Molecular mechanisms for vascular complications of targeted cancer therapies

2016 ◽  
Vol 130 (20) ◽  
pp. 1763-1779 ◽  
Author(s):  
Srila Gopal ◽  
Kenneth B. Miller ◽  
Iris Z. Jaffe
Keyword(s):  
Cancer Patients ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Vascular Complications ◽  
Vascular Complication ◽  
Cancer Therapies ◽  
Vegf Inhibitors ◽  
Increased Risk ◽  
Anti Cancer ◽  
Targeted Cancer Therapies

Molecularly targeted anti-cancer therapies have revolutionized cancer treatment by improving both quality of life and survival in cancer patients. However, many of these drugs are associated with cardiovascular toxicities that are sometimes dose-limiting. Moreover, the long-term cardiovascular consequences of these drugs, some of which are used chronically, are not yet known. Although the scope and mechanisms of the cardiac toxicities are better defined, the mechanisms for vascular toxicities are only beginning to be elucidated. This review summarizes what is known about the vascular adverse events associated with three classes of novel anti-cancer therapies: vascular endothelial growth factor (VEGF) inhibitors, breakpoint cluster-Abelson (BCR-ABL) kinase inhibitors used to treat chronic myelogenous leukaemia (CML) and immunomodulatory agents (IMiDs) used in myeloma therapeutics. Three of the best described vascular toxicities are reviewed including hypertension, increased risk of acute cardiovascular ischaemic events and arteriovenous thrombosis. The available data regarding the mechanism by which each therapy causes vascular complication are summarized. When data are limited, potential mechanisms are inferred from the known effects of inhibiting each target on vascular cell function and disease. Enhanced understanding of the molecular mechanisms of vascular side effects of targeted cancer therapy is necessary to effectively manage cancer patients and to design safer targeted cancer therapies for the future.

scholarly journals ECG Scoring for the Evaluation of Therapy-Naïve Cancer Patients to Predict Cardiotoxicity

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1197
Author(s):  
Julia Pohl ◽  
Raluca-Ileana Mincu ◽  
Simone M. Mrotzek ◽  
Reza Wakili ◽  
Amir A. Mahabadi ◽  
...  
Keyword(s):  
High Risk ◽  
Cancer Patients ◽  
Left Ventricular ◽  
Cardiac Biomarkers ◽  
Cancer Therapies ◽  
University Hospitals ◽  
Anti Cancer ◽  
Risk Patients ◽  
Qrs Duration ◽  
Ecg Score

Objective: To evaluate a new electrocardiographic (ECG) score reflecting domains of electrical and structural alterations in therapy-naïve cancer patients to assess their risk of cardiotoxicity. Methods: We performed a retrospective analysis of 134 therapy-naïve consecutive cancer patients in our two university hospitals concerning four ECG score parameters: Contiguous Q-waves, markers of left ventricular (LV) hypertrophy, QRS duration and JTc prolongation. Cardiotoxicity was assessed after a short-term follow-up (up to 12 months). Results: Of all the patients (n = 25), 19% reached 0 points, 50% (n = 67) reached 1 point, 25% (n = 33) reached 2 points, 5% (n = 7) reached 3 points and 0.7% reached 4 or 5 points (n = 1 respectively). The incidence of cardiotoxicity (n = 28 [21%]) increased with the ECG score, with 0 points at 0%, 1 point 7.5%, 2 points 55%, 3 points 71% and ≥3 points 50%. In the ROC (Receiver operating curves) analysis, the best cut-off for predicting cardiotoxicity was an ECG score of ≥2 points (sensitivity 82%, specificity 82%, AUC 0.84, 95% CI 0.77–0.92, p < 0.0001) which was then defined as a high-risk score. High-risk patients did not differ concerning their age, LV ejection fraction, classical cardiovascular risk factors or cardiac biomarkers compared to those with a low-risk ECG score. Conclusion: ECG scoring prior to the start of anti-cancer therapies may help to identify therapy-naïve cancer patients at a higher risk for the development of cardiotoxicity.

scholarly journals Systemic Capillary Leak Syndrome (Clarkson Syndrome) in Cancer Patients: A Systematic Review

2018 ◽  
Vol 7 (11) ◽  
pp. 418 ◽  
Author(s):  
Jae Shin ◽  
Keum Lee ◽  
I. Lee ◽  
Ji Oh ◽  
Dong Kim ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Case Reports ◽  
Laboratory Data ◽  
Capillary Leak Syndrome ◽  
Treatment Modalities ◽  
Capillary Leak ◽  
Contributing Factors ◽  
Systemic Capillary Leak Syndrome ◽  
Increased Risk ◽  
Anti Cancer

Systemic capillary leak syndrome (SCLS) is a rare disease characterized by shock caused by capillary hyperpermeability. The disease can occur in cancer patients and effective therapeutic strategies have not been established yet. The aim of the study was to analyze the clinical and laboratory data, treatment modalities, and mortality rate of patients and to identify contributing factors leading to mortality of SCLS in cancer. We searched MEDLINE (inception to July 2018) and of 4612 articles, we identified 62 case reports on SCLS associated with cancer or cancer-related drugs in a total of 53 articles. SCLS was associated with cancer itself in 43.6%, with anti-cancer agents in 51.6% and bone marrow transplantation (BMT) in 4.8%. Among anti-cancer agents, granulocyte-colony stimulating factor (G-CSF) was the most frequently associated drug (14.6%), followed by interleukin (IL)-2 (11.4%). The most common associated malignancies were hematologic (61.3%) with non-Hodgkin lymphoma (22.7%) and multiple myeloma (12.9%) being the leading causes. Common symptoms and signs included dyspnea (27.4%), edema (67.7%), hypotension (32.2%), pleural effusion (29.0%), ascites (22.7%), oliguria (22.7%), and weight gain (21.0%). Patients with SCLS were treated with steroids (59.7%), volume replacement (33.8%), diuretics (24.2%), inotropes (9.6%), methylxanthines (12.8%), β2 agonists (4.8%), while intravenous immunoglobulins (IVIG) were administered in 2 patients (3.2%) only. Among sixteen deaths during follow-up, four were directly attributed to SCLS. Hematologic malignancies were associated with an increased risk for mortality (hazard ratio (HR) 8.820, 95% confidence interval (CI) 1.126–69.063, p = 0.038). Taken together, SCLS can be one important adverse event in cancer patients and careful monitoring of fluid volume is required in the management of SCLS.

scholarly journals Angiogenic Abnormalities in Diabetes Mellitus: Mechanistic and Clinical Aspects

2019 ◽  
Vol 104 (11) ◽  
pp. 5431-5444 ◽  
Author(s):  
Gian Paolo Fadini ◽  
Mattia Albiero ◽  
Benedetta Maria Bonora ◽  
Angelo Avogaro
Keyword(s):  
English Language ◽  
Molecular Mechanisms ◽  
Evidence Synthesis ◽  
Clinical Manifestations ◽  
Vascular Complications ◽  
Peripheral Circulation ◽  
Clinical Aspects ◽  
Therapeutic Implications ◽  
Diabetes Onset ◽  
Increased Risk

Abstract Context Diabetes causes severe pathological changes to the microvasculature in many organs and tissues and is at the same time associated with an increased risk of coronary and peripheral macrovascular events. We herein review alterations in angiogenesis observed in human and experimental diabetes and how they contribute to diabetes onset and development of vascular complications. Evidence Acquisition The English language medical literature was searched for articles reporting on angiogenesis/vasculogenesis abnormalities in diabetes and their clinical manifestations, mechanistic aspects, and possible therapeutic implications. Evidence Synthesis Angiogenesis is a complex process, driven by a multiplicity of molecular mechanisms and involved in several physiological and pathological conditions. Incompetent angiogenesis is pervasive in diabetic vascular complications, with both excessive and defective angiogenesis observed in various tissues. A striking different angiogenic response typically occurs in the retina vs the myocardium and peripheral circulation, but some commonalities in abnormal angiogenesis can explain the well-known association between microangiopathy and macroangiopathy. Impaired angiogenesis can also affect endocrine islet and adipose tissue function, providing a link to diabetes onset. Exposure to high glucose itself directly affects angiogenic/vasculogenic processes, and the mechanisms include defective responses to hypoxia and proangiogenic factors, impaired nitric oxide bioavailability, shortage of proangiogenic cells, and loss of pericytes. Conclusions Dissecting the molecular drivers of tissue-specific alterations of angiogenesis/vasculogenesis is an important challenge to devise new therapeutic approaches. Angiogenesis-modulating therapies should be carefully evaluated in view of their potential off-target effects. At present, glycemic control remains the most reasonable therapeutic strategy to normalize angiogenesis in diabetes.

Cancer and Signaling Pathway Deregulation

2011 ◽  
pp. 369-379
Author(s):  
Yingchun Liu
Keyword(s):  
Cancer Patients ◽  
Tumor Cells ◽  
Malignant Tumor ◽  
Molecular Mechanisms ◽  
Complex Disease ◽  
Cancer Therapies ◽  
Normal Cells ◽  
Genetic Aberrations ◽  
Cancer Subtypes ◽  
Pathway Deregulation

Cancer is a complex disease that is associated with a variety of genetic aberrations. The diagnosis and treatment of cancer have been difficult because of poor understanding of cancer and lack of effective cancer therapies. Many studies have investigated cancer from different perspectives. It remains unclear what molecular mechanisms have triggered and sustained the transition of normal cells to malignant tumor cells in cancer patients. This chapter gives an introduction to the genetic aberrations associated with cancer and a brief view of the topics key to decode cancer, from identifying clinically relevant cancer subtypes to uncovering the pathways deregulated in particular subtypes of cancer.

Dermatological side effects of immunotherapy drugs and targeted cancer therapies: Importance of dermatology and oncology collaboration

2020 ◽  
pp. 107815522097062
Author(s):  
Uğur Çelik ◽  
Ertuğrul H Aydemir ◽  
Burhan Engin ◽  
Muazzez Ç Oba ◽  
Mesut Yılmaz ◽  
...  
Keyword(s):  
Side Effects ◽  
Outpatient Clinic ◽  
Targeted Therapies ◽  
Side Effect ◽  
Common Side Effect ◽  
Cancer Therapies ◽  
Anti Cancer ◽  
Targeted Cancer Therapies ◽  
Dermatological Side Effects ◽  
Skin Side Effects

Introduction Novel anti-cancer drugs such as targeted cancer therapies and immune check-point inhibitors (ICIs) have adverse events, especially concerning the skin. The aim of this study is to report an overview of the commonly consulted dermatological side effects of ICIs and targeted cancer therapies in clinical practice, along with their management. Methods In this single-center study, we evaluated consecutive oncological patients who were referred from the oncology outpatient clinic to the dermatology outpatient clinic due to skin side effects of ICIs and targeted therapies. All patients were examined and treated at the same day of referral by experienced dermatologists. Patient characteristics, clinical findings, diagnostic workups and treatments were retrieved from outpatient records. Results Sixty three patients were enrolled. Most common diagnoses were lung carcinoma, melanoma and colon carcinoma. Fifty patients (79%) were using targeted therapies while 13 (21%) were using ICIs. Xerosis was the most common side effect (44%), followed by acneiform rash, paronychia, eczema and pruritus. Majority of the side effects were grade 2 and 3. Psoriasis was a common side effect of ICIs. One patient had a newly developed dysplastic nevus on vemurafenib treatment. Oncological treatment was not withheld in any of the patients. Conclusions This study revealed the most commonly consulted skin side effects of novel anti-cancer drugs and their management in daily practice. We underlie the importance of collaborative work of oncology and dermatology professionals as early management of cutaneous side effects of targeted therapies and ICIs improves patient outcomes.

A systemic review and meta-analysis to evaluate the efficacy and postprogression survival of second-line chemotherapy for gemcitabine-refractory pancreatic cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15768-e15768
Author(s):  
Akiyoshi Kasuga ◽  
Yasuo Hamamoto ◽  
Yu Aoki ◽  
Kenta Kawasaki ◽  
Takeshi Suzuki ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Patients ◽  
Systemic Therapy ◽  
Randomized Trials ◽  
Meta Analysis ◽  
Cancer Therapies ◽  
Second Line ◽  
Anti Cancer ◽  
Gemcitabine Refractory ◽  
Post Trial

e15768 Background: We previously reported positive relationship between overall survival (OS) and both of postprogression survival (PPS) and post-trial anti-cancer therapies in first-line pancreatic cancer patients. We conducted a meta-analysis to gain a better understanding of the impact of PPS and post-trial anti-cancer therapies on OS and to determine the efficacy of second-line systemic therapy. Methods: We searched randomized trials of second-line systemic therapy for pancreatic cancer patients. We evaluated the relation between OS and either progression-free survival (PFS) or PPS and calculated the pooled effect size by using random effects models. Results: Eleven randomized trials with 23 treatment arms that involved examining 2267 patients were analyzed. Median OS was strongly associated with median PPS and PFS (r = 0.908 and 0.754, respectively), but no correlation between rate of post-trial anti-cancer therapies and OS was detected (r = 0.050). Average OS, PFS and PPS were significantly longer in recent trials than in older trials, (6.08 versus 4.17 months, p < 0.001), (2.65 versus 1.95 months, p < 0.001) and (3.43 versus 2.25 months, p < 0.001), respectively. Overall, experimental therapies compared to control did not significantly improve PFS (HR, 0.83; 95% CI, 0.67-1.03; I2 = 73%) or OS (HR, 0.89; 95% CI, 0.72-1.11; I2 = 69%). When the analysis was restricted to fluoropyrimidine compared to irinotecan or oxaliplatin in combination with fluoropyrimidine, each therapy produced advantage in a term of PFS (HR, 0.65; 95% CI, 0.47-0.88; I2 = 39% for irinotecan, HR, 0.81; 95% CI, 0.67-0.98; I2 = 13% for oxaliplatin) but only irinotecan produced advantage in a term of OS (HR, 0.70; 95% CI, 0.55-0.89; I2 = 0% for irinotecan, HR, 1.04; 95% CI, 0.65-1.65; I2 = 82% for oxaliplatin). Conclusions: Although second-line treatment benefit for OS can be skewed by PPS in patients with gemcitabine-refractory pancreatic cancer, the effects of subsequent therapies are weak in the salvage setting.

scholarly journals How plausible is the use of dietary n-3 PUFA in the adjuvant therapy of cancer?

2016 ◽  
Vol 29 (1) ◽  
pp. 102-125 ◽  
Author(s):  
Simona Serini ◽  
Renata Ottes Vasconcelos ◽  
Elena Fasano ◽  
Gabriella Calviello
Keyword(s):  
Anticancer Agents ◽  
Molecular Mechanisms ◽  
Published Data ◽  
Cancer Therapies ◽  
Considerable Effort ◽  
Antineoplastic Effect ◽  
Anti Cancer ◽  
Considerable Debate ◽  
Carcinogenic Effects ◽  
Lower Drug

AbstractConsiderable debate exists regarding the potential antineoplastic effect of dietary long-chain n-3 PUFA contained in fatty fishes. Since the majority of published data has proven that their intake does not induce toxic or carcinogenic effects in humans, their possible preventive use against cancer has been suggested. On the other hand, it is unlikely that they could be effective in cancer patients as a single therapy. Nevertheless, a considerable effort has been put forth in recent years to evaluate the hypothesis that n-3 PUFA might improve the antineoplastic efficiency of currently used anticancer agents. The rationale for this therapeutic combinatory strategy is trying to increase cancer sensitivity to conventional therapies. This could allow the use of lower drug/radiation doses and, thereby, a reduction in the detrimental health effects associated with these treatments. We will here critically examine the studies that have investigated this possibility, by focusing particularly on the biological and molecular mechanisms underlying the antineoplastic effect of these combined treatments. A possible use of n-3 PUFA in combination with the innovative single-targeted anti-cancer therapies, that often are not completely devoid of dangerous side-effects, is also suggested.

scholarly journals Microparticles as Biomarkers of Blood Coagulation in Cancer

2015 ◽  
Vol 7 ◽  
pp. BIC.S30347 ◽  
Author(s):  
Shosaku Nomura ◽  
Maiko Niki ◽  
Tohru Nisizawa ◽  
Takeshi Tamaki ◽  
Michiomi Shimizu
Keyword(s):  
Cancer Cells ◽  
Cancer Patients ◽  
Cancer Progression ◽  
Vascular Complications ◽  
Membrane Vesicles ◽  
Cell Types ◽  
Target Cells ◽  
Breast Cancer Patients ◽  
Patient Morbidity ◽  
Increased Risk

Cancer is associated with hypercoagulopathy and increased risk of thrombosis. This negatively influences patient morbidity and mortality. Cancer is also frequently complicated by the development of venous thromboembolism (VTE). Tumor-derived tissue factor (TF)-bearing microparticles (MPs) are associated with VTE events in malignancy. MPs are small membrane vesicles released from many different cell types by exocytic budding of the plasma membrane in response to cellular activation or apoptosis. MPs may also be involved in clinical diseases through expression of procoagulative phospholipids. The detection of TF-expressing MPs in cancer patients may be clinically useful. In lung and breast cancer patients, MPs induce metastasis and angiogenesis and may be indicators of vascular complications. Additionally, MPs in patients with various types of cancer possess adhesion proteins and bind target cells to promoting cancer progression or metastasis. Overexpression of TF by cancer cells is closely associated with tumor progression, and shedding of TF-expressing MPs by cancer cells correlates with the genetic status of cancer. Consequently, TF-expressing MPs represent important markers to consider in the prevention of and therapy for VTE complications in cancer patients.

scholarly journals Diet-induced alteration of intestinal stem cell function underlies obesity and prediabetes in mice

2021 ◽  
Vol 3 (9) ◽  
pp. 1202-1216
Author(s):  
Alexandra Aliluev ◽  
Sophie Tritschler ◽  
Michael Sterr ◽  
Lena Oppenländer ◽  
Julia Hinterdobler ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cell Function ◽  
Hormone Secretion ◽  
Cell Types ◽  
Acid Synthesis ◽  
Enteroendocrine Cell ◽  
The Metabolic Syndrome ◽  
Increased Risk ◽  
Ppar Signaling ◽  
Obesogenic Diet

AbstractExcess nutrient uptake and altered hormone secretion in the gut contribute to a systemic energy imbalance, which causes obesity and an increased risk of type 2 diabetes and colorectal cancer. This functional maladaptation is thought to emerge at the level of the intestinal stem cells (ISCs). However, it is not clear how an obesogenic diet affects ISC identity and fate. Here we show that an obesogenic diet induces ISC and progenitor hyperproliferation, enhances ISC differentiation and cell turnover and changes the regional identities of ISCs and enterocytes in mice. Single-cell resolution of the enteroendocrine lineage reveals an increase in progenitors and peptidergic enteroendocrine cell types and a decrease in serotonergic enteroendocrine cell types. Mechanistically, we link increased fatty acid synthesis, Ppar signaling and the Insr–Igf1r–Akt pathway to mucosal changes. This study describes molecular mechanisms of diet-induced intestinal maladaptation that promote obesity and therefore underlie the pathogenesis of the metabolic syndrome and associated complications.

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