Does the Chemotherapy Backbone Impact on the Efficacy of Targeted Agents in Metastatic Colorectal Cancer? A Systematic Review and Meta-Analysis of the Literature

ImportanceThe EGFR inhibitors (EGFR-I) cetuximab and panitumumab and the angiogenesis inhibitors (AIs) bevacizumab and aflibercept have demonstrated varying efficacy in mCRC.ObjectiveTo document the overall impact of specific chemotherapy regimens on the efficacy of targeted agents in treating patients with mCRC. Data sources: MEDLINE, EMBASE and Cochrane databases were searched to 2014, supplemented by hand-searching ASCO/ESMO conference abstracts.ResultsEGFR-I added to irinotecan-based chemotherapy modestly improved OS with HR 0.90 (95% CI 0.81–1.00, p = 0.04), but more so PFS with HR 0.77 (95% CI 0.69–0.86, p<0.00001). No benefit was evident for EGFR-I added to oxaliplatin-based chemotherapy (OS HR 0.97 (95% CI 0.87–1.09) and PFS HR 0.92 (95% CI 0.83–1.02)). Significant oxaliplatin-irinotecan subgroup interactions were present for PFS with I² = 82%, p = 0.02. Further analyses of oxaliplatin+EGFR-I trials showed greater efficacy with infusional 5FU regimens (PFS HR 0.82, 95% CI 0.72–0.94) compared to capecitabine (HR 1.09; 95% CI 0.91–1.30) and bolus 5FU (HR 1.07; 95% CI 0.79–1.45); subgroup interaction was present with I² = 72%, p = 0.03. The oxaliplatin-irinotecan interaction was not evident for infusional 5FU regimens. For AIs, OS benefit was observed with both oxaliplatin-based (HR 0.83) and irinotecan-based (HR 0.77) regimens without significant subgroup interactions. Oxaliplatin+AI trials showed no subgroup interactions by type of FP, whilst an interaction was present for irinotecan+AI trials although aflibercept was only used with infusional FP (I² = 89.7%, p = 0.002).

Conclusion and Relevance

The addition of EGFR-I to irinotecan-based chemotherapy has consistent efficacy, regardless of FP regimen, whereas EGFR-I and oxaliplatin-based regimens were most active with infusional 5FU. No such differential activity was observed with the varying chemotherapy schedules when combined with AIs.     

Curcumin Enhances the Effect of Chemotherapy against Colorectal Cancer Cells by Inhibition of NF-κB and Src Protein Kinase Signaling Pathways

Objective

Development of treatment resistance and adverse toxicity associated with classical chemotherapeutic agents highlights the need for safer and effective therapeutic approaches. Herein, we examined the effectiveness of a combination treatment regimen of 5-fluorouracil (5-FU) and curcumin in colorectal cancer (CRC) cells.

Methods

Wild type HCT116 cells and HCT116+ch3 cells (complemented with chromosome 3) were treated with curcumin and 5-FU in a time- and dose-dependent manner and evaluated by cell proliferation assays, DAPI staining, transmission electron microscopy, cell cycle analysis and immunoblotting for key signaling proteins.

Results

The individual IC₅₀ of curcumin and 5-FU were approximately 20 µM and 5 µM in HCT116 cells and 5 µM and 1 µM in HCT116+ch3 cells, respectively (p<0.05). Pretreatment with curcumin significantly reduced survival in both cells; HCT116+ch3 cells were considerably more sensitive to treatment with curcumin and/or 5-FU than wild-type HCT116 cells. The IC₅₀ values for combination treatment were approximately 5 µM and 1 µM in HCT116 and 5 µM and 0.1 µM in HCT116+ch3, respectively (p<0.05). Curcumin induced apoptosis in both cells by inducing mitochondrial degeneration and cytochrome c release. Cell cycle analysis revealed that the anti-proliferative effect of curcumin and/or 5-FU was preceded by accumulation of CRC cells in the S cell cycle phase and induction of apoptosis. Curcumin potentiated 5-FU-induced expression or cleavage of pro-apoptotic proteins (caspase-8, -9, -3, PARP and Bax), and down-regulated anti-apoptotic (Bcl-xL) and proliferative (cyclin D1) proteins. Although 5-FU activated NF-κB/PI-3K/Src pathway in CRC cells, this was down-regulated by curcumin treatment through inhibition of IκBα kinase activation and IκBα phosphorylation.

Conclusions

Combining curcumin with conventional chemotherapeutic agents such as 5-FU could provide more effective treatment strategies against chemoresistant colon cancer cells. The mechanisms involved may be mediated via NF-κB/PI-3K/Src pathways and NF-κB regulated gene products.     

Does the Type of Anesthetic Technique Affect In-Hospital and One-Year Outcomes after Off-Pump Coronary Arterial Bypass Surgery?

Despite numerous previous studies, there is little data on the effects of anesthetics on clinical outcome after off-pump coronary arterial bypass grafting (OPCAB). Therefore, we retrospectively compared the effects of anesthetic choice on in-hospital major adverse events (MAEs) and one-year major adverse cardiovascular and cerebral events (MACCEs) in patients undergoing OPCAB. Electronic medical records were reviewed in 192 patients who received propofol-remifenanil total intravenous anesthesia (TIVA) and propensity score-matched 662 patients who received isoflurane anesthesia. The primary endpoints were in-hospital MAEs and one-year MACCEs. The components of in-hospital MAEs were in-hospital death, myocardial infarction (MI), coronary revascularization, stroke, renal failure, prolonged mechanical ventilation longer than 72 h, and postoperative new cardiac arrhythmia requiring treatment. One-year MACCEs was defined as a composite of all-cause mortality, MI, coronary revascularization, and stroke. There was no significant difference in risk of in-hospital MAEs (OR = 1.29, 95% CI = 0.88–1.88, P = 0.20) or one-year MACCEs (OR = 0.81; 95% CI = 0.46–1.42, P = 0.46) between the groups. The risk of postoperative new arrhythmia including new atrial fibrillation significantly increased in the TIVA group compared to the isoflurane anesthesia group (OR = 1.72, 95% CI = 1.12–2.63, P = 0.01). In conclusion, the choice between propofol-remifentanil TIVA and isoflurane anesthesia did not show differences in incidence of in-hospital MAEs or one-year MACCEs in patients undergoing OPCAB. However, further studies on the effects of anesthetics on development of in-hospital new arrhythmia will be needed.     

Meta-Analysis of the Association between COX-2 Polymorphisms and Risk of Colorectal Cancer Based on Case–Control Studies

Objective

Cyclooxygenase-2 (COX-2) is an inducible enzyme converting arachidonic acid to prostaglandins and playing important roles in inflammatory diseases as well as tumor development. Previous studies investigating the association between COX-2 polymorphisms and colorectal cancer (CRC) risk reported conflicting results. We performed a meta-analysis of all available studies to explore this association.

Methods

All studies published up to October 2013 on the association between COX-2 polymorphisms and CRC risk were identified by searching electronic databases PubMed, EMBASE, and Cochrane library. The association between COX-2 polymorphisms and CRC risk was assessed by odds ratios (ORs) together with their 95% confidence intervals (CIs).

Results

Ten studies with 6,774 cases and 9,772 controls were included for −1195A>G polymorphism, 13 studies including 6,807 cases and 10,052 controls were available for −765G>C polymorphism, and 8 studies containing 5,121 cases and 7,487 controls were included for 8473T>C polymorphism. With respect to −765G>C polymorphism, we did not find a significant association with CRC risk when all eligible studies were pooled into the meta-analysis. However, in subgroup analyses by ethnicity and cancer location, with a Bonferroni corrected alpha of 0.05/2, statistical significant increased CRC risk was found in the Asian populations (dominant model CC+CG vs. GG: OR = 1.399, 95%CI: 1.113–1.760, P = 0.004) and rectum cancer patients (CC vs. GG: OR = 2.270, 95%CI: 1.295–3.980, P = 0.004; Recessive model CC vs. CG+GG: OR = 2.269, 95%CI: 1.297–3.970, P = 0.004). In subgroup analysis according to source of control, no significant association was detected. With respect to −1195A>G and 8473T>C polymorphisms, no significant association with CRC risk was demonstrated in the overall and subgroup analyses.

Conclusions

The present meta-analysis suggests that the COX-2 −765G>C polymorphism may be a risk factor for CRC in Asians and rectum cancer patients. Further large and well-designed studies are needed to confirm this association.     

Major Factors Affecting Incidence of Childhood Thyroid Cancer in Belarus after the Chernobyl Accident: Do Nitrates in Drinking Water Play a Role?

One of the major health consequences of the Chernobyl Nuclear Power Plant accident in 1986 was a dramatic increase in incidence of thyroid cancer among those who were aged less than 18 years at the time of the accident. This increase has been directly linked in several analytic epidemiological studies to iodine-131 (¹³¹I) thyroid doses received from the accident. However, there remains limited understanding of factors that modify the ¹³¹I-related risk. Focusing on post-Chernobyl pediatric thyroid cancer in Belarus, we reviewed evidence of the effects of radiation, thyroid screening, and iodine deficiency on regional differences in incidence rates of thyroid cancer. We also reviewed current evidence on content of nitrate in groundwater and thyroid cancer risk drawing attention to high levels of nitrates in open well water in several contaminated regions of Belarus, i.e. Gomel and Brest, related to the usage of nitrogen fertilizers. In this hypothesis generating study, based on ecological data and biological plausibility, we suggest that nitrate pollution may modify the radiation-related risk of thyroid cancer contributing to regional differences in rates of pediatric thyroid cancer in Belarus. Analytic epidemiological studies designed to evaluate joint effect of nitrate content in groundwater and radiation present a promising avenue of research and may provide useful insights into etiology of thyroid cancer.     

Bisphosphonates in the Adjuvant Setting of Breast Cancer Therapy—Effect on Survival: A Systematic Review and Meta-Analysis

Background

The role of bisphosphonates (BP) in early breast cancer (BC) has been considered controversial. We performed a meta-analysis of all randomized controlled trials (RCTs) that appraised the effects of BP on survival in early BC.

Methods

RCTs were identified by searching the Cochrane Library, MEDLINE databases and conference proceedings. Hazard ratios (HRs) of overall survival (OS), disease-free survival (DFS) and relative risks of adverse events were estimated and pooled.

Results

Thirteen trials met the inclusion criteria, evaluating a total of 15,762 patients. Meta-analysis of ten trials which reported OS revealed no statistically significant benefit in OS for BP (HR 0.89, 95% CI = 0.79 to 1.01). Meta-analysis of nine trials which reported the DFS revealed no benefit in DFS (HR 0.95 (0.81–1.12)). Meta-analysis upon menopausal status showed a statistically significant better DFS in the BP-treated patients (HR 0.81(0.69–0.95)). In meta-regression, chemotherapy was negatively associated with HR of survival.

Conclusions

Our meta-analysis indicates a positive effect for adjuvant BP on survival only in postmenopausal patients. Meta-regression demonstrated a negative association between chemotherapy use BP effect on survival. Further large scale RCTs are warranted to unravel the specific subgroups that would benefit from the addition of BP in the adjuvant setting.     

A Nested Case–Control Study of Metabolically Defined Body Size Phenotypes and Risk of Colorectal Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC)

BackgroundObesity is positively associated with colorectal cancer. Recently, body size subtypes categorised by the prevalence of hyperinsulinaemia have been defined, and metabolically healthy overweight/obese individuals (without hyperinsulinaemia) have been suggested to be at lower risk of cardiovascular disease than their metabolically unhealthy (hyperinsulinaemic) overweight/obese counterparts. Whether similarly variable relationships exist for metabolically defined body size phenotypes and colorectal cancer risk is unknown.ConclusionsThese results support the idea that individuals with the metabolically healthy/overweight phenotype (with normal insulin levels) are at lower colorectal cancer risk than those with hyperinsulinaemia. The combination of anthropometric measures with metabolic parameters, such as C-peptide, may be useful for defining strata of the population at greater risk of colorectal cancer.     

Factors Affecting the Duration of Nestling Period and Fledging Order in Tengmalm’s Owl (Aegolius funereus): Effect of Wing Length and Hatching Sequence

In altricial birds, the nestling period is an important part of the breeding phase because the juveniles may spend quite a long time in the nest, with associated high energy costs for the parents. The length of the nestling period can be variable and its duration may be influenced by both biotic and abiotic factors; however, studies of this have mostly been undertaken on passerine birds. We studied individual duration of nestling period of 98 Tengmalm’s owl chicks (Aegolius funereus) at 27 nests during five breeding seasons using a camera and chip system and radio-telemetry. We found the nestlings stayed in the nest box for 27 – 38 days from hatching (mean ± SD, 32.4 ± 2.2 days). The individual duration of nestling period was negatively related to wing length, but no formally significant effect was found for body weight, sex, prey availability and/or weather conditions. The fledging sequence of individual nestlings was primarily related to hatching order; no relationship with wing length and/or other factors was found in this case. We suggest the length of wing is the most important measure of body condition and individual quality in Tengmalm’s owl young determining the duration of the nestling period. Other differences from passerines (e.g., the lack of effect of weather or prey availability on nestling period) are considered likely to be due to different life-history traits, in particular different food habits and nesting sites and greater risk of nest predation among passerines.     

Socioeconomic Factors and Cultural Changes Explain the Knowledge and Use of Ouricuri Palm (Syagrus coronata) by the Fulni–ô Indigenous People of Northeast Brazil

Economic Botany - Socioeconomic Factors and Cultural Changes Explain the Knowledge and Use of Ouricuri Palm (Syagrus coronata) by the Fulni–ô Indigenous&nbsp;People of Northeast...     

Impact of polymorphism of the regulatory subunit of the ��-calpain (CAPN1S) on the proteolysis process and meat tenderness of young cattle

The objective of this study was to estimate the impact of the polymorphism of ??-calpain (CAPN1S) gene on protein changes of the cattle muscle tissue and its tenderness during 10-day cold storage. The analysis was performed on the longest dorsal and lumbar muscles collected from 76 bulls 6 to 12 months of age. Polymorphism identification of the above-mentioned gene was conducted using the PCR-RFLP technique. Its effect on the course of the proteolysis process was assessed by monitoring changes in proportions of tissue proteins during 10-day process of meat ageing. Special attention was focused on changes in native titin (T1) share and products of its degradation (proteins of molecular weight (m.w.) of 2400 and 200 kDa), ??-actinin and protein of 37 kDa as well as myosin heavy chains (MHC). In the case of the last proteins, their polymorphism was evaluated as well. Meat tenderness was estimated measuring the value of shear force and sensorially. The highest tenderness was ascertained for the heterozygote. Its improvement was associated with a significant decrease in proportions of proteins of molecular weight of approximately 37 kDa accompanied by an increase of those with 200 kDa molecular weight. Muscles derived from cattle of CT genotype were characterised by the highest proportions of type 2a MHC isoform. Value differences between proportions determined for the heterozygote and CC and TT homozygotes of the CAPN1S gene were statistically significant. Therefore, it can be presumed that the process of meat tenderisation was especially connected with MHC polymorphism.     

No Negative Impact of Palliative Sedation on Relatives’ Experience of the Dying Phase and Their Wellbeing after the Patient’s Death: An Observational Study

Background

Palliative sedation is the widely-used intervention of administering sedating agents to induce a state of unconsciousness to take away a dying patient’s perception of otherwise irrelievable symptoms. However, it remains questionable whether this ethically complex intervention is beneficial for patients and whether the associated lack of communication in the last phase of life has a negative impact on relatives’ wellbeing.

Methods

An observational questionnaire study was conducted among relatives of a consecutive sample of patients who died a non-sudden death in the Erasmus MC Cancer Institute or in the hospice ‘Laurens Cadenza’ (both in Rotterdam) between 2010 and 2013.

Results

Relatives filled in questionnaires regarding 151 patients who had been sedated and 90 patients who had not been sedated. The median time since all patients had passed away was 21 (IQR 14–32) months. No significant differences were found in relatives´ assessments of the quality of end-of-life care, patients´ quality of life in the last week before death and their quality of dying, between patients who did and did not receive sedation, or in relatives’ satisfaction with their own life, their general health and their mental wellbeing after the patient’s death.

Conclusions

The use of sedation in these patients appears to have no negative effect on bereaved relatives’ evaluation of the patient’s dying phase, or on their own wellbeing after the patient’s death.     

Impact of human activity on the distribution of native and non-native cockroach species (Dictyoptera) in La Réunion and Mayotte

Establishment of non-native species and human-driven alteration of habitats are major causes of the decline of native faunas. Interference between native and non-native cockroach species was evaluated here by comparing their distribution areas in two oceanic islands: Mayotte and La Réunion. A factorial correspondence analysis showed that their presence is related to environmental parameters among which human activity, humidity and altitude are the three most important. Human activity and humidity favour establishment and development of non-native species, whereas altitude limits their presence. Non-native species form guilds (up to seven species). Their distribution areas overlap and illustrate their colonizing capacities. On the contrary, distribution areas of native species never overlap, although some co-occur with non-native species. Native species are more endangered when they are established in cultivated areas than when they are in protected natural areas.     

Impact of Gender,Co-Morbidity and Social Factors on Labour Market Affiliation after First Admission for Acute Coronary Syndrome. A Cohort Study of Danish Patients 2001–2009

Background

Over the last decades survival after acute coronary syndrome (ACS) has improved, leading to an increasing number of patients returning to work, but little is known about factors that may influence their labour market affiliation. This study examines the impact of gender, co-morbidity and socio-economic position on subsequent labour market affiliation and transition between various social services in patients admitted for the first time with ACS.

Methods

From 2001 to 2009 all first-time hospitalisations for ACS were identified in the Danish National Patient Registry (n = 79,714). For this population, data on sick leave, unemployment and retirement were obtained from an administrative register covering all citizens. The 21,926 patients, aged 18–63 years, who had survived 30 days and were part of the workforce at the time of diagnosis were included in the analyses where subsequent transition between the above labour market states was examined using Kaplan-Meier estimates and Cox proportional hazards models.

Findings

A total of 37% of patients were in work 30 days after first ACS diagnosis, while 55% were on sick leave and 8% were unemployed. Seventy-nine per cent returned to work once during follow-up. This probability was highest among males, those below 50 years, living with a partner, the highest educated, with higher occupations, having specific events (NSTEMI, and percutaneous coronary intervention) and with no co-morbidity. During five years follow-up, 43% retired due to disability or voluntary early pension. Female gender, low education, basic occupation, co-morbidity and having a severer event (invasive procedures) and receiving sickness benefits or being unemployed 30 days after admission were associated with increased probability of early retirement.

Conclusion

About half of patients with first-time ACS stay in or return to work shortly after the event. Women, the socially disadvantaged, those with presumed severer events and co-morbidity have lower rates of return.     

Does the Fractionalization of Daily Physical Activity (Sporadic vs. Bouts) Impact Cardiometabolic Risk Factors in Children and Youth?

Objective

Children and youth accumulate their daily moderate-to-vigorous physical activity (MVPA) in bouts (i.e., ≥5 consecutive minutes) and in a sporadic manner (i.e., <5 consecutive minutes). The study objective was to determine, within children and youth, whether MVPA accumulated in bouts is more strongly associated with cardiometabolic risk factors than an equivalent volume of MVPA accumulated sporadically.

Methods

Participants consisted of 2754 children and youth aged 6–19 years from the 2003–2006 National Health and Nutrition Examination Survey, a representative cross-sectional study. Bouts and sporadic MVPA were measured objectively over 7 days using Actigraph accelerometers. Thresholds of 5 and 10 consecutive minutes were used to differentiate between bouts and sporadic MVPA. A high cardiometabolic risk factor score (CRS) was created based on measures of waist circumference, non-high-density lipoprotein cholesterol, C-reactive protein, and systolic blood pressure. Associations were examined using logistic regression and controlled for covariates (sex, age, ethnicity, socioeconomic status, dietary fat and sodium, smoking, and accelerometry wear time).

Results

The odds of a high CRS decreased in a dose-response for both the sporadic and bout MVPA measures. Relative to quartile 1, the odds ratio (95% confidence interval) for a high CRS in quartile 4 was 0.25 (0.10–0.60) for sporadic MVPA, 0.17 (0.09–0.34) for ≥5 minute bouts of MVPA, and 0.19 (0.11–0.34) for ≥10 minute bouts of MVPA. The sporadic and bout MVPA measures had a similar ability to distinguish between participants with high and normal CRS. Relative to 0 minutes of MVPA, an equivalent number of minutes of sporadic MVPA and bouts of MVPA had an almost identical odds ratio for a high CRS. The findings were consistent for 5 and 10 minute bout thresholds.

Conclusions

The relations between sporadic MVPA and bouts of MVPA with cardiometabolic risk factors were remarkably similar in children and youth.     

Use of traps to capture black and gold howlers (Alouatta caraya) on the Islands of the upper Paraná River, Southern Brazil

Howlers (genus Alouatta) are widely captured with the use of anesthetic projectiles; however, no capture protocol involving the use of traps has been described to date. In the present study we describe the first efficient capture program for black and gold howlers (Alouatta caraya) using traps, which was implemented on the islands of the upper Paraná River in southern Brazil. We constructed two trap models with either manual or automatic activation (trap A with two entrances and guillotine-type doors; trap B with one entrance and a guillotine-type door). The traps were suspended in the canopy by means of vertical climbing techniques, and were baited regularly and abundantly with bananas and mangoes. We captured 70 howlers (86% using manual activation and 14% using automatic activation) on four different islands. We restrained 41 of these animals and measured their body mass, which averaged 5.30 kg+/-1.79. Given our results, we suggest that the system described in the present study represents an alternative capture program for howlers in areas that have low food diversity and no other mammal species that will compete for the bait, as has been observed in riparian environments, islands, and forest fragments.     

Impact of diabetic polyneuropathy and cardiovascular autonomic neuropathy on the excretion of urinary 8-epi-PGF2α and its metabolites (2, 3-dinor and 2, 3-dinor-5, 6-dihydro)

The objective of this study was to establish if diabetes in the presence of polyneuropathy (PN) and/or cardiovascular autonomic neuropathy (CAN) is associated with alterations in the amounts of 8-epi-PGF_2α (IP) and its metabolites including 2, 3-dinor-8-epi-PGF_2α (dinor-IP) and 2, 3-dinor-5, 6 dihydro-8-epi-PGF_2α (dinor-dihydro-IP) in urine. Mass spectrometric separation showed that excretion of IP was similar in the PN+/CAN ? and PN+/CAN+ groups but higher than in the PN ? /CAN ? group (n = 103, 22 and 60, respectively; P < 0.05). By contrast, excretion of dinor-IP or dinor-dihydro-IP were similar in the PN ? /CAN ? and PN+/CAN ? groups but higher than in PN+/CAN+ group. Correlations were obtained between IP and dinor-IP or dinor-dihydro-IP (r = 0.30; P < 0.001 and r = 0.31; P < 0.001, respectively). A significant association was also observed between dinor-IP and dinor-dihydro-IP (r = 0.48; P < 0.001). In conclusion, these biomarkers should prove useful in studies evaluating the impact of therapeutic drugs or antioxidant interventions aimed at delaying the onset of diabetic complications.