Japanese cancer screening programs during the COVID-19 pandemic: Changes in participation between 2017-2020

BackgroundThe impact of the coronavirus disease 2019 (COVID-19) pandemic on cancer screening participation is a global concern. A national database of screening performance is available in Japan for population-based cancer screening, estimated to cover approximately half of all cancer screenings.MethodsUtilizing the fiscal year (FY) 2017–2020 national database, the number of participants in screenings for gastric cancer (upper gastrointestinal [UGI] series or endoscopy), colorectal cancer (fecal occult blood test), lung cancer (chest X-ray), breast cancer (mammography), and cervical cancer (Pap smear) were identified. The percent change in the number of participants was calculated.ResultsCompared with the pre-pandemic period (FY 2017–2019), in percentage terms FY 2020 recorded the largest decline in gastric cancer UGI series (2.82 million to 1.91 million, percent change was −32.2 %), followed by screening for breast cancer (3.10 million to 2.57 million, percent change was −17.2 %), lung cancer (7.92 million to 6.59 million, percent change was −16.7 %), colorectal cancer (8.42 million to 7.30 million, percent change was −13.4 %), cervical cancer (4.26 million to 3.77 million, percent change was −11.6 %), and gastric cancer via endoscopy (1.02 million to 0.93 million, percent change was −9.0 %).ConclusionThe number of participants in population-based screenings in Japan decreased by approximately 10–30 % during the pandemic. The impact of these declines on cancer detection or mortality should be carefully monitored.     

Signaling in colon cancer stem cells

ABSTRACT: Colorectal cancer is the fourth most common form of cancer worldwide and ranks third among the cancer-related deaths in the US and other Western countries. It occurs with equal frequency in men and women, constituting 10 percent of new cancer cases in men and 11percent in women. Despite recent advancement in therapeutics, the survival rates from metastatic are less than 5 percent. Growing evidence supports the contention that epithelial cancers including colorectal cancer, the incidence of which increases with aging, are diseases driven by the pluripotent, self-renewing cancer stem cells (CSCs). Dysregulation of Wnt, Notch, Hedgehog and/or TGF-beta signaling pathways that are involved in proliferation and maintenance of CSCs leads to the development of CRC. This review focuses on the signaling pathways relevant for CRC to understand the mechanisms leading to tumor progression and therapy resistance, which may help in the development of therapeutic strategies for CRC.     

Non-coding RNAs as emerging regulators and biomarkers in colorectal cancer

Molecular and Cellular Biochemistry - CRC is the third most common cancer occurring worldwide and the second leading cause of cancer deaths. In the year 2020, 1,931,590 new cases of CRC and 935,173...     

Colorectal cancer screening for average-risk North Americans: an economic evaluation

Background

Colorectal cancer (CRC) fulfills the World Health Organization criteria for mass screening, but screening uptake is low in most countries. CRC screening is resource intensive, and it is unclear if an optimal strategy exists. The objective of this study was to perform an economic evaluation of CRC screening in average risk North American individuals considering all relevant screening modalities and current CRC treatment costs.

Methods and Findings

An incremental cost-utility analysis using a Markov model was performed comparing guaiac-based fecal occult blood test (FOBT) or fecal immunochemical test (FIT) annually, fecal DNA every 3 years, flexible sigmoidoscopy or computed tomographic colonography every 5 years, and colonoscopy every 10 years. All strategies were also compared to a no screening natural history arm. Given that different FIT assays and collection methods have been previously tested, three distinct FIT testing strategies were considered, on the basis of studies that have reported “low,” “mid,” and “high” test performance characteristics for detecting adenomas and CRC. Adenoma and CRC prevalence rates were based on a recent systematic review whereas screening adherence, test performance, and CRC treatment costs were based on publicly available data. The outcome measures included lifetime costs, number of cancers, cancer-related deaths, quality-adjusted life-years gained, and incremental cost-utility ratios. Sensitivity and scenario analyses were performed. Annual FIT, assuming mid-range testing characteristics, was more effective and less costly compared to all strategies (including no screening) except FIT-high. Among the lifetimes of 100,000 average-risk patients, the number of cancers could be reduced from 4,857 to 1,782 and the number of CRC deaths from 1,393 to 457, while saving CAN$68 per person. Although screening patients with FIT became more expensive than a strategy of no screening when the test performance of FIT was reduced, or the cost of managing CRC was lowered (e.g., for jurisdictions that do not fund expensive biologic chemotherapeutic regimens), CRC screening with FIT remained economically attractive.

Conclusions

CRC screening with FIT reduces the risk of CRC and CRC-related deaths, and lowers health care costs in comparison to no screening and to other existing screening strategies. Health policy decision makers should consider prioritizing funding for CRC screening using FIT. Please see later in the article for the Editors'' Summary     

Increased incidence of colon cancer among individuals younger than 50 years: A 17 years analysis from the cancer registry of the municipality of Milan,Italy

BackgroundColorectal cancer (CRC) overall incidence has been decreasing in the last decade. However, there is evidence of an increasing frequency of early-onset CRC in young individuals in several countries. The aim of this study is to evaluate the trends of CRC occurrence over 17 years in the municipality of Milan, Italy, focusing on early-onset CRC.Population and methodsThis retrospective study was performed using the Cancer Registry of the municipality of Milan, including all cases of CRC diagnosed 1999-2015. Incidence rates were stratified by age and anatomic subsite, and trends over time were measured using the estimated annual percentage change. Age-period-cohort modelling was used to disentangle the different effects.Results18,783 cases of CRC were included. CRC incidence rates among individuals aged 50–60 years declined annually by 3% both in colon and in rectal cancer. Conversely, in adults younger than 50 years, overall CRC occurrence increased annually by 0.7%, with a diverging trend for colon (+2.6%) and rectal (−5.3%) cancer. Among individuals aged 60 years and older, CRC incidence rates increased by 1.0% annually up to 2007, and decrease thereafter by 4% per year, both for colon and rectal cancer. Age-period-cohort models showed a reduction of CRC risk for the cohorts born up to 1979, followed by an increase in younger cohorts. In contrast, rectal cancer among women showed a systematic risk decrease for all birth cohorts.ConclusionsThe study highlights increasing incidence of colon cancer in younger subjects and a decrease in incidence rates for rectal cancer in females.     

Healthy lifestyle,endoscopic screening,and colorectal cancer incidence and mortality in the United States: A nationwide cohort study

BackgroundHealthy lifestyle and screening represent 2 major approaches to colorectal cancer (CRC) prevention. It remains unknown whether the CRC-preventive benefit of healthy lifestyle differs by endoscopic screening status, and how the combination of healthy lifestyle with endoscopic screening can improve CRC prevention.Methods and findingsWe assessed lifestyle and endoscopic screening biennially among 75,873 women (Nurses’ Health Study, 1988 to 2014) and 42,875 men (Health Professionals Follow-up Study, 1988 to 2014). We defined a healthy lifestyle score based on body mass index, smoking, physical activity, alcohol consumption, and diet. We calculated hazard ratios (HRs) and population-attributable risks (PARs) for CRC incidence and mortality in relation to healthy lifestyle score according to endoscopic screening. Participants’ mean age (standard deviation) at baseline was 54 (8) years. During a median of 26 years (2,827,088 person-years) follow-up, we documented 2,836 incident CRC cases and 1,013 CRC deaths. We found a similar association between healthy lifestyle score and lower CRC incidence among individuals with and without endoscopic screening, with the multivariable HR per one-unit increment of 0.85 (95% CI, 0.80 to 0.90) and 0.85 (95% CI, 0.81 to 0.88), respectively (P-interaction = 0.99). The fraction of CRC cases that might be prevented (PAR) by endoscopic screening alone was 32% (95% CI, 31% to 33%) and increased to 61% (95% CI, 42% to 75%) when combined with healthy lifestyle (score = 5). The corresponding PAR (95% CI) increased from 15% (13% to 16%) to 51% (17% to 74%) for proximal colon cancer and from 47% (45% to 50%) to 75% (61% to 84%) for distal CRC. Results were similar for CRC mortality. A limitation of our study is that our study participants are all health professionals and predominantly whites, which may not be representative of the general population.ConclusionsOur study suggests that healthy lifestyle is associated with lower CRC incidence and mortality independent of endoscopic screening. An integration of healthy lifestyle with endoscopic screening may substantially enhance prevention for CRC, particularly for proximal colon cancer, compared to endoscopic screening alone.

Kai Wang and colleagues study contributions of healthy lifestyles and endoscopic screening to colorectal cancer outcomes.     

Subsite- and stage-specific colorectal cancer trends in Estonia prior to implementation of screening

BackgroundThe occurrence of colorectal cancer (CRC) in Estonia has been characterised by increasing incidence, low survival and no screening. The study aimed to examine long-term incidence and survival trends of CRC in Estonia with specific focus on subsite and stage.MethodsWe analysed CRC incidence and relative survival using Estonian Cancer Registry data on all cases of colorectal cancer (ICD-10 C18–21) diagnosed in 1995–2014. TNM classification was used to categorise stage.ResultsAge-standardized incidence of colon cancer increased both in men and women at a rate of approximately 1% per year. Significant increase was seen for right-sided tumours, but not for left-sided tumours. Rectal cancer incidence increased significantly only in men and anal cancer incidence only in women. Age-standardized five-year relative survival for colon cancer increased from 50% in 1995–1999 to 59% in 2010–2014; for rectal cancer, from 38% to 56%. Colon cancer survival improved significantly for left-sided tumours (from 51% to 62%) and stage IV disease (from 6% to 15%). For rectal cancer, significant survival gain was seen for stage II (from 58% to 75%), stage III (from 34% to 70%) and stage IV (from 1% to 12%).ConclusionIn the pre-screening era in Estonia, increase in colon cancer incidence was limited to right-sided tumours. Large stage-specific survival gain, particularly for rectal cancer, was probably due to better staging and advances in multimodality treatment. Nonetheless, more than one quarter of new CRC cases are diagnosed at stage IV, emphasising the need for an efficient screening program.     

MSH2 c.1452-1455delAATG is a founder mutation and an important cause of hereditary nonpolyposis colorectal cancer in the southern Chinese population

Hereditary nonpolyposis colorectal cancer (HNPCC) accounts for approximately 2% of all colorectal cancer (CRC) cases and is the most common hereditary CRC syndrome. We have previously reported a high incidence of microsatellite instability (MSI) and germline mismatch repair (MMR) gene mutations in young Hong Kong Chinese with CRC. Ongoing studies at the Hereditary Gastrointestinal Cancer Registry in Hong Kong have revealed a unique germline MSH2 c.1452-1455delAATG mutation that has not been reported in other ethnic groups. Detailed analysis showed that this specific MSH2 mutation constituted 21% of all germline MMR gene mutations and 36% of all MSH2 germline mutations identified. We designed a specific PCR-based diagnostic test on paraffin-embedded tissues and identified this germline mutation in 2 (1.5%) of 138 consecutive patients with early-onset CRC (<46 years of age at diagnosis). Haplotype analysis was performed using 11 microsatellite markers located between D2S391 and D2S123. All 10 families had the same disease haplotype, suggesting a founder effect. These 10 families all originated from the Chinese province of Guangdong, which historically included Hong Kong. It is the most populous of the Chinese provinces, with a population of >93 million. Further analysis suggested that this founder mutation may date back to between 22 and 103 generations ago. The identification of this MSH2 founder mutation has important implications for the design of mutation-detection strategies for the southern Chinese population. Since there were major emigrations from Hong Kong and Guangdong province during the 19th and 20th centuries, this finding is also significant for Chinese communities worldwide.     

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.     

Breast cancer and the environment

The most recent estimate of the overall worldwide burden of cancer is that in the year 2000 more than 10 million new cancer cases occurred and approximately 6 million cancer deaths. Breast cancer accounts for about 1 in 10 cancers and is the most frequent cancer affecting women. Since 10% of all cancers in the world are breast cancer (only affecting half of the population as breast cancer almost exclusively concerns only women), it is being considered an epidemic. In terms of the absolute number of incident cases, breast cancer now ranks first not only in the industrialized world but also in the developing world. The worldwide mortality figure for the year 2000 was 370,000. However, there are marked geographical differences, with Africa and Asia currently having incidence rates some 10 times lower than those of North America and northern Europe. Studies of migrant populations have long indicated that the genetic background only plays a tiny, if any, role in these differences. Over time, clear increases have been seen in the global number of cases: from 572,000 in 1980 to 1,050,000 in 2000. This corresponds not only to a modest increase in incidence rates in countries with a long history of frequent breast cancer but also to marked increases in countries with previously low rates. The reasons for these increases are currently unexplained and a possible hypothesis relates to environmental factors. By contrast, in a number of countries in the western world mortality rates are stable, and, in the USA and the United Kingdom, even decreasing slightly. The aetiology of breast cancer has been the subject of hundreds of studies since the pioneering investigation of Lane Claypon in 1926. Risk factors belong to different domains: reproductive life, hormonal factors, diet, genetics (BRCA1, BRCA2) and exposure to radiation and selected chemicals. Yet, much breast cancer remains unexplained and new aetiological links must be sought such as occupational factors and exposure to pesticides and other endocrine disrupters. A recent international summit on breast cancer and the environment outlined the need for more research to be conducted into the effects of exposure in the vicinity of nuclear power plants or chemical landfill sites and, more generally, into contaminants in food, air, water and soil. This is particularly relevant in some parts of the world such as Africa.     

Cost-Effectiveness of Colorectal Cancer Screening Protocols in Urban Chinese Populations

Colorectal cancer (CRC) takes a second and fourth position in the incidence and mortality lists respectively among all malignant tumors in urban populations in China. This study was designed to evaluate the cost-effectiveness of two different CRC screening protocols: faecal occult blood test (FOBT) alone, and FOBT plus a high-risk factor questionnaire (HRFQ) as the respective initial screens, followed by colonoscopy. We developed a Markov model to simulate the progression of a cohort of 100,000 average risk asymptomatic individuals moving through a defined series of states between the ages of 40 to 74 years. The parameters used for the modeling came from the CESP (Comparison and Evaluation of Screening Programs for Colorectal Cancer in Urban Communities in China) study and published literature. Eight CRC screening scenarios were tested in the Markov model. The cost-effectiveness of CRC screening under each scenario was measured by an incremental cost-effectiveness ratio (ICER) compared with a scenario without CRC screening. The study revealed that a combined use of FOBT and HRFQ is preferable in CRC screening programs as an initial screening instrument. Annual FOBT+HRFQ screening is recommended for those who have a negative initial result and those who have a positive result but have failed to continue to colonoscopic examination. Repeated colonoscopy (for those with a positive result in initial screening but a negative colonoscopy result) should be performed at a ten-year interval instead of one-year. Such a protocol would cost 7732 Yuan per life year saved, which is the most cost-effective option. In conclusion, the current Chinese Trial Version for CRC Screening Strategy should be revised in line with the most cost-effective protocol identified in this study.     

Iron chelation inhibits cancer cell growth and modulates global histone methylation status in colorectal cancer

Colorectal cancer (CRC) is one of the most common malignancies worldwide, and new treatment strategies for CRC are required because of the existing chemotherapy resistance. Iron chelators, which have been used widely for the treatment of iron-overload disease, were reported to exert anti-proliferative effects in cancer. However, the role of iron chelation in CRC was largely unknown. In this study, we found that the iron chelator DFO inhibited CRC cell growth significantly. In addition, the gene expression profile was greatly changed by DFO treatment, and many cell growth-related genes were dysregulated. Further study showed that DFO induced a significant increase in global histone methylation in CRC cells. However, the levels of histone methyltransferases and histone demethylases did not change in response to DFO treatment, implying that the enzymatic activity of these enzymes might be regulated by iron chelation. In conclusion, this study reveals a novel role for DFO in CRC cell growth, and is the first to demonstrate that global histone methylation is modulated by iron chelation in CRC cells.     

Colorectal cancer incidence in Germany: Stage-shift 6 years after implementation of a colonoscopy screening program

Background: In 2002, colonoscopy was introduced as a tool for colorectal cancer screening in Germany. The long-term objective was to reduce the incidence in colorectal cancer (CRC) by detection and removal of advanced adenomas. Currently, the effect of colonoscopy screening on the population-based incidence of CRC in Germany is unknown. Methods: We provide data on stage-specific (age-standardized) incidence rates in three federal states in Germany, 6 years after the implementation of colonoscopy. Results: Between 2002 and 2008 a statistically significant decrease in CRC incidence could be observed (annually 3.0%, 95% confidence interval [CI]: -3.8; -2.2). The decline could be observed in all advanced tumor categories (T2, T3, and T4), whereas the incidence of in situ carcinomas (Tis) increased annually by 51.6% (95% CI: 28.0; 79.4) until 2004, and remained stable until 2008. Conclusion: The observed changes cannot be attributed definitively to the screening activities, but the presented data support a possible causal association.     

Should Flanders consider lowering its target age for colorectal cancer screening to 45–49?

IntroductionColorectal cancer (CRC) screening generally starts screening by the age of 50 based on guidelines. Lately however, a U.S. guideline recommended to start CRC screening from age 45 and, very recently, two studies were published that addressed young-onset in Europe (in part) (Vuik et al., 2019; Araghi et al., 2019).Materials and MethodsFlemish CRC incidence and mortality data contextualise trend results for age groups under 50 and what the implications could be for practice.ResultsCRC incidence rates showed considerable variability over a 12-year period without a clear increase in disease burden for the age group 45–49 in Flanders. In several age groups under 39 an increasing incidence trend was visible for both genders. Data was analysed in a period where no CRC screening was present in Flanders.DiscussionDecreasing the target age for the Flemish CRC screening does not seem to be straightforward and primary prevention should be considered more prominently.     

The association of diet,gut microbiota and colorectal cancer: what we eat may imply what we get

Despite the success of colonoscopy screening and recent advances in cancer treatment, colorectal cancer (CRC) still remains one of the most commonly diagnosed and deadly cancers, with a significantly increased incidence in developing countries where people are adapting to Western lifestyle. Diet has an important impact on risk of CRC. Multiple epidemiological studies have suggested that excessive animal protein and fat intake, especially red meat and processed meat, could increase the risk of developing CRC while fiber could protect against colorectal tumorigenesis. Mechanisms have been investigated by animal studies.Diet could re-shape the community structure of gut microbiota and influence its function by modulating the production of metabolites. Butyrate, one of the short-chain fatty acids (SCFAs), which act as a favorable source for colonocytes, could protect colonic epithelial cells from tumorigenesis via anti-inflammatory and antineoplastic properties through cell metabolism, microbiota homeostasis, antiproliferative, immunomodulatory and genetic/epigenetic regulation ways. In contrast, protein fermentation and bile acid deconjugation, which cause damage to colonic cells through proinflammatory and proneoplastic ways, lead to increasedriskofdevelopingCRC.In conclusion, abalanced diet with an increased abundance of fiber should be adopted to reduce the risk and prevent CRC.     

Blood-Based Protein Biomarker Panel for the Detection of Colorectal Cancer

Background

The majority of colorectal cancer (CRC) cases are preventable by early detection and removal of precancerous polyps. Even though CRC is the second most common internal cancer in Australia, only 30 per cent of the population considered to have risk factors participate in stool-based test screening programs. Evidence indicates a robust, blood-based, diagnostic assay would increase screening compliance. A number of potential diagnostic blood-based protein biomarkers for CRC have been reported, but all lack sensitivity or specificity for use as a stand-alone diagnostic. The aim of this study was to identify and validate a panel of protein-based biomarkers in independent cohorts that could be translated to a reliable, non-invasive blood-based screening test.

Principal Findings

In two independent cohorts (n = 145 and n = 197), we evaluated seven single biomarkers in serum of CRC patients and age/gender matched controls that showed a significant difference between controls and CRC, but individually lack the sensitivity for diagnostic application. Using logistic regression strategies, we identified a panel of three biomarkers that discriminated between controls and CRC with 73% sensitivity at 95% specificity, when applied to either of the two cohorts. This panel comprised of Insulin like growth factor binding protein 2 (IGFBP2), Dickkopf-3 (DKK3), and Pyruvate kinase M2(PKM2).

Conclusions

Due to the heterogeneous nature of CRC, a single biomarker is unlikely to have sufficient sensitivity or specificity for use as a stand-alone diagnostic screening test and a panel of markers may be more effective. We have identified a 3 biomarker panel that has higher sensitivity and specificity for early stage (Stage I and -II) disease than the faecal occult blood test, raising the possibility for its use as a non-invasive blood diagnostic or screening test.