEX to sustain inhibition of glioma growth for a prolonged period of time. We initially developed a recombinant form of the inhibitor and showed that this form had similar in vitro and in vivo activities to the natural one. Human PEX was then administered to nude mice intracranial human glioma model, in combination with metronomic chemotherapy, for a period of 185 days, starting 15 days after tumor cells implantation. RESULTS: Our data showed that the systemic administration of human PEX mantained a very prolonged inhibition of glioma growth (50% survival of animals treated with 2 mg/kg/days was 160 days vs 24 days of the control) and had a synergistic effect with low dose chemotherapy. Histological analysis of tumors, showed that treatment with PEX was associated with a decrease of vascularity, cell proliferation, and increase in apoptosis. CONCLUSION: These data indicate that human PEX controls tumor growth by separate mechanisms. In addition, treatment with PEX produced well delineated tumors, indicating the persistence of a direct anti-invasive effect of the molecule even after a prolonged period of treatment.

Low-dose chemotherapy combined with an antiangiogenic drug reduces human glioma growth in vivo.

This study evaluates the efficacy of the combination of an antiangiogenic drug and conventional chemotherapeutics for the treatment of experimental human gliomas. As an antiangiogenic, we used recombinant human PEX, a fragment of matrix metalloproteinase-2 that we have previously shown to have a significant antimitotic, anti-invasive, and antiangiogenic properties against human glioblastoma in vitro and in vivo. We used carboplatin and etoposide as the two chemotherapeutic drugs routinely used in our institution (Ospedale Maggiore de Milano) for the treatment of malignant gliomas. Conventional chemotherapeutic drugs were administered at high dose or at a low and semicontinuous regimen. Combined treatment of high-dose chemotherapy and PEX did not produce an improvement of survival in comparison with chemotherapy alone, but it was associated with a decrease in tumor volume, vascularity, and proliferative index and an increased apoptosis. All of these animals experienced severe side effects. The longest survival was documented in animals submitted to low and semicontinuous chemotherapy and antiangiogenic treatment. This regimen was associated with no side effects, marked decrease in tumor volume, vascularity, and proliferative index, and an increased apoptosis. Our data suggest that low-dose chemotherapy in combination with PEX can be successfully used against human malignant glioma in vivo.

Melatonin involvement in immunity and cancer.

The most studied endocrine product of the pineal gland, melatonin, has been reported to be involved in the feedback between neuroendocrine and immune functions and to exert oncostatic action, at least in certain experimental conditions. Melatonin seems to be an integral part of the immune system, by exerting direct and/or indirect stimulatory effects on both cellular and humoral immunity. Likewise, an antitumor activity of melatonin has been shown in several experimental models in vivo and in vitro. The means by which melatonin exerts its effects on immunity and neoplastic growth have not been elucidated. The different putative mechanisms of action of melatonin investigated so far are here briefly discussed.

Melatonin involvement in immunity and cancer

The most studied endocrine product of the pineal gland, melatonin, has been reported to be involved in the feedback between neuroendocrine and immune functions and to exert oncostatic action, at least in certain experimental conditions. Melatonin seems to be an integral part of the immune system, by exerting direct and/or indirect stimulatory effects on both cellular and humoral immunity. Likewise, an antitumor activity of melatonin has been shown in several experimental models in vivo and in vitro. The means by which melatonin exerts its effects on immunity and neoplastic growth have not been elucidated. The different putative mechanisms of action of melatonin investigated so far are here briefly discussed.

Double-blind, multicenter, randomized trial to compare the effect of two doses of adrenocorticotropic hormone versus placebo in controlling delayed emesis after high-dose cisplatin in adult patients with cancer.

PURPOSE: To compare, in a double-blind, placebo-controlled, randomized trial, the efficacy of two different doses of the depot formulation of adrenocorticotropic hormone (ACTH) in controlling delayed emesis after cisplatin. PATIENTS AND METHODS: One hundred fifty-two patients were enrolled onto the study. On day 1, all patients received cisplatin (60 to 120 mg/m2) and a combination of dexamethasone 20 mg plus ondansetron or metoclopramide to prevent acute emesis. On day 2 (24 hours after cisplatin administration), patients were randomized to receive placebo, or ACTH 1 mg intramuscularly (I.M.), or ACTH 2 mg I.M. plus one additional dose of 1 mg on day 4. Details of vomiting, nausea, and adverse effects were recorded daily for every 24-hour period from day 2 to day 6. In a subset of patients, serum cortisol levels were measured between 20 and 72 hours after cisplatin administration. RESULTS: One hundred fifty patients were assessable. Over the 5 days of the study, delayed vomiting occurred less frequently in the patients treated with ACTH 2 mg plus 1 mg than in those treated with ACTH 1 mg or placebo (28%, 38%, and 65%, respectively; P = .001). The greatest observed differences were seen on days 2 (24 to 48 hours; P = .01) and 3 (48 to 72 hours; P = .01). On days 4, 5, and 6 (96 to 144 hours), no significant differences were observed among the three arms. The severity of delayed emesis expressed as the mean number of emetic episodes per day was 0.48, 0.70, and 0.80, respectively (P = .002). Patients treated with the higher dose of ACTH had the least nausea on day 3 (P = .02) and day 4 (P = .03). Adrenal cortisol secretion rapidly increased after ACTH injection, but was suppressed for approximately 44 hours in the placebo group. Toxicity was mild and transient in all groups. CONCLUSION: ACTH reduces the incidence and severity of delayed vomiting and nausea after cisplatin. A dose of 2 mg 24 hours after cisplatin is better than one of 1 mg. Whether the activity of ACTH is mediated only by adrenal corticosteroids needs to be verified.

Ceftibuten concentrations in human tonsillar tissue.

In a study designed to determine ceftibuten concentrations in tonsillar tissue, subjects scheduled to undergo tonsillectomy were administered 400 mg of ceftibuten in a single oral dose. Between 2 and 24 h after the dose was given, tonsillar tissue samples were taken during surgery and assayed for ceftibuten. Mean concentrations in tonsillar tissue 4.4 h and 24.6 h after the 400 mg dose were 5.3 +/- 2.7 and 0.3 +/- mg/g, respectively. Concurrent mean serum concentrations were 7.42 +/- 1.66 and 0.15 +/- 0.13 mg/ml, respectively. The apparent half-life of drug in the tissue was 5.3 h. The presence of high ceftibuten concentrations in tonsillar tissue suggests that a once-daily regimen may be effective in treating tonsillitis and pharyngitis.

Letrozole, a new oral non-steroidal aromastase inhibitor in treating postmenopausal patients with advanced breast cancer. A pilot study.

PURPOSE: To evaluate the endocrine effects as well as the pharmacokinetic parameters, efficacy and safety of letrozole, a new fourth-generation non-steroidal aromatase inhibitor. PATIENTS AND METHODS: Fourteen postmenopausal women with progressive metastatic breast cancer, previously treated with endocrine therapy and/or chemotherapy for advanced disease, were treated with 0.5 mg daily doses of letrozole, orally. Endocrine and pharmacokinetic measurements were made before treatment and on days 14, 28, 56, and 84 of therapy. RESULTS: Letrozole induced a >86% decrease in plasma estrone and a approximately 67% reduction in circulating estradiol from day 14 on. There was a statistically significant decrease in plasma cortisol, which appeared clinically irrelevant since all values remained within the normal range. No significant changes in aldosterone concentration were noted. One patient achieved a complete response (CR) and 4 patients a partial response (PR), with an objective response rate of 36% (95% CI 13% to 65%). Median duration of response was 24 months, ranging from 4 to 44 months. No toxic effects attributable to letrozole were noted in any patient. CONCLUSION: Letrozole appears to be a very promising new antiaromatase drug. The characteristics of the patients more likely to respond, taking into account prior systemic treatment, should be defined by future studies. Further phase II and phase III studies comparing letrozole to other available second or even first-line endocrine-therapy agents, are warranted.

Effect of antibiotics on Bordetella pertussis adhering activity: hypothesis regarding mechanism of action.

Microbial adherence to epithelial cell surfaces has been implicated as the first step in the initiation of several infectious diseases. The ability of antibiotics to affect the properties of bacterial adherence to cell surfaces may be a criterion in selecting antibiotics for therapy. This study was performed in order to investigate the activity of amoxicillin, chloramphenicol, and clarithromycin in modifying the adhering activity of Bordetella pertussis to human epithelial cells. The actions of antibiotics, alone or combined with aprotinin, were compared with that of trypsin, aprotinin and trypsin+aprotinin, to investigate the chemical nature of the ligand where antibiotics could act. The adhering activity was evaluated on human epithelial cells, collected from the oral mucosa, challenged with B. pertussis A2963 previously incubated in the presence of the tested substances for 1 h at 37 degrees C in a shaker incubator. After staining, the percentage of mucosal cells with more than 50 adhering bacteria was evaluated. Under the described experimental conditions, trypsin significantly reduced the adherence of B. pertussis. Aprotinin had no effect but was able to counteract the inhibitory action of trypsin. Both clarithromycin and chloramphenicol markedly reduced adhering activity and their actions were not counteracted by aprotinin. Amoxicillin was without effect. It was hypothesized that chloramphenicol and clarithromycin, exerting their antimicrobial action by inhibiting bacterial protein synthesis, affected bacterial adhesion through an unknown mechanism without proteolytic effect.