Deep Learning Models for Predicting Malignancy Risk in CT-Detected Pulmonary Nodules: A Systematic Review and Meta-analysis.

BACKGROUND: There has been growing interest in using artificial intelligence/deep learning (DL) to help diagnose prevalent diseases earlier. In this study we sought to survey the landscape of externally validated DL-based computer-aided diagnostic (CADx) models, and assess their diagnostic performance for predicting the risk of malignancy in computed tomography (CT)-detected pulmonary nodules. METHODS: An electronic search was performed in four databases (from inception to 10 August 2023). Studies were eligible if they were peer-reviewed experimental or observational articles comparing the diagnostic performance of externally validated DL-based CADx models with models widely used in clinical practice to predict the risk of malignancy. A bivariate random-effect approach for the meta-analysis on the included studies was used. RESULTS: Seventeen studies were included, comprising 8553 participants and 9884 nodules. Pooled analyses showed DL-based CADx models were 11.6% more sensitive than physician judgement alone, and 14.5% more than clinical risk models alone. They had a similar pooled specificity to physician judgement alone [0.77 (95% CI 0.68-0.84) v 0.81 (95% CI 0.71-0.88)], and were 7.4% more specific than clinical risk models alone. They had superior pooled areas under the receiver operating curve (AUC), with relative pooled AUCs of 1.03 (95% CI 1.00-1.07) and 1.10 (95% CI 1.07-1.13) versus physician judgement and clinical risk models alone, respectively. CONCLUSION: DL-based models are already used in clinical practice in certain settings for nodule management. Our results show their diagnostic performance potentially justifies wider, more routine deployment alongside experienced physician readers to help inform multidisciplinary team decision-making.

Does a high Mandard score really define a poor response to chemotherapy in oesophageal adenocarcinoma?

BACKGROUND: A high Mandard score implies a non-response to chemotherapy in oesophageal adenocarcinoma. However, some patients exhibit tumour volume reduction and a nodal response despite a high score. This study examines survival and recurrence patterns in these patients. METHODS: Clinicopathological factors were analysed using multivariable Cox regression assessing time to death and recurrence. Computed tomography-estimated tumour volume change was examined in a subgroup of consecutive patients. RESULTS: Five hundred and fifty-five patients were included. Median survival was 55 months (Mandard 1-3) and 21 months (Mandard 4 and 5). In the Mandard 4 and 5 group (332 patients), comparison between complete nodal responders and persistent nodal disease showed improved survival (90 vs 18 months), recurrence rates (locoregional 14.75 vs 28.74%, systemic 24.59 vs 48.42%) and circumferential resection margin positivity (22.95 vs 68.11%). Complete nodal response independently predicted improved survival (hazard ratio 0.34 (0.16-0.74). Post-chemotherapy tumour volume reduction was greater in patients with a complete nodal response (-16.3 vs -7.7 cm3, p = 0.033) with no significant difference between Mandard groups. CONCLUSION: Patients with a complete nodal response to chemotherapy have significantly improved outcomes despite a poor Mandard score. High Mandard score does not correspond with a non-response to chemotherapy in all cases and patients with nodal downstaging may still benefit from adjuvant chemotherapy.

The role of surgery after prolonged primary chemotherapy for advanced oesophageal adenocarcinoma.

BACKGROUND: Most patients presenting with oesophageal cancer do so with advanced disease not suitable for surgery. However, there are examples of encouraging survival following surgery in highly selected patients who respond well to chemotherapy. METHODS: This was a retrospective cohort study of patients who presented with advanced but nonvisceral metastatic oesophageal cancer. Consecutive patients on a prolonged primary chemotherapy pathway who underwent surgical resection following a favourable response to chemotherapy were included. Survival and recurrence rates were analysed using Cox regression, providing hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: A total of 57 patients included in the cohort operated between 2007 and 2015, the overall median survival was 44 months and the 5-year survival was 42%. Prechemotherapy cN0/cN1 (HR: 0.27, 95% CI: 0.12-0.62) conferred an independent survival advantage compared to cN2 and cN3 disease. Poor differentiation (HR: 2.46, 95% CI: 1.11-5.42), R1 resection (HR: 2.43, 95% CI: 1.14-5.19) and advanced nodal status (HR: 3.28, 95% CI: 1.44-7.47) predicted worse survival on univariable analysis. Poor differentiation (HR: 3.93, 95% CI: 1.62-9.56) was independently associated with poor survival when adjusted for other variables. CONCLUSION: Patients who present with advanced inoperable oesophageal cancer who have a favourable response to chemotherapy represent a limited group of patients who may benefit from surgery.

The Relationship of Early-Life Adversity With Adulthood Weight and Cardiometabolic Health Status in the 1946 National Survey of Health and Development.

OBJECTIVE: Evidence linking early-life adversity with an adverse cardiometabolic profile in adulthood is equivocal. This study investigates early-life adversity in relation to weight and cardiometabolic health status at ages 60 to 64 years. METHODS: We included 1059 individuals from the 1946 National Survey of Health and Development. Data on adversity between ages 0 to 15 years were used to create a cumulative childhood psychosocial adversity score and a socioeconomic adversity score. Cardiometabolic and weight/height data collected at ages 60 to 64 years were used to create four groups: metabolically healthy normal weight, metabolically unhealthy normal weight, metabolically healthy overweight/obese, and metabolically unhealthy overweight/obese. Associations between the two exposure scores and weight/health status were examined using multinomial logistic regression, with adjustment for sex and age at the outcome visit. RESULTS: Sixty-two percent of normal-weight individuals were metabolically healthy, whereas only 34% of overweight/obese individuals were metabolically healthy. In a mutually adjusted model including both exposure scores, a psychosocial score of ≥3 (compared with 0) was associated with increased risk of being metabolically unhealthy (compared with healthy) in both normal-weight adults (relative risk = 2.49; 95% confidence interval = 0.87-7.13) and overweight/obese adults (1.87; 0.96-3.61). However, the socioeconomic adversity score was more strongly related to metabolic health status in overweight/obese adults (1.60; 0.98-2.60) than in normal-weight adults (0.95; 0.46-1.96). CONCLUSIONS: Independently of socioeconomic adversity, psychosocial adversity in childhood may be associated with a poor cardiometabolic health profile, in both normal-weight and overweight/obese adults.

Risk factors of distant metastasis after surgery among different breast cancer subtypes: a hospital-based study in Indonesia.

BACKGROUND: More than one third of breast cancer patients including those that are diagnosed in early stages will develop distant metastasis. Patterns of distant metastasis and the associated risks according to the molecular subtypes are not completely revealed particularly in populations of patients with delayed diagnosis and advanced stages. METHODS: Breast cancer patients (n = 1304) admitted to our institute (2014-2017) were evaluated to identify the metastatic patterns and the associated risks. Metastatic breast cancers at diagnosis were found in 245 patients (18.7%), and 1059 patients were then grouped into non-metastatic and metastatic groups after a median follow-up of 3.8 years. RESULTS: Infiltration of the tumor to the skin and chest wall prevailed as the most powerful predictor for distant metastasis (OR 2.115, 95% CI 1.544-2.898) particularly in the luminal A-like subtype (OR 2.685, 95% CI 1.649-4.371). Nodal involvement was also significantly associated with the risk of distant metastasis (OR 1.855, 95% CI 1.319-2.611), and the risk was higher in the Luminal A-like subtype (OR 2.572, 95% CI 1.547-4.278). Luminal A-like subtype had a significant higher risk of bone metastasis (OR 1.601, 95% CI 1.106-2.358). In respect to treatment, a combination of anthracyclines and taxanes-based chemotherapy was significantly associated with lower distant organ spread in comparison with anthracycline-based chemotherapy (OR 0.510, 95% CI 0.355-0.766) and the effect was stronger in Luminal A-like subtype (OR 0.417, 95% CI 0.226-0.769). Classification into Luminal and non-Luminal subtypes revealed significant higher risks of bone metastasis in the Luminal subtype (OR 1.793, 95% CI 1.209-2.660) and pulmonary metastasis in non-Luminal breast cancer (OR 1.445, 95% CI 1.003-2.083). CONCLUSION: In addition to guiding the treatment plan, a comprehensive analysis of clinicopathological variables including the molecular subtypes could assist in the determination of distant metastasis risks of breast cancer patients. Our study offers new perspectives concerning the risks of distant metastasis in breast cancer subtypes in order to plan intensive surveillance or escalation of treatment particularly in a setting where patients are predominantly diagnosed in late stages.

Metabolomic correlates of central adiposity and earlier-life body mass index.

BMI is correlated with circulating metabolites, but few studies discuss other adiposity measures, and little is known about metabolomic correlates of BMI from early life. We investigated associations between different adiposity measures, BMI from childhood through adulthood, and metabolites quantified from serum using 1H NMR spectroscopy in 900 British men and women aged 60-64. We assessed BMI, waist-to-hip ratio (WHR), android-to-gynoid fat ratio (AGR), and BMI from childhood through adulthood. Linear regression with Bonferroni adjustment was performed to assess adiposity and metabolites. Of 233 metabolites, 168; 126; and 133 were associated with BMI, WHR, and AGR at age 60-64, respectively. Associations were strongest for HDL, particularly HDL particle size-e.g., there was 0.08 SD decrease in HDL diameter (95% CI: 0.07-0.10) with each unit increase in BMI. BMI-adjusted AGR or WHR were associated with 31 metabolites where there was no metabolome-wide association with BMI. We identified inverse associations between BMI at age 7 and glucose or glycoprotein at age 60-64 and relatively large LDL cholesteryl ester with postadolescent BMI gains. In summary, we identified metabolomic correlates of central adiposity and earlier-life BMI. These findings support opportunities to leverage metabolomics in early prevention of cardiovascular risk attributable to body fatness.

Glycaemic control trends in people with type 1 diabetes in Scotland 2004-2016.

AIMS/HYPOTHESIS: The aim of this work was to examine whether glycaemic control has improved in those with type 1 diabetes in Scotland between 2004 and 2016, and whether any trends differed by sociodemographic factors. METHODS: We analysed records from 30,717 people with type 1 diabetes, registered anytime between 2004 and 2016 in the national diabetes database, which contained repeated measures of HbA1c. An additive mixed regression model was used to estimate calendar time and other effects on HbA1c. RESULTS: Overall, median (IQR) HbA1c decreased from 72 (21) mmol/mol [8.7 (4.1)%] in 2004 to 68 (21) mmol/mol (8.4 [4.1]%) in 2016. However, all of the improvement across the period occurred in the latter 4 years: the regression model showed that the only period of significant change in HbA1c was 2012-2016 where there was a fall of 3 (95% CI 1.82, 3.43) mmol/mol. The largest reductions in HbA1c in this period were seen in children, from 69 (16) mmol/mol (8.5 [3.6]%) to 63 (14) mmol/mol (7.9 [3.4]%), and adolescents, from 75 (25) mmol/mol (9.0 [4.4]%) to 70 (23) mmol/mol (8.6 [4.3]%). Socioeconomic status (according to Scottish Index of Multiple Deprivation) affected the HbA1c values: from the regression model, the 20% of people living in the most-deprived areas had HbA1c levels on average 8.0 (95% CI 7.4, 8.9) mmol/mol higher than those of the 20% of people living in the least-deprived areas. However this difference did not change significantly over time. From the regression model HbA1c was on average 1.7 (95% CI 1.6, 1.8) mmol/mol higher in women than in men. This sex difference did not narrow over time. CONCLUSIONS/INTERPRETATION: In this high-income country, we identified a modest but important improvement in HbA1c since 2012 that was most marked in children and adolescents. These changes coincided with national initiatives to reduce HbA1c including an expansion of pump therapy. However, in most people, overall glycaemic control remains far from target levels and further improvement is badly needed, particularly in those from more-deprived areas.

Pathological profiles and clinical management challenges of breast cancer emerging in young women in Indonesia: a hospital-based study.

BACKGROUND: Breast cancer diagnosed at a young age is often associated with aggressive biology, advanced stage, and unfavorable prognosis. The median age of breast cancer diagnosis in Indonesia is younger (48 vs. 68 years-old in Europe) with a relatively higher proportion of patients younger than 40 years old. Although prognosis and outcome of young breast cancer are well studied in developed nations, research evaluating biological characteristics, delivered treatment, and clinical outcomes is very limited in Indonesia. METHODS: We analyzed all breast cancer patients who underwent surgery at Dr. Sardjito Hospital, Indonesia, in 2012-2017. Details of pathology profiles, treatment administrated, and outcomes, as well as reproductive factors among patients younger than 40 years old, were collected and analyzed. Kaplan-Meier curve was used to assess conditional survival based on baseline characteristics. RESULTS: From the total of 1259 breast cancer patients (median age 51 years), 144 (11.4%) were younger than 40 years old (median age 37 years). Of these young patients, 19 (13.2%) were bilateral and 92 (64%) were diagnosed in advanced stages (stages IIIA-C and IV). Median tumor diameter was 5.5 cm and nodal infiltration was present in 73%. Distant metastasis was found in 16% at the time of diagnosis. Moderate and poor differentiation of tumor were 20.8 and 78.5%, respectively, and lymphovascular invasion was found in 90.3%. Around 40% were hormone receptor-positive, 30.6% human epidermal growth factor receptor 2 positive, and 38.2% triple negative. Patients underwent radical surgery in 121 cases (84%) and breast conserving surgery in 7 cases (4.9%). Adjuvant chemotherapy was administrated in 68% and hormonal therapy in 34%. Progression-free survival was significantly shorter in patients with advanced stage, skin and chest wall involvement (T4), positive lymph node infiltration, positive hormonal receptor, and triple negative subtype (log-rank Mantel-Cox tests, p < 0.05). CONCLUSION: We found a high frequency of young breast cancer with biologically more aggressive tumors, late diagnosis, frequent relapse, and poor prognosis. Further actions to improve clinical management and meet psychosocial needs in young breast cancer patients are warranted.

Determinants of cancer screening awareness and participation among Indonesian women.

BACKGROUND: Cancer screening awareness and participation may be lower in low- and middle-income countries that lack established national screening programmes compared with those that do. We evaluated potential determinants of awareness about and participation in breast and cervical cancer screening, and breast self-examination (BSE) in women using survey data from Indonesia. METHODS: From the fifth Indonesian Family Life Survey (2014-2015), a total of 5397 women aged 40 and older without any history of cancer who responded to questionnaires concerning Pap smears, mammography, and BSE were included. Multilevel modelling was used to assess potential determinants in relation to awareness about Pap smears and mammography, and participation in Pap smears and BSE practice. Multivariable analyses were performed to identify independent predictors of cancer screening. RESULTS: Of the 5397 respondents, 1058 (20%) women were aware of Pap smears, of which 297 had never had the procedure. Only 251 (5%) participants were aware of mammography. A total of 605 (12%) of women reported they performed BSE. Higher education and household expenditure were consistently associated with higher odds of awareness about Pap smears and mammography (e.g. odds ratio [OR] of being aware of Pap smear and mammography: 7.82 (95% CI: 6.30-9.70) and 7.70 (6.19-9.58), respectively, for high school graduates compared to women with less educational attainment in the multivariable models), and participation in Pap smears and BSE. We also identified enabling factors linked with greater cancer screening awareness and participation, including health insurance, shorter distance to health services, and social participation. CONCLUSION: There are socioeconomic disparities in cancer screening awareness and participation among Indonesian women. Our findings may help inform targeted health promotion and screening for cancer in the presence of limited resources.

Circulating gamma-glutamyl transferase and development of specific breast cancer subtypes: findings from the Apolipoprotein Mortality Risk (AMORIS) cohort.

BACKGROUND: Different etiological pathways may precede development of specific breast cancer subtypes and impact prevention or treatment strategies. We investigated the association between gamma-glutamyl transferase (GGT) and development of specific breast cancer subtypes based on oestrogen receptor (ER), progesterone receptor (PR) and HER2 status. METHODS: We included 231,283 cancer-free women in a Swedish cohort. Associations between GGT and breast cancer subtypes were investigated with nested case-control and case-case analyses. We used logistic regression models to assess serum GGT in relation to breast cancer subtype, based on individual and combined receptor status. RESULTS: Positive associations were found between serum GGT and development of ER+, ER- and PR+ breast cancers compared to controls (odds ratio (OR) 1.14 (95% confidence interval (CI) 1.08-1.19), 1.11 (1.01-1.23) and 1.18 (1.12-1.24), respectively) and of ER+/PR+ tumours. We found inverse associations between GGT levels and PR- breast cancers compared to PR+ (OR 0.87 (0.80-0.95)), between ER+/PR- tumours compared to ER+/PR+ tumours and between ER-/PR-/HER+ compared to ER+/HER2 or PR+/HER2 tumours (OR 0.55 (95% CI 0.34-0.90). CONCLUSION: The observed associations between pre-diagnostic serum GGT and different breast cancer subtypes may indicate distinct underlying pathways and require further investigations to tease out their clinical implications.

Circulating Prostate-Specific Antigen and Telomere Length in a Nationally Representative Sample of Men Without History of Prostate Cancer.

BACKGROUND: We investigated the association of prostate-specific antigen (PSA) with leukocyte telomere length, which may be altered in preclinical prostate malignancies. METHODS: This study was based on the 2001-2002 U.S. National Health and Nutrition Examination Survey (NHANES). A subsample of 1,127 men aged 40-85 years without prior history of prostate cancer who provided informed consent and blood samples were selected. Leukocyte telomere length (LTL) relative to standard DNA reference (T/S ratio) was quantified by polymerase chain reaction (PCR). Survey-weighted multivariable linear regression was performed to examine T/S ratio across quintiles of total and free PSA and free-to-total PSA ratio (%fPSA). A sensitivity analysis was performed by excluding men dying from prostate cancer during follow-up through to December 31, 2006. Stratification analyses were carried out to assess any effect modification by age group, race, body mass index (BMI), and levels of C-reactive protein (CRP), a marker of inflammation. RESULTS: Higher total PSA levels were associated to longer LTL, with approximately 8% increase in log-transformed T/S ratio (95% confidence interval [CI]: 2-13%) among men in the highest quintile of total PSA compared to the lowest in the fully adjusted model (Ptrend = 0.01). No significant association was found for free PSA or %fPSA, although nonlinearity between all PSA measures and T/S ratio was indicated. Similar results were found after excluding men who died from prostate cancer during follow-up. We also found the associations between total PSA and T/S ratio to be strongest among non-Hispanic blacks, non-obese men (BMI <30 kg/m2 ), and those with low CRP. However, a significant interaction was only found between total PSA and race/ethnicity (Pinteraction = 0.01). CONCLUSION: Total PSA levels were strongly associated to LTL, particularly among non-Hispanic blacks. Our findings support a potential link between PSA and specific mechanisms contributing to prostate cancer development. Prostate 77:22-32, 2017. © 2016 Wiley Periodicals, Inc.

Serum inflammatory markers and colorectal cancer risk and survival.

BACKGROUND: Inflammation has been linked with development of some cancers. We investigated systemic inflammation in relation to colorectal cancer incidence and subsequent survival using common serum inflammatory markersDesign:A cohort of men and women aged 20 years and older in greater Stockholm area with serum C-reactive protein (CRP) and albumin measured between 1986 and 1999 were included (n=325 599). A subset of these had baseline measurements of haptoglobin and leukocytes. Multivariable Cox regression was performed to assess risk of colorectal cancer by levels of inflammatory markers, adjusting for potential confounders. Analyses were stratified by circulating glucose, total cholesterol and triglycerides. Overall and CRC-specific death following diagnosis were assessed as secondary outcomes. RESULTS: A total of 4764 individuals were diagnosed with colorectal cancer. A positive association between haptoglobin and colorectal cancer incidence was found (hazard ratio (HR): 1.17; 95% CI: 1.06-1.28). A positive association was also observed with leukocytes (HR: 1.21; 95% CI: 1.03-1.42). No evidence of association was noted between CRP and colorectal cancer risk. Higher risks of all-cause death were seen with haptoglobin and leukocytes levels. Higher haptoglobin levels were linked with an increased risk of colorectal cancer death (HR: 1.19; 95% CI: 1.01-1.41). CONCLUSIONS: Prediagnostic systemic inflammation may impact colorectal cancer incidence and survival; therefore, prompting investigations linking inflammatory pathways preceding colorectal cancer with disease severity and progression.

Are you now a good surgeon? T2 positive margin status as a quality outcome measure following radical prostatectomy.

OBJECTIVE: To assess potential biases, such as the reporting pathologist, that may affect objectivity of T2 positive margin rates as a quality outcome measure following radical prostatectomy. PATIENTS AND METHODS: Prospective data on 183 consecutive LRP patients with pT2 disease, operated on by a single surgeon (2003-2009), were studied. Outcomes were grouped as pre-, peri-, and post-operative and included: age, ethnicity, Gleason score, reporting pathologist, percentage of positive cores, operative time, blood loss, nerve-sparing status, hospital stay and prostate weight. Descriptive analysis and logistic regression analysis were carried out to compare these variables by positive margin status. RESULTS: A total of 30 (16.4 %) positive surgical margins (PSMs) were reported. Surgical stage, earlier date of surgery, and lower prostatic weight showed statistically significant associations with PSM status in both univariate and multivariate analysis. The reporting pathologist was not found to be predictive of PSMs (P = 0.855). CONCLUSION: We showed that the reporting pathologist does not influence T2 positive margin status, in contrast to tumour characteristics and surgeon experience. T2 positive margin assessment therefore appears to be an objective quality outcome measure.

Cigarette smoking and telomere length: A systematic review of 84 studies and meta-analysis.

BACKGROUND: Cigarette smoking is a risk factor for ageing-related disease, but its association with biological ageing, indicated by telomere length, is unclear. METHODS: We systematically reviewed evidence evaluating association between smoking status and telomere length. Searches were performed in MEDLINE (Ovid) and EMBASE (Ovid) databases, combining variation of keywords "smoking" and "telomere". Data was extracted for study characteristics and estimates for association between smoking and telomere length. Quality of studies was assessed with a risk of bias score, and publication bias was assessed with a funnel plot. I2 test was used to observe heterogeneity. Meta-analysis was carried out to compare mean difference in telomere length by smoking status, and a dose-response approach was carried out for pack-years of smoking and telomere length. A sensitivity analysis was carried out to examine sources of heterogeneity. RESULTS: A total of 84 studies were included in the review, and 30 among them were included in our meta-analysis. Potential bias was addressed in half of included studies, and there was little evidence of small study bias. Telomere length was shorter among ever smokers compared to never smokers (summary standard mean difference [SMD]: -0.11 (95% CI -0.16 to -0.07)). Similarly, shorter telomere length was found among smokers compared to non-smokers, and among current smokers compared to never or former smokers. Dose-response meta-analysis suggested an inverse trend between pack-years of smoking and telomere length. However, heterogeneity among some analyses was observed. CONCLUSION: Shorter telomeres among ever smokers compared to those who never smoked may imply mechanisms linking tobacco smoke exposure to ageing-related disease.

Transposable Elements in Human Cancer: Causes and Consequences of Deregulation.

Transposable elements (TEs) comprise nearly half of the human genome and play an essential role in the maintenance of genomic stability, chromosomal architecture, and transcriptional regulation. TEs are repetitive sequences consisting of RNA transposons, DNA transposons, and endogenous retroviruses that can invade the human genome with a substantial contribution in human evolution and genomic diversity. TEs are therefore firmly regulated from early embryonic development and during the entire course of human life by epigenetic mechanisms, in particular DNA methylation and histone modifications. The deregulation of TEs has been reported in some developmental diseases, as well as for different types of human cancers. To date, the role of TEs, the mechanisms underlying TE reactivation, and the interplay with DNA methylation in human cancers remain largely unexplained. We reviewed the loss of epigenetic regulation and subsequent genomic instability, chromosomal aberrations, transcriptional deregulation, oncogenic activation, and aberrations of non-coding RNAs as the potential mechanisms underlying TE deregulation in human cancers.

Irinotecan chemotherapy combined with fluoropyrimidines versus irinotecan alone for overall survival and progression-free survival in patients with advanced and/or metastatic colorectal cancer.

BACKGROUND: Chemotherapy is the treatment of choice in patients with advanced or metastatic colorectal cancer (CRC) where surgical resection of metastases is not an option. Both irinotecan (IRI) and fluoropyrimidines are often included in first- or second- line chemotherapy treatment regimens in such patients. However, it is not clear whether combining these agents is superior to irinotecan alone. OBJECTIVES: To compare the efficacy and safety of two chemotherapeutic regimens, irinotecan monotherapy or irinotecan in combination with fluoropyrimidines, for patients with advanced CRC when administered in the first or second-line settings. SEARCH METHODS: We searched the following electronic databases to identify randomized controlled trials: Cochrane Colorectal Cancer Group Specialised Register (January 13, 2016), Cochrane Central Register of Controlled Trials (CENTRAL)(The Cochrane Library Issue 12, 2016), Ovid MEDLINE (1950 to January 13, 2016), Ovid EMBASE (1974 to January 13, 2016), registers of controlled trials in progress, references cited in relevant publications and conference proceedings in related fields (BioMed Central and Medscape's Conference). The key authors or investigators of all eligible studies, and professionals in the field were contacted when necessary. The search from January 2016 identified one eligible study, an ongoing trial currently presented as an abstract, to be considered in an update of this review. SELECTION CRITERIA: Randomized controlled trials (RCTs) investigating the efficacy and safety of IRI chemotherapy combined with fluoropyrimidine compared with IRI alone for the treatment of patients with advanced CRC, regardless of treatment line settings. DATA COLLECTION AND ANALYSIS: Study eligibility and methodological quality were assessed independently by the two authors, and any disagreement was solved by a third author. The data collected from the studies were reviewed qualitatively and quantitatively using the Cochrane Collaboration statistical software RevMan 5.3. MAIN RESULTS: Five studies were included in this review with a total of 1,726 patients. The top-up search resulted in an additional ongoing trial, the results of which have not been incorporated in this review. Among five included studies, no reduction in all-cause mortality was observed in the combination arm, with a summary hazard ratio (HR) of 0.91 (95% CI: 0.81-1.02). Longer progression-free survival was observed in those treated with the combination chemotherapy (HR: 0.68, 95% CI: 0.53-0.87), however, this result may have been driven by findings from the single first-line treatment setting study.The quality of evidence for overall survival was low and for progression-free survival was moderate, mainly due to study limitation from the lack of information on randomisation methods and allocation concealment.There were higher risks of toxicity outcomes grade 3 or 4 diarrhoea and grade 1 or 2 alopecia, and a lower risk of grade 3 or 4 neutropenia in controls compared to the invervention group. Evidence for toxicity has been assessed to be low to moderate quality. AUTHORS' CONCLUSIONS: There was no overall survival benefit of the irinotecan and fluoropyrimidine treatment over irinotecan alone, thus both regimens remain reasonable options in treating patients with advanced or metastatic CRC. Given the low and moderate quality of the evidence, future studies with sufficient numbers of patients in each treatment arms are needed to clarify the benefit observed in progression-free survival with combination irinotecan and fluoropyrimidines.

Serum Calcium and the Risk of Breast Cancer: Findings from the Swedish AMORIS Study and a Meta-Analysis of Prospective Studies.

To investigate the association between serum calcium and risk of breast cancer using a large cohort and a systematic review with meta-analysis. From the Swedish Apolipoprotein Mortality Risk (AMORIS) Study we included 229,674 women who had baseline measurements of serum total calcium and albumin. Multivariable Cox regression was used to assess the association between total and albumin-corrected calcium and breast cancer risk. For the systematic review, an electronic search of MEDLINE and EMBASE databases was performed to identify other prospective cohorts assessing the relationship between serum calcium and breast cancer risk. We pooled the results of our AMORIS cohort with other eligible studies in a meta-analysis using a random effects model. I² test was used to assess heterogeneity. In the AMORIS study, 10,863 women were diagnosed with breast cancer (mean follow-up: 19 years). We found an inverse association between total serum calcium and breast cancer when comparing the fourth quartile to the first quartile (HR: 0.94, 95% CI: 0.88-0.99, p value for trend 0.04) and similar results using albumin-corrected calcium. In the systematic review, we identified another two prospective cohorts evaluating pre-diagnostic serum total calcium and breast cancer. Combining these studies and our findings in AMORIS in a meta-analysis showed a protective effect of serum calcium against breast cancer, with a summary RR of 0.80 (95% CI: 0.66-0.97). No substantial heterogeneity was observed. Our findings in AMORIS and the meta-analysis support an inverse association between serum calcium and breast cancer risk, which warrants mechanistic investigations.

Prediagnostic serum inflammatory markers in relation to breast cancer risk, severity at diagnosis and survival in breast cancer patients.

Inflammation has been linked to cancer but its role in breast cancer is unclear. We investigated common serum markers of inflammation: C-reactive protein (CRP), albumin, haptoglobin and white blood cells (WBC) in relation to breast cancer incidence, severity and survival. A total of 155179 women aged 20 and older without any history of cancer were selected from a large Swedish cohort. Hazard ratios (HRs) for breast cancer were estimated with Cox regression, adjusting for potential confounders. Ordered and binomial logistic regression models were used to assess the associations of serum inflammatory markers with breast cancer severity and oestrogen receptor (ER) positivity at diagnosis, on the other. Cumulative incidence functions by levels of inflammatory markers were assessed for early death from breast cancer and all causes. During a mean follow-up of 18.3 years, 6606 women were diagnosed with breast cancer, of whom 1474 died. A positive association with incident breast cancer was seen for haptoglobin ≥ 1.4g/l [HR 1.09; 95% confidence interval (CI): 1.00-1.18] compared to lower levels. No association was observed between inflammatory markers and breast cancer severity or ER positivity. Higher haptoglobin was linked to risk of early death from breast cancer (HR: 1.27, 95% CI: 1.02-1.59), whereas higher risk of early death from all causes was additionally found with CRP ≥ 10mg/l (HR: 1.19, 95% CI: 1.04-1.36) and WBC ≥ 10×10(9)/l (HR: 1.57, 1.14-2.16). Our findings indicate that prediagnostic serum inflammatory markers were weakly linked to incident breast cancer but corresponded to worse survival after diagnosis.

Serum lactate dehydrogenase and survival following cancer diagnosis.

BACKGROUND: There is evidence that high level of serum lactate dehydrogenase (LDH) is associated with poorer overall survival in several malignancies, but its link to cancer-specific survival is unclear. METHODS: A total of 7895 individuals diagnosed with cancer between 1986 and 1999 were selected for this study. Multivariable Cox proportional hazards regression was used to assess overall and cancer-specific death by the z-score and clinical categories of serum LDH prospectively collected within 3 years before diagnosis. Site-specific analysis was performed for major cancers. Analysis was repeated by different lag times between LDH measurements and diagnosis. RESULTS: At the end of follow-up, 5799 participants were deceased. Hazard ratios (HRs) and 95% confidence intervals (CIs) for overall and cancer-specific death in the multivariable model were 1.43 (1.31-1.56) and 1.46 (1.32-1.61), respectively, for high compared with low prediagnostic LDH. Site-specific analysis showed high LDH to correlate with an increased risk of death from prostate, pulmonary, colorectal, gastro-oesophageal, gynaecological and haematological cancers. Serum LDH assessed within intervals closer to diagnosis was more strongly associated with overall and cancer-specific death. CONCLUSIONS: Our findings demonstrated an inverse association of baseline serum LDH with cancer-specific survival, corroborating its role in cancer progression.