Metformin increases cancer specific survival in colorectal cancer patients—National cohort study

PurposeWe aimed to assess oncological outcomes in colorectal cancer patients with type 2 diabetes mellitus (T2DM) using metformin.MethodsPatients with colorectal cancer and T2DM during 2000–2012 period were identified form Lithuanian Cancer Registry and the National Health Insurance Fund database. Colorectal cancer-specific survival (CS) was the primary outcome. It was measured from date of colorectal cancer diagnosis to date of death due to colorectal cancer, or last known date alive.Results15,052 people who met eligibility criteria for this analysis, including 1094 (7.27%) with pre-existing type 2 diabetes (271 metformin never users and 823 metformin users) and 13 958 people without diabetes assessed. During follow-up (mean follow-up time was 4.4 years, with range from 1 day to 17 years) there were 10,927 deaths including 8559 from colorectal cancer. Significantly lower risk in CS between diabetic and non-diabetic people with lower risk of cancer-specific mortality (HR 0.87, 95% CI 0.80–0.94) in diabetic patient population was seen. After adjustment for age, stage at diagnosis and metformin usage, significant difference in colorectal CS between metformin users in diabetic patient population compared to non-diabetics and metformin non-users in diabetic patient population was found (0.80 (0.72–0.89) vs 1.00 and vs 1.05 (0.91–1.23)). Overall survival (OS) was better for diabetic patients with significant difference in diabetic metformin users (HR 0.91, 95% CI 0.79–0.94).ConclusionsColorectal cancer patients with T2DM treated with metformin as part of their diabetic therapy appear to have a superior OS and CS. However, prospective controlled studies are still needed to evaluate the efficacy of metformin as an anti-tumor agent.     

Keratin 20 - a diagnostic and prognostic marker in colorectal cancer?

Colorectal cancer cells characteristically show strong expression of keratin 20 (K20) and lack expression of keratin 7 (K7). The biological significance of reduced K20 expression, however, is unclear. 381 colorectal cancers with 148 corresponding metastases were evaluated for K20 and K7 expression by immunohistochemistry using a tissue microarray technique. K20 immunoreactivity was assessed semiquantitatively as either negative, low (<50% of cancer cells) or high (≥50% of cancer cells). Progression-free and cancer-specific survivals were determined using the Kaplan-Meier method. Expression of K20 was observed in 348 out of 372 (94%) evaluable primary tumors, with 135 (36%) cases showing low K20 and 213 (57%) cases high K20 expression, while 24 (6%) tumors completely lacked K20 immunoreactivity. Reduced K20 expression (lack of staining or low expression) was significantly associated with poor differentiation, large tumor size and mismatch repair deficiency, but did not significantly affect patients' outcome. Immunoreactivity of K20 and K7 in metastatic tissues matched well with that of corresponding primary tumors, with high concordance for lymph node (p<0.001) and distant metastases (p<0.001), respectively. In conclusion, our data illustrate the value of keratin subtyping in carcinoma of unknown primary (CUP) syndrome: K20 expression is common in colorectal cancer and the K20 high / K7 negative immunoprofile represents the predominant phenotype. Reduced K20 expression may, however, lead to false-negative assessment of metastatic deposits if only small amounts of tissue are obtained (e.g. in needle biopsies), particularly in poorly differentiated cancers. Reduced expression of K20 may be used to select tumors for microsatellite instability testing.     

Serum tumor markers in bile duct cancer – a review

Abstract

Context: Bile duct cancer (BDC) is a disease with a very grave prognosis, often diagnosed too late.

Objective: The aim of this review is to evaluate available literature on tumor markers in serum from patients with BDC.

Methods: Using the search words “serum markers”, “bile duct cancer”, “cholangiocarcinoma”, “biomarker” and “tumor marker”, a search was carried out.

Results: Seventy-five studies were included in the review.

Conclusion: CA19-9 is by far the most studied and most promising diagnostic and/or prognostic marker in BDC. But also the different mucins are interesting as new markers of BDC in serum.     

Adenomas – Genetic factors in colorectal cancer prevention

Colorectal cancer is the second most common type of cancer both in Europe and Poland. During the last 30 years more than a 3-fold increase has been observed in Poland due to environmental and genetic factors. Almost all colorectal malignancies are related to the formation and malignant transformation of colorectal dysplasia and adenoma. Efforts aiming to decrease the number of colorectal cancer deaths are focused on the disease early detection. Genetic diagnosis for hereditary syndromes predisposing to colorectal cancer has been developed and is a part of the routine treatment. Most cancers are sporadic. They often develop from polyps in the colon. In addition to the genetic events described in the 1990s, showing the adenoma transformation into carcinoma that has been a prime example of malignant transformation for a long time, there are also other possibilities of neoplastic transformation. The recognition of colorectal cancer risk factors make sense as their nature is lifestyle- and diet-related. In this review paper those risk factors are presented and the prevention of colorectal cancer is discussed taking into account genetic factors.     

Is colorectal cancer a more aggressive disease in young patients? A population-based study from the Czech Republic

IntroductionThe incidence of colorectal cancer in young patients is increasing. The goal of this study was to investigate whether clinicopathological features and survival differed between young, middle-aged and elderly patients.MethodsThe Czech National Cancer Registry was searched to identify all cases of colorectal cancer between 1982 and 2014. Three subgroups of patients were created: young patients, defined as being between 18 and 40 years of age, middle-aged patients, defined as being between 41 and 74 years of age, and elderly patients, defined as being over the age of 75 years.ResultsA total of 192,241 patients diagnosed with colorectal cancer between the years 1982 and 2014 were included in the study. Out of these, 3,287 patients (1.7%) were between 18 and 40 years of age, 134,139 patients (69.8%) were between 41 and 74 years of age and 54,815 patients (28.5%) were 75 years of age or older. The young patients had a higher incidence of mucinous adenocarcinoma and signet ring cell carcinoma, more advanced disease and more rectal tumours than elderly patients. Nonetheless, young patients received treatment more frequently and had better cancer-specific survival than the older patients.ConclusionThe better prognosis in young patients is presumably due to their better physiological reserve and lower incidence of comorbidities. Efforts should be made in younger patients to diagnose early and treat aggressively.     

Cardiotonic steroids as potential Na+/K+-ATPase inhibitors – a computational study

Abstract

Cardiotonic steroids (CTS) are steroidal drugs, processed from the seeds and dried leaves of the genus Digitalis as well as from the skin and parotid gland of amphibians. The most commonly known CTS are ouabain, digoxin, digoxigenin and bufalin. CTS can be used for safer medication of congestive heart failure and other related conditions due to promising pharmacological and medicinal properties. Ouabain isolated from plants is widely utilized in in vitro studies to specifically block the sodium potassium (Na⁺/K⁺-ATPase) pump. For checking, whether ouabain derivatives are robust inhibitors of Na⁺/K⁺-ATPase pump, molecular docking simulation was performed between ouabain and its derivatives using YASARA software. The docking energy falls within the range of 8.470?kcal/mol to 7.234?kcal/mol, in which digoxigenin was found to be the potential ligand with the best docking energy of 8.470?kcal/mol. Furthermore, pharmacophore modeling was applied to decipher the electronic features of CTS. Molecular dynamics simulation was also employed to determine the conformational properties of Na⁺/K⁺-ATPase-ouabain and Na⁺/K⁺-ATPase-digoxigenin complexes with the plausible structural integrity through conformational ensembles for 100?ns which promoted digoxigenin as the most promising CTS for treating conditions of congestive heart failure patients.     

Bone grafts impregnated with antibiotics as a tool for treating infected implants in orthopedic surgery – one stage revision results

Infection of an orthopedic implant is considered a devastating complication, necessitating its complete removal and thorough debridement of the site. Osseous defects are common in such conditions and need to be addressed before a new implant may be inserted. So far bone grafting has been contraindicated in bacterially contaminated areas and could only be performed as soon as all signs of infection have ceased. Usually long term antibiotic treatment and a multitude of surgical interventions within a period of several months is required until a definitive supply can be achieved. Allograft bone may be impregnated with high loads of antibiotics using special incubation techniques. Based on this technology 48 exchange procedures of infected orthopaedic implants were performed in a single stage, all of them without the use of bone cement. There were 37 infected hips, 8 knees and 3 infected osteosyntheses. Two hips required re-revision because of persisting infection, the remaining 46 patients stayed infect free for a period between 1 and 7 years after surgery. No adverse side effects could be found. Incorporation appeared as after grafting with unimpregnated bone grafts. Antibiotic loaded allograft bone is a powerful tool in septic revision surgery, enabling restoration of bone stock, insertion of a new implant and control of infection in a single operation.     

Survival of breast cancer patients in German-Danish border regions – A registry-based cohort study

Background and AimDenmark reports slightly lower breast cancer survival before 2010 than its neighbouring country Germany. Previous research is limited by lacking stage and treatment information. This study aims to investigate differences in breast cancer survival between the bordering regions Schleswig-Holstein (Germany), Southern Denmark and Zealand (Denmark) using registry data including stage and treatment information.MethodInvasive female breast cancer cases diagnosed during 2004−2013 with follow up through 31st December 2014 were extracted from cancer registries. Cases notified by death certificates only and those aged 90+ years were excluded. Kaplan-Meier curves and log-rank tests were computed. Cox regression analysis was conducted with adjustment for year of diagnosis, age, stage, and treatment.ResultsThe analytical sample included 42,966 cases. Kaplan-Meier curves and log-rank tests show significant survival differences between the regions. The Cox regression model adjusted for year of diagnosis and age shows significantly worse overall survival of breast cancer patients in both Danish regions compared to Schleswig-Holstein with hazard ratios (HR) of 1.09 (95 % CI: 1.04; 1.15) for patients from Southern Denmark (SD) and 1.25 (95 % CI: 1.18; 1.32) for residents of Zealand (ZL). This effect diminished after adjustment for stage and treatment (HR: 1.05 (SD), 1.09 (ZL) 95 % CI: 0.99; 1.10 (SD), 1.03; 1.15 (ZL)).ConclusionSurvival differences can be explained by differing stage distribution and treatment administration, which formerly were more favourable in Schleswig-Holstein. The survival gap will probably close due to Denmark’s national screening program and increased use of adjuvant cancer therapy.     

Circadian rhythm characteristics of salivary alpha-amylase – a potential stress marker,in breast cancer in- and out-patients: a follow-up study

Salivary alpha-amylase has been implemented as renewed non-invasive biomarker of interest to measure the levels of stress in humans. In the current clinical study, two-factor repeated-measures cross-sectional design was implemented to determine the salivary alpha-amylase levels and its rhythm characteristics in newly diagnosed female breast cancer in- and out-patients. Alpha-amylase levels were determined using the Salimetrics® salivary alpha-amylase assay kit. Rhythm characteristics of alpha-amylase were computed using the Cosinor Rhythmometry technique. Results showed that the levels of alpha-amylase significantly increased from/to the increasing number of chemotherapy cycle in patients of both group; however the levels were higher in in-patients. Further, results revealed significant differences in rhythm characteristics of alpha-amylase characterized by higher MESOR, lower amplitude, and advanced acrophase in in-patients as compared to out-patients. Current findings indicate that patients of both the groups were associated with progression under stress levels across the number of chemotherapy cycle; however, the levels of stress were higher in in-patients as compared to out-patients. Higher level of stress in cancer in-patients could be attributed to the possible effect of hospitalization and/or relative social isolation.     

Design of novel lead molecules against RhoG protein as cancer target – a computational study

Cancer is a class of diseases characterized by uncontrolled cell growth. Every year more than 2 million people are affected by the disease. Rho family proteins are actively involved in cytoskeleton regulation. Over-expression of Rho family proteins show oncogenic activity and promote cancer progression. In the present work RhoG protein is considered as novel target of cancer. It is a member of Rho family and Rac subfamily protein, which plays pivotal role in regulation of microtubule formation, cell migration and contributes in cancer progression. In order to understand the binding interaction between RhoG protein and the DH domain of Ephexin-4 protein, the 3D structure of RhoG was evaluated and Molecular Dynamic Simulations was performed to stabilize the structure. The 3D structure of RhoG protein was validated and active site identified using standard computational protocols. Protein–protein docking of RhoG with Ephexin-4 was done to understand binding interactions and the active site structure. Virtual screening was carried out with ligand databases against the active site of RhoG protein. The efficiency of virtual screening is analysed with enrichment factor and area under curve values. The binding free energy of docked complexes was calculated using prime MM-GBSA module. The SASA, FOSA, FISA, PISA and PSA values of ligands were carried out. New ligands with high docking score, glide energy and acceptable ADME properties were prioritized as potential inhibitors of RhoG protein.     

Incidence of hospitalization in patients receiving short course palliative cranial radiotherapy on outpatient basis in a limited resource setting – Experience from a regional cancer center in India

AimTo investigate incidence of toxicity and related hospitalization among patients treated at our institute by a short course of palliative cranial radiotherapy against a longer, widely established schedule.BackgroundShorter schedule palliative cranial radiotherapy is more convenient for patients and reduce waiting times. Although many studies have established safety of short schedules, the need for hospitalization due to acute treatment toxicity remains under-explored. Hospital admissions are an economic burden both for the patient and healthcare system in a limited resource setting. Delivery of treatment on an outpatient basis and within shorter times is preferred by patients, caregivers and healthcare staff.Materials and methodsThis was a prospective study on 68 patients treated with palliative whole brain radiotherapy between November 2010 and October 2012. One group received 20 Gy in 5 fractions over 1 week and the other group, 30 Gy in 10 fractions over 2 weeks. Treatment toxicity due to cranial radiotherapy was assessed as per RTOG acute and late toxicity criteria. Need for hospitalization owing to acute toxicity was also noted. Significant differences in the study parameters between the two groups were calculated by Fisher's t-test.ResultsRequirement for hospital stay due to acute toxicity was not significantly different between the two groups. Patients in both groups experienced similar toxicity both during and after treatment.ConclusionsThe shorter course entailed no significant increase in toxicity related admissions, suitable for limited resource settings where patient transport is difficult, there are financial constraints, and the healthcare system is overburdened.     

Current status and future prospects of transforming growth factor-β as a potential prognostic and therapeutic target in the treatment of breast cancer

The transforming growth factor-β (TGF-β) signaling pathway is one of the important pathways involved in the cancer cell proliferation, invasion, migration, angiogenesis, apoptosis, as well as in metastasis by agitation or invasion of metastasis-related factors, including matrix metalloproteinase (MMP), epithelial-to-mesenchymal transition (EMT), tumor microenvironment (TME), cancer stem cells (CSCs), and cell adhesion molecules (CAMs). These data suggest its potential value as a therapeutic object in the treatment of malignancies including breast cancer. Several pharmacological approaches have been established to suppress TGF-β pathway; such as vaccines, small molecular inhibitors, antisense oligonucleotides, and monoclonal antibodies. Some of these are now approved by the US Food and Drug Administration for targeting the TGF-β signaling pathway. This study attempts to summarize the current data about the functions of TGF-β in cancer cells, and their probable application in the cancer therapy with a specific emphasis on recent preclinical and clinical research in the treatment of breast cancer and its prognostic value.     

LTBP-2 acts as a novel marker in human heart failure – a preliminary study

Background: We have observed increased expression of latent TGF-β binding protein (LTBP)-2 mRNA in human failing hearts. This study was aimed to further confirm LTBP-2 act as a novel marker in human acute heart failure.

Methods and results: We demonstrated that median level of LTBP-2 in myocardial samples from heart failure patients was significantly elevated, and TGF-β1 significantly promoted LTBP-2 expression in neonatal rat cardiomyocytes. To investigate the potential of LTBP-2 as a biomarker to diagnose heart failure with reduced ejection fraction (HFREF), another cohort of 133 consecutive patients with dyspnea were enrolled. In receiver operating characteristic (ROC) curve analyses to detect HFREF, LTBP-2 achieved an area under curve (AUC) of 0.67 (95% confidence intervals (CI) 0.58–0.75), comparable to the diagnostic ability of NT-proBNP 0.68 (95% CI 0.59–0.77).

Conclusion: The serum LTBP-2 levels might act as a promising biomarker in HFREF.     

NFκB signaling in carcinogenesis and as a potential molecular target for cancer therapy

It has become increasingly clear that deregulation of the NFκB signaling cascade is a common underlying feature of many human ailments including cancers. The past two decades of intensive research on NFκB has identified the basic mechanisms that govern the functioning of this pathway but uncovering the details of why this pathway works differently in different cellular contexts or how it interacts with other signaling pathways remains a challenge. A thorough understanding of these processes is needed to design better and more efficient therapeutic approaches to treat complex diseases like cancer. In this review, we summarize the literature documenting the involvement of NFκB in cancer, and then focus on the approaches that are being undertaken to develop NFκB inhibitors towards treatment of human cancers.     

Age and metastasis – How age influences metastatic spread in cancer. Colorectal cancer as a model

Metastasis is the major cause of death in cancer patients. Whereas colorectal cancer (CRC) incidence increases with age, metastatic spread seems to decline. Furthermore, the epidemiology of CRC is changing. There is an increase in CRC incidence in the young, presenting at an advanced stage with higher likelihood of synchronous or metachronous metastases, and a decline in CRC incidence and metastatic spread in the oldest-old. Emerging data suggest that age-related changes with regard to tumor biology (e.g. genomic instability), the tumor microenvironment (e.g. inflammaging) and the immune system (e.g. immunosenescence), complemented by interaction between the genome and exposome might contribute to the observed metastatic patterns. As aging is a key prognostic factor, this highlights the need for further studies investigating age-related patterns and underlying mechanisms of tumor growth and dissemination. Eventually, this might allow for better risk stratification, refinement of screening strategies and follow-up care as well as therapies tailored to reflect patient age and that might possibly target responsible biomarkers in a precision medicine approach. This review aims to discuss the influence of aging on metastatic spread in colorectal cancer and elucidate underlying mechanisms responsible for the observed metastatic patterns.