Showing papers in "International Journal of Cancer in 2013"
TL;DR: The latest estimates of global cancer incidence and survival were used to update previous figures of limited duration prevalence to the year 2008 and highlight the need for long‐term care targeted at managing patients with certain very frequently diagnosed cancer forms.
Abstract: Recent estimates of global cancer incidence and survival were used to update previous figures of limited duration prevalence to the year 2008. The number of patients with cancer diagnosed between 2004 and 2008 who were still alive at the end of 2008 in the adult population is described by world region, country and the human development index. The 5-year global cancer prevalence is estimated to be 28.8 million in 2008. Close to half of the prevalence burden is in areas of very high human development that comprise only one-sixth of the world's population. Breast cancer continues to be the most prevalent cancer in the vast majority of countries globally; cervix cancer is the most prevalent cancer in much of Sub-Saharan Africa and Southern Asia and prostate cancer dominates in North America, Oceania and Northern and Western Europe. Stomach cancer is the most prevalent cancer in Eastern Asia (including China); oral cancer ranks as the most prevalent cancer in Indian men and Kaposi sarcoma has the highest 5-year prevalence among men in 11 countries in Sub-Saharan Africa. The methods used to estimate point prevalence appears to give reasonable results at the global level. The figures highlight the need for long-term care targeted at managing patients with certain very frequently diagnosed cancer forms. To be of greater relevance to cancer planning, the estimation of other time-based measures of global prevalence is warranted.
1,782 citations
TL;DR: Findings provide support that primary and secondary prevention can halt and reverse the observed increasing burden of melanoma, and indicate that those prevention measures require further endorsement in many countries.
Abstract: The incidence of cutaneous malignant melanoma has steadily increased over the past 50 years in predominately fair-skinned populations. This increase is reported to have leveled off recently in several Northern and Western European countries, Australia, New Zealand and in North America. We studied the global patterns and time trends in incidence of melanoma by country and sex, with a focus on and age- and cohort-specific variations. We analyzed the incidence data from 39 population-based cancer registries, examining all-ages and age-truncated standardized incidence rates of melanoma, estimating the annual percentage change and incidence rate ratios from age-period-cohort models. Incidence rates of melanoma continue to rise in most European countries (primarily Southern and Eastern Europe), whereas in Australia, New Zealand, the U.S., Canada, Israel and Norway, rates have become rather stable in recent years. Indications of a stabilization or decreasing trend were observed mainly in the youngest age group (25-44 years). Rates have been rising steadily in generations born up to the end of the 1940s, followed by a stabilization or decline in rates for more recently born cohorts in Australia, New Zealand, the U.S., Canada and Norway. In addition to the birth cohort effect, there was a suggestion of a period-related influence on melanoma trends in certain populations. Although our findings provide support that primary and secondary prevention can halt and reverse the observed increasing burden of melanoma, they also indicate that those prevention measures require further endorsement in many countries.
562 citations
TL;DR: The depletion of the intracellular iron stores achieved by using the iron chelator deferoxamine (DFX) strikingly protects HCC cells from the cytotoxic effects of sorafenib, identifying ferroptosis as an effective mechanism for the induction of cell death in HCC.
Abstract: The multikinase inhibitor sorafenib is currently the treatment of reference for advanced hepatocellular carcinoma (HCC) In our report, we examined the cytotoxic effects of sorafenib on HCC cells We report that the depletion of the intracellular iron stores achieved by using the iron chelator deferoxamine (DFX) strikingly protects HCC cells from the cytotoxic effects of sorafenib The protective effect of the depletion of intracellular iron stores could not be explained by an interference with conventional forms of programmed cell death, such as apoptosis or autophagic cell death We also found that DFX did not prevent sorafenib from reaching its intracellular target kinases Instead, the depletion of intracellular iron stores prevented sorafenib from inducing oxidative stress in HCC cells We examined the possibility that sorafenib might exert a cytotoxic effect that resembles ferroptosis, a form of cell death in which iron-dependent oxidative mechanisms play a pivotal role In agreement with this possibility, we found that pharmacological inhibitors (ferrostatin-1) and genetic procedures (RNA interference against IREB-2) previously reported to modulate ferroptosis, readily block the cytotoxic effects of sorafenib in HCC cells Collectively, our findings identify ferroptosis as an effective mechanism for the induction of cell death in HCC Ferroptosis could potentially become a goal for the medical treatment of HCC, thus opening new avenues for the optimization of the use of sorafenib in these tumors
386 citations
TL;DR: Post‐transplant cancer risk varied by transplanted organ and by cancer site, with the bulk of the excess risk driven by an exceptionally high and accelerating risk of SCC.
Abstract: Organ transplant recipients are at increased risk of a wide range of malignancies, especially cutaneous squamous cell carcinomas (SCC). Few previous population-based studies have quantified and compared cancer risks according to graft type and with long-term follow-up. Using nationwide Swedish registers, we identified 10,476 recipients transplanted from 1970 to 2008 and followed them for cancer occurrence. Relative risks of cancer in comparison with the general population were expressed as standardized incidence ratios (SIR) and within the transplanted cohort as incidence rate ratios (IRR). During a total follow-up of 93,432 person-years, patients were diagnosed with 1,175 cancers excluding SCC, and with 2,231 SCC, SIRcancer excl SCC 2.4 (95% CI, 2.2–2.5); SIRSCC 121 (95% CI, 116–127). Cancer risks were most increased among heart and/or lung recipients SIRcancer excl SCC 3.3 (95% CI, 2.8–4.0); SIRSCC 198 (95% CI, 174–224), followed by kidney SIRcancer excl SCC 2.3 (95% CI, 2.1–2.4); SIRSCC 121 (95% CI, 116–127) and liver recipients SIRcancer excl SCC 2.3 (95% CI, 1.9–2.8); SIRSCC 32 (95% CI, 24–42). During follow-up, risk of cancer excluding SCC remained stable while risk of SCC tripled over 20 years irrespective of graft type, partly due to a subgroup of patients developing new SCCs at a rapidly increasing rate. In summary, post-transplant cancer risk varied by transplanted organ and by cancer site, with the bulk of the excess risk driven by an exceptionally high and accelerating risk of SCC. These findings underscore the importance of regular skin screening in organ transplant recipients.
293 citations
TL;DR: The identified miRNAs might be of potential use in the development of a multimarker blood‐based test to complement and improve early detection of breast cancer.
Abstract: In recent years, circulating miRNAs have attracted a great deal of attention as promising novel markers for various diseases. Here, we investigated their potential to serve as minimally invasive, early detection markers for breast cancer in blood plasma. We profiled miRNAs extracted from the plasma of early stage breast cancer patients (taken at the time-point of diagnosis) and healthy control individuals using TaqMan low-density arrays (TLDA). Selected candidates identified in the initial screen were further validated in an extended study cohort of 207 individuals including 127 sporadic breast cancer cases and 80 healthy controls via RT-qPCR. Four miRNAs (miR-148b, miR-376c, miR-409-3p and miR-801) were shown to be significantly upregulated in the plasma of breast cancer patients. ROC curve analysis showed that the combination of only three miRNAs (miR-148b, miR-409-3p and miR-801) had an equal discriminatory power between breast cancer cases and healthy controls as all four miRNAs together (AUC = 0.69). In conclusion, the identified miRNAs might be of potential use in the development of a multimarker blood-based test to complement and improve early detection of breast cancer. Such a multimarker blood test might for instance provide a prescreening tool, especially for younger women, to facilitate decisions about which individuals to recommend for further diagnostic tests.
244 citations
TL;DR: Crosstalk between the ZEB/miR‐200 axis and several signal transduction pathways activated at different stages of tumor development is reviewed and suggests that ZEB1 and ZEB2 may have different, possibly even opposing, roles in some forms of human cancer.
Abstract: Embryonic differentiation programs of epithelial-mesenchymal and mesenchymal-epithelial transition (EMT and MET) represent a mechanistic basis for epithelial cell plasticity implicated in cancer. Transcription factors of the ZEB protein family (ZEB1 and ZEB2) and several microRNA species (predominantly miR-200 family members) form a double negative feedback loop, which controls EMT and MET programs in both development and tumorigenesis. In this article, we review crosstalk between the ZEB/miR-200 axis and several signal transduction pathways activated at different stages of tumor development. The close association of ZEB proteins with these pathways is indirect evidence for the involvement of a ZEB/miR-200 loop in tumor initiation, progression and spread. Additionally, the configuration of signaling pathways involving ZEB/miR-200 loop suggests that ZEB1 and ZEB2 may have different, possibly even opposing, roles in some forms of human cancer.
230 citations
TL;DR: An updated review of the literature suggests that HPV self‐sampling could be an additional strategy that can improve screening performance compared to current cytology‐based call‐recall programs.
Abstract: This review elaborates on the accuracy and feasibility of human papillomavirus (HPV) self-sampling, i.e., offering self-sampling of (cervico-)vaginal cell material by women themselves in nonclinical settings for high-risk HPV (hrHPV) detection in the laboratory, for cervical screening. To that end a bibliographic database search (PubMed) was performed to identify studies (published between January 1992 and January 2012) that compared clinical accuracy of HPV testing on self-sampled material with that of cytology or HPV testing on clinician-taken samples, and studies comparing response to offering HPV self-sampling with a recall invitation. Overall, hrHPV testing on self-samples appeared to be at least as, if not more, sensitive for cervical intraepithelial neoplasia grade 2 or worse (CIN2+) as cytology on clinician-obtained cervical samples, though often less specific. In most studies, hrHPV testing on self- and clinician-sampled specimens is similarly accurate with respect to CIN2+ detection. Variations in clinical performance likely reflect the use of different combinations of collection devices and HPV tests. Because it is known that underscreened women are at increased risk of cervical cancer, targeting non-attendees of the screening program could improve the effectiveness of cervical screening. In developed countries offering self-sampling has shown to be superior to a recall invitation for cytology in re-attracting original non-attendees into the screening program. Additionally, self-testing has shown to facilitate access to cervical screening for women in low resource areas. This updated review of the literature suggests that HPV self-sampling could be an additional strategy that can improve screening performance compared to current cytology-based call-recall programs.
224 citations
TL;DR: An operational definition of “immunogenic modulation,” where exposure of tumor cells to nonlethal/sublethal doses of chemotherapy alters tumor phenotype to render the tumor more sensitive to CTL killing is provided.
Abstract: Certain chemotherapeutic regimens trigger cancer cell death while inducing dendritic cell maturation and subsequent immune responses. However, chemotherapy-induced immunogenic cell death (ICD) has thus far been restricted to select agents. In contrast, several chemotherapeutic drugs modulate antitumor immune responses, despite not inducing classic ICD. In addition, in many cases tumor cells do not die after treatment. Here, using docetaxel, one of the most widely used cancer chemotherapeutic agents, as a model, we examined phenotypic and functional consequences of tumor cells that do not die from ICD. Docetaxel treatment of tumor cells did not induce ATP or high-mobility group box 1 (HMGB1) secretion, or cell death. However, calreticulin (CRT) exposure was observed in all cell lines examined after chemotherapy treatment. Killing by carcinoembryonic antigen (CEA), MUC-1, or PSA-specific CD8(+) CTLs was significantly enhanced after docetaxel treatment. This killing was associated with increases in components of antigen-processing machinery, and mediated largely by CRT membrane translocation, as determined by functional knockdown of CRT, PERK, or CRT-blocking peptide. A docetaxel-resistant cell line was selected (MDR-1(+), CD133(+)) by continuous exposure to docetaxel. These cells, while resistant to direct cytostatic effects of docetaxel, were not resistant to the chemomodulatory effects that resulted in enhancement of CTL killing. Here, we provide an operational definition of "immunogenic modulation," where exposure of tumor cells to nonlethal/sublethal doses of chemotherapy alters tumor phenotype to render the tumor more sensitive to CTL killing. These observations are distinct and complementary to ICD and highlight a mechanism whereby chemotherapy can be used in combination with immunotherapy.
212 citations
TL;DR: Five‐year distant‐recurrence‐free‐interval (DRFI) probabilities confirmed the additional prognostic value of the 70‐gene signature to clinicopathological risk estimations such as AOL.
Abstract: The 70-gene signature (MammaPrint™) has been developed on retrospective series of breast cancer patients to predict the risk of breast cancer distant metastases. The microarRAy-prognoSTics-in-breast-cancER (RASTER) study was the first study designed to prospectively evaluate the performance of the 70-gene signature, which result was available for 427 patients (cT1-3N0M0). Adjuvant systemic treatment decisions were based on the Dutch CBO 2004 guidelines, the 70-gene signature and doctors' and patients' preferences. Five-year distant-recurrence-free-interval (DRFI) probabilities were compared between subgroups based on the 70-gene signature and Adjuvant! Online (AOL) (10-year survival probability <90% was defined as high-risk). Median follow-up was 61.6 months. Fifteen percent (33/219) of the 70-gene signature low-risk patients received adjuvant chemotherapy (ACT) versus 81% (169/208) of the 70-gene signature high-risk patients. The 5-year DRFI probabilities for 70-gene signature low-risk (n = 219) and high-risk (n = 208) patients were 97.0% and 91.7%. The 5-year DRFI probabilities for AOL low-risk (n = 132) and high-risk (n = 295) patients were 96.7% and 93.4%. For 70-gene signature low-risk-AOL high-risk patients (n = 124), of whom 76% (n = 94) had not received ACT, 5-year DRFI was 98.4%. In the AOL high-risk group, 32% (94/295) less patients would be eligible to receive ACT if the 70-gene signature was used. In this prospective community-based observational study, the 5-year DRFI probabilities confirmed the additional prognostic value of the 70-gene signature to clinicopathological risk estimations such as AOL. Omission of adjuvant chemotherapy as judged appropriate by doctors and patients and instigated by a low-risk 70-gene signature result, appeared not to compromise outcome.
211 citations
TL;DR: The role and clinical relevance of miR‐138 is demonstrated, providing a potential therapeutic strategy for suppression of ovarian cancer metastasis by targeting SOX4 and HIF‐1α pathways.
Abstract: Metastasis is the major factor affecting patient survival in ovarian cancer However, its molecular mechanisms remain unclear Our study used isogenic pairs of low- and high-invasive ovarian cancer cell lines to demonstrate the downregulation of miRNA-138 in the highly invasive cells, and its functioning as an inhibitor of cell migration and invasion An orthotopic xenograft mouse model further demonstrated that the expression of miRNA-138 inhibited ovarian cancer metastasis to other organs Results indicated that miR-138 directly targeted SRY-related high mobility group box 4 (SOX4) and hypoxia-inducible factor-1α (HIF-1α), and overexpression of SOX4 and HIF-1α effectively reversed the miR-138-mediated suppression of cell invasion Epidermal growth factor receptor acted as the downstream molecule of SOX4 by way of direct transcriptional control, whereas Slug was the downstream molecule of HIF-1α by way of proteasome-mediated degradation Analysis of human ovarian tumors further revealed downregulation of miR-138 and upregulation of SOX4 in late-stage tumors Patients with miR-138(low)/SOX(high) signature are predominant in late stage and tend to have malignant phenotypes including lymph nodes metastasis, larger ascites volume and higher tumor grade Our study demonstrates the role and clinical relevance of miR-138 in ovarian cancer cell invasion and metastasis, providing a potential therapeutic strategy for suppression of ovarian cancer metastasis by targeting SOX4 and HIF-1α pathways
208 citations
TL;DR: A comprehensive meta‐analysis of 20 published miRNA expression studies in lung cancer, including a total of 598 tumor and 528 non‐cancerous control samples, found that meta‐signature miRNAs cooperatively target functionally related and biologically relevant genes in signaling and developmental pathways.
Abstract: The prognostic and diagnostic value of microRNA (miRNA) expression aberrations in lung cancer has been studied intensely in recent years. However, due to the application of different technological platforms and small sample size, the miRNA expression profiling efforts have led to inconsistent results between the studies. We performed a comprehensive meta-analysis of 20 published miRNA expression studies in lung cancer, including a total of 598 tumor and 528 non-cancerous control samples. Using a recently published robust rank aggregation method, we identified a statistically significant miRNA meta-signature of seven upregulated (miR-21, miR-210, miR-182, miR-31, miR-200b, miR-205 and miR-183) and eight downregulated (miR-126-3p, miR-30a, miR-30d, miR-486-5p, miR-451a, miR-126-5p, miR-143 and miR-145) miRNAs. We conducted a gene set enrichment analysis to identify pathways that are most strongly affected by altered expression of these miRNAs. We found that meta-signature miRNAs cooperatively target functionally related and biologically relevant genes in signaling and developmental pathways. We have shown that such meta-analysis approach is suitable and effective solution for identification of statistically significant miRNA meta-signature by combining several miRNA expression studies. This method allows the analysis of data produced by different technological platforms that cannot be otherwise directly compared or in the case when raw data are unavailable.
TL;DR: Data using prospective structured smoking assessments demonstrate that current smoking increased long‐term OM and DSM risks as compared with recent quit and in disease sites with proportionately large recent quit cohorts (lung and head/neck).
Abstract: The effect of smoking on survival in cancer patients is limited by the lack of structured prospective assessments of smoking at diagnosis. To assess the effect of smoking at diagnosis on survival, structured smoking assessments were obtained in a cohort of 5,185 cancer patients within 30 days of a cancer diagnosis between 1982 and 1998. Hazard ratios (HRs) or odds ratios were generated to analyze the effects of smoking at diagnosis on overall mortality (OM) and disease-specific mortality (DSM) in a patient cohort from 13 disease sites containing at least 100 patients in each disease site. With a minimum of 12 years of follow-up, current smoking increased OM risk versus recent quit (HR 1.17), former (HR 1.29) and never smokers (HR 1.38) in the overall cohort. Current smoking increased DSM risk versus former (HR 1.23) and never smokers (HR 1.18). In disease sites with proportionately large (>20%) recent quit cohorts (lung and head/neck), current smoking increased OM and DSM risks as compared with recent quit. Current smoking increased mortality risks in lung, head/neck, prostate and leukemia in men and breast, ovary, uterus and melanoma in women. Current smoking was not associated with any survival benefit in any disease site. Data using prospective structured smoking assessments demonstrate that current smoking increased long-term OM and DSM. Standardized smoking assessment at diagnosis is an important variable for evaluating outcomes in cancer patients.
TL;DR: The accuracy of the test algorithm for HPV detection in FFPE tumor specimen is confirmed and a significant increase in the prevalence of HPV in OPSCC over the last two decades at the authors' center is found.
Abstract: Human papillomavirus (HPV) infection has been etiologically linked to oropharyngeal squamous cell carcinoma (OPSCC). The prevalence of HPV-positive OPSCC varies between studies, ranging from 20 to 90%. This may be related to the lack of a standardized HPV detection assay as well as to the time period in which HPV prevalence is investigated, as rising incidence rates are reported over the last decades. Here, we validated our previously defined test algorithm for HPV detection in formalin-fixed paraffin-embedded (FFPE) tumor specimen consisting of p16INK4A immunostaining followed by high-risk HPV DNA detection by GP5+/6+ PCR on the positive cases (Smeets et al., Int J Cancer 2007;121:2465-72). In addition, we analyzed HPV prevalence rates in OPSCCs in the years 1990-2010. The test algorithm was validated on a consecutive series of 86 OPSCCs collected during 2008-2011, of which both fresh frozen and FFPE samples were available. We performed HPV-E6 RT-PCR on the frozen samples as gold standard and applied the algorithm to the corresponding FFPE samples. The test algorithm showed an accuracy of 98%. Using the validated algorithm, we determined the presence of an oncogenic HPV infection in 240 OPSCCs of patients diagnosed in the years 1990-2010 at our center. A significant increase in the proportion of HPV-positive samples was observed, from 5.1% in 1990 to 29.0% in 2010 (p = 0.001). In conclusion, we confirmed the accuracy of the test algorithm for HPV detection in FFPE tumor specimen and we found a significant increase in the prevalence of HPV in OPSCC over the last two decades at our center.
TL;DR: This study demonstrates frequent presence of EpCAM‐positive CTC in patients with intermediate or advanced HCC and its prognostic value for OS with possible implications for future treatment stratification.
Abstract: Current imaging technologies do not sufficiently detect micrometastasis and therefore do not allow adequate stratification of patients with hepatocellular carcinoma (HCC) for curative or systemic therapy. In HCC, presence of stem cell-like, epithelial cell adhesion molecule (EpCAM)-positive cells correlates with tumor aggressiveness and formation of metastasis. Therefore, we investigated the prognostic relevance of EpCAM-positive circulating tumor cells (CTCs) in patients with HCC. Blood from 78 patients (19 patients in the control cohort and 59 patients with HCC) was tested for CTCs with the CellSearch™ system. Correlation analysis to overall survival (OS), the Barcelona Clinic Liver Cancer (BCLC) staging system, macroscopic and microscopic vascular invasion and alpha-fetoprotein (AFP) levels were performed. We detected ≥1 CTC in 18/59 HCC patients and in 1/19 patients with cirrhosis or benign hepatic tumor (p = 0.026). OS was significantly shorter (460 vs. 746 days) in the CTC-positive cohort (p = 0.017). Comparing BCLC stages, significant differences in CTC detection rates were also observed: BCLC stages A 1/9, B 6/31 and C 11/19 (p = 0.006). Ten of 18 patients with macroscopic and 10/16 patients with microscopic vascular invasion exhibited positive findings in CTC testing (p = 0.004 and p = 0.006). Furthermore, CTC results correlated to AFP (cutoff > 400 ng/mL) levels (p = 0.050). Our study demonstrates frequent presence of EpCAM-positive CTC in patients with intermediate or advanced HCC and its prognostic value for OS with possible implications for future treatment stratification.
University of Barcelona1, South University2, Institut Gustave Roussy3, National and Kapodistrian University of Athens4, Academy of Athens5, Harvard University6, Utrecht University7, Imperial College London8, University Medical Center Utrecht9, Wageningen University and Research Centre10, Cancer Epidemiology Unit11, University of Cambridge12, Prevention Institute13, Andalusian School of Public Health14, Aarhus University Hospital15, Lund University16, Umeå University17, University of Tromsø18, University of Oslo19
TL;DR: The findings show that adherence to a MD excluding alcohol was related to a modest reduced risk of BC in postmenopausal women, and this association was stronger in receptor‐negative tumors, which support the potential scope for BC prevention through dietary modification.
Abstract: Epidemiological evidence suggests that the Mediterranean diet (MD) could reduce the risk of breast cancer (BC). As evidence from the prospective studies remains scarce and conflicting, we investigated the association between adherence to the MD and risk of BC among 335,062 women recruited from 1992 to 2000, in ten European countries, and followed for 11 years on average. Adherence to the MD was estimated through an adapted relative Mediterranean diet (arMED) score excluding alcohol. Cox proportional hazards regression models were used while adjusting for BC risk factors. A total of 9,009 postmenopausal and 1,216 premenopausal first primary incident invasive BC were identified (5,862 estrogen or progesterone receptor positive [ER+/PR+] and 1,018 estrogen and progesterone receptor negative [ER-/PR-]). The arMED was inversely associated with the risk of BC overall and in postmenopausal women (high vs. low arMED score; hazard ratio [HR] = 0.94 [95% confidence interval [CI]: 0.88, 1.00] ptrend = 0.048, and HR = 0.93 [95% CI: 0.87, 0.99] ptrend = 0.037, respectively). The association was more pronounced in ER-/PR- tumors (HR = 0.80 [95% CI: 0.65, 0.99] ptrend = 0.043). The arMED score was not associated with BC in premenopausal women. Our findings show that adherence to a MD excluding alcohol was related to a modest reduced risk of BC in postmenopausal women, and this association was stronger in receptor-negative tumors. The results support the potential scope for BC prevention through dietary modification.
TL;DR: In Europe, HPV16 predominates in both HG‐CIN and ICC, whereas HPV18/45 are associated with a low median age of ICC, and the need for primary prevention of HPV16/18‐45‐related cervical lesions is supported.
Abstract: Knowledge of differences in human papillomavirus (HPV)-type prevalence between high-grade cervical intraepithelial neoplasia (HG-CIN) and invasive cervical cancer (ICC) is crucial for understanding the natural history of HPV-infected cervical lesions and the potential impact of HPV vaccination on cervical cancer prevention. More than 6,000 women diagnosed with HG-CIN or ICC from 17 European countries were enrolled in two parallel cross-sectional studies (108288/108290). Centralised histopathology review and standardised HPV-DNA typing were applied to formalin-fixed paraffin-embedded cervical specimens dated 2001-2008. The pooled prevalence of individual HPV types was estimated using meta-analytic methods. A total of 3,103 women were diagnosed with HG-CIN and a total of 3,162 with ICC (median ages: 34 and 49 years, respectively), of which 98.5 and 91.8% were HPV-positive, respectively. The most common HPV types in women with HG-CIN were HPV16/33/31 (59.9/10.5/9.0%) and in ICC were HPV16/18/45 (63.3/15.2/5.3%). In squamous cell carcinomas, HPV16/18/33 were most frequent (66.2/10.8/5.3%), and in adenocarcinomas, HPV16/18/45 (54.2/40.4/8.3%). The prevalence of HPV16/18/45 was 1.1/3.5/2.5 times higher in ICC than in HG-CIN. The difference in age at diagnosis between CIN3 and squamous cervical cancer for HPV18 (9 years) was significantly less compared to HPV31/33/'other' (23/20/17 years), and for HPV45 (1 year) than HPV16/31/33/'other' (15/23/20/17 years). In Europe, HPV16 predominates in both HG-CIN and ICC, whereas HPV18/45 are associated with a low median age of ICC. HPV18/45 are more frequent in ICC than HG-CIN and associated with a high median age of HG-CIN, with a narrow age interval between HG-CIN and ICC detection. These findings support the need for primary prevention of HPV16/18/45-related cervical lesions.
TL;DR: It is estimated that approximately half of HPV infections persist past 6 to 12 months, and repeat HPV testing at 12‐month intervals could identify women at increased risk of high‐grade cervical precancer due to persistent HPV infections.
Abstract: Persistent high-risk human papillomavirus (HR-HPV) infection is the strongest risk factor for high-grade cervical precancer. We performed a systematic review and meta-analysis of HPV persistence patterns worldwide. Medline and ISI Web of Science were searched through January 1, 2010 for articles estimating HPV persistence or duration of detection. Descriptive and meta-regression techniques were used to summarize variability and the influence of study definitions and characteristics on duration and persistence of cervical HPV infections in women. Among 86 studies providing data on over 100,000 women, 73% defined persistence as HPV positivity at a minimum of two time points. Persistence varied notably across studies and was largely mediated by study region and HPV type, with HPV-16, 31, 33 and 52 being most persistent. Weighted median duration of any-HPV detection was 9.8 months. HR-HPV (9.3 months) persisted longer than low-risk HPV (8.4 months), and HPV-16 (12.4 months) persisted longer than HPV-18 (9.8 months). Among populations of HPV-positive women with normal cytology, the median duration of any-HPV detection was 11.5 and HR-HPV detection was 10.9 months. In conclusion, we estimated that approximately half of HPV infections persist past 6 to 12 months. Repeat HPV testing at 12-month intervals could identify women at increased risk of high-grade cervical precancer due to persistent HPV infections.
TL;DR: This study shows that preoperative BMI is an independent prognostic indicator for survival among patients with RCC, and corroborated that high BMI significantly improved OS and CSS.
Abstract: Growing evidence suggests that obesity, an established cause of renal cell cancer (RCC), may also be associated with a better prognosis. To evaluate the association between RCC survival and obesity, we analyzed a large cohort of patients with RCC and undertook a meta-analysis of the published evidence. We collected clinical and pathologic data from 1,543 patients who underwent nephrectomy for RCC between 1994 and 2008 with complete follow-up through 2008. Patients were grouped according to BMI (kg/m(2) ): underweight <18.5, normal weight 18.5 to <23, overweight 23 to <25 and obese ≥25. We estimated survival using the Kaplan-Meier method and Cox proportional hazard models to examine the impact of BMI on overall survival (OS) and cancer-specific survival (CSS) with adjustment for covariates. We performed a meta-analysis of BMI and OS, CSS and recurrence-free survival (RFS) from all relevant studies using a random-effects model. The 5-year CSS increased from 76.1% in the lowest to 92.7% in the highest BMI category. A multivariate analysis showed higher OS [hazard ratio (HR) = 0.45; 95% CI: 0.29-0.68) and CSS (HR = 0.47; 95% CI: 0.29-0.77] in obese patients than in normal weight patients. The meta-analysis further corroborated that high BMI significantly improved OS (HR = 0.57; 95% CI: 0.43-0.76), CSS (HR = 0.59; 95% CI: 0.48-0.74) and RFS (HR = 0.49; 95% CI: 0.30-0.81). Our study shows that preoperative BMI is an independent prognostic indicator for survival among patients with RCC.
TL;DR: A screening of 1,039 CRC samples was performed to assess the prevalence of KRAS amplification in this tumor type and the role of this genetic alteration on the sensitivity to anti EGFR therapies and found it was mutually exclusive with KRAS mutations.
Abstract: KRAS mutations are the most common oncogenic event in colorectal cancer (CRC) progression and their occurrence is associated with lack of response to anti epidermal growth factor receptor (EGFR) targeted therapies. Using preclinical models and patients' samples we recently reported that the emergence of KRAS mutations but also KRAS amplification is associated with acquired resistance to the EGFR inhibitors cetuximab or panitumumab. We reasoned that KRAS amplification may also be responsible for primary resistance to these agents. Furthermore, while the prevalence of KRAS mutations has been well established in CRC, little is known about the frequency of KRAS amplification in large CRC series. We performed a screening of 1,039 CRC samples to assess the prevalence of KRAS amplification in this tumor type and further evaluated the role of this genetic alteration on the sensitivity to anti EGFR therapies. We detected KRAS amplification in 7/1,039 (0.67%) and 1/102 evaluable CRC specimens and cell lines, respectively. KRAS amplification was mutually exclusive with KRAS mutations. Tumors or cell lines harboring this genetic lesion are not responsive to anti-EGFR inhibitors. Although KRAS amplification is an infrequent event in CRC, it might be responsible for precluding response to anti-EGFR treatment in a small proportion of patients.
TL;DR: The abilities of RUNX proteins, in particular RUNX3, to integrate oncogenic signals or environmental cues and to initiate appropriate tumor suppressive responses are discussed.
Abstract: The Runt-related transcription factors (RUNX) belong to an ancient family of metazoan genes involved in developmental processes. Through multiple protein-interacting partners, RUNX proteins have been implicated in diverse signaling pathways and cellular processes. The frequent inactivation of RUNX genes in cancer indicates crucial roles for RUNX in tumor suppression. This review discusses the abilities of RUNX proteins, in particular RUNX3, to integrate oncogenic signals or environmental cues and to initiate appropriate tumor suppressive responses.
TL;DR: The seven serum miRNAs identified in this study hold potential as noninvasive biomarker for malignant astrocytomas and exhibited a global decrease in tumor tissues relative to normal tissues.
Abstract: The involvement of circulating microRNAs (miRNAs) in cancer and their potential as biomarkers of diagnosis and prognosis are becoming increasingly appreciated; however, little is known about circulating miRNA profiles in astrocytomas. In our study, we performed genome-wide serum miRNA analysis by the Solexa sequencing followed by validation conducted in the training and verification sets with a stem-loop quantitative reverse-transcription PCR (RT-qPCR) assay from serum samples of 122 untreated astrocytomas patients (WHO grades III–IV) and 123 normal controls. Identified miRNAs were subsequently examined in 55 grade II, 15 grade I astrocytomas, 11 astrogliosis, 42 other primary brain tumors and 8 tumor tissues from grades II–IV astrocytomas. In addition, paired serum samples before and after operation were collected from 14 malignant astrocytomas to determine the effect of surgery on the miRNAs' levels. A marked difference in serum miRNA profile was observed between high-grade astrocytomas and normal controls. Seven miRNAs were validated by RT-qPCR assay to be significantly decreased in grades II–IV patients (p < 0.001), including miR-15b*, miR-23a, miR-133a, miR-150*, miR-197, miR-497 and miR-548b-5p, and the seven-miRNA panel demonstrated a high sensitivity (88.00%) and specificity (97.87%) for malignant astrocytomas prediction. These identified miRNAs also exhibited a global decrease in tumor tissues relative to normal tissues. Furthermore, these miRNAs in serum were markedly elevated after operation (p < 0.001). In addition, some of these serum miRNAs were significantly different between malignant and benign cases, astrogliosis and other primary brain tumors. The seven serum miRNAs identified in our study hold potential as noninvasive biomarker for malignant astrocytomas.
TL;DR: A 24‐plex single nucleotide polymorphism profiling assay, called multiplex cell authentication (MCA), which could complement routine cell line authentication and replace the standard authentication STR technique in case of MSI cell lines.
Abstract: Use of false cell lines remains a major problem in biological research. Short tandem repeat (STR) profiling represents the gold standard technique for cell line authentication. However, mismatch repair (MMR)-deficient cell lines are characterized by microsatellite instability, which could force allelic drifts in combination with a selective outgrowth of otherwise persisting side lines, and, thus, are likely to be misclassified by STR profiling. On the basis of the high-throughput Luminex platform, we developed a 24-plex single nucleotide polymorphism profiling assay, called multiplex cell authentication (MCA), for determining authentication of human cell lines. MCA was evaluated by analyzing a collection of 436 human cell lines from the German Collection of Microorganisms and Cell Cultures, previously characterized by eight-loci STR profiling. Both assays showed a very high degree of concordance and similar average matching probabilities (~1 × 10(-8) for STR profiling and ~1 × 10(-9) for MCA). MCA enabled the detection of less than 3% of contaminating human cells. By analyzing MMR-deficient cell lines, evidence was obtained for a higher robustness of the MCA compared to STR profiling. In conclusion, MCA could complement routine cell line authentication and replace the standard authentication STR technique in case of MSI cell lines.
TL;DR: This work determined the plasma DNA size distribution and the fraction of mutated plasma DNA fragments with deep sequencing and an ultrasensitive mutation‐detection method, and described a biphasic distribution in a surprisingly high proportion of cancer patients, which may have important implications for tumor diagnosis and monitoring.
Abstract: With the increasing number of available predictive biomarkers, clinical management of cancer is becoming increasingly reliant on the accurate serial monitoring of tumor genotypes. We tested whether tumor-specific copy number changes can be inferred from the peripheral blood of patients with cancer. To this end, we determined the plasma DNA size distribution and the fraction of mutated plasma DNA fragments with deep sequencing and an ultrasensitive mutation-detection method, i.e., the Beads, Emulsion, Amplification, and Magnetics (BEAMing) assay. When analyzing the plasma DNA of 32 patients with Stage IV colorectal carcinoma, we found that a subset of the patients (34.4%) had a biphasic size distribution of plasma DNA fragments that was associated with increased circulating tumor cell numbers and elevated concentration of mutated plasma DNA fragments. In these cases, we were able to establish genome-wide tumor-specific copy number alterations directly from plasma DNA. Thus, we could analyze the current copy number status of the tumor genome, which was in some cases many years after diagnosis of the primary tumor. An unexpected finding was that not all patients with progressive metastatic disease appear to release tumor DNA into the circulation in measurable quantities. When we analyzed plasma DNA from 35 patients with metastatic breast cancer, we made similar observations suggesting that our approach may be applicable to a variety of tumor entities. This is the first description of such a biphasic distribution in a surprisingly high proportion of cancer patients which may have important implications for tumor diagnosis and monitoring.
TL;DR: Both prediagnosis and postdiagnosis PA were associated with reduced colorectal cancer‐specific mortality and all‐cause mortality.
Abstract: Several prospective cohort studies have examined the association between prediagnosis and/or postdiagnosis physical activity (PA) on colorectal cancer outcomes and reported conflicting results. To quantitatively assess this association, we have conducted a meta-analysis of prospective studies. Databases and reference lists of relevant studies were searched using MEDLINE and EMBASE up to January 2013. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated using random-effects models. For this meta-analysis, a total of seven prospective cohort studies were included. The analysis included 5,299 patients for prediagnosis PA and 6,348 patients for postdiagnosis PA, followed up over a period ranging from 3.8 to 11.9 years. The analyses showed that patients who participated in any amount of PA before diagnosis had a RR of 0.75 (95% CI: 0.65-0.87, p < 0.001) for colorectal cancer-specific mortality compared to patients who did not participate in any PA. Those who participated in high PA before diagnosis (vs. low PA) had a RR of 0.70 (95% CI: 0.56-0.87, p = 0.002). Similarly, patients who participated in any PA after diagnosis had a RR of 0.74 (95% CI: 0.58-0.95, p = 0.02) for colorectal cancer-specific mortality compared to patients who did not participate in any PA. Those who participated in high PA after diagnosis (vs. low PA) had a RR of 0.65 (95% CI: 0.47-0.92, p = 0.01). Similar inverse associations of prediagnosis or postdiagnosis PA were found for all-cause mortality. In conclusion, both prediagnosis and postdiagnosis PA were associated with reduced colorectal cancer-specific mortality and all-cause mortality.
TL;DR: A 3‐miRNA signature was found to be related to MIBC tumor aggressiveness and was associated with both recurrence‐free and overall survival in univariate analysis with a trend to significance in the multivariate analysis.
Abstract: The aim of this study was to evaluate the expression levels of microRNAs (miRNAs) in bladder tumors in order to identify miRNAs involved in bladder carcinogenesis with potential prognostic implications. Expression levels of miRNAs were assessed by quantitative real-time RT-PCR in 11 human normal bladder and 166 bladder tumor samples (86 non-muscle-invasive bladder cancer (NMIBC) and 80 muscle-invasive bladder cancer (MIBC)). The expression level of 804 miRNAs was initially measured in a well-defined series of seven NMIBC, MIBC and normal bladder samples (screening set). The most strongly deregulated miRNAs in tumor samples compared to normal bladder tissue were then selected for RT-PCR validation in a well-characterized independent series of 152 bladder tumors (validation set), and in six bladder cancer cell lines. Expression levels of these miRNAs were tested for their association with clinical outcome. A robust group of 15 miRNAs was found to be significantly deregulated in bladder cancer. Except for two miRNAs, miR-146b and miR-9, which were specifically upregulated in MIBC, the majority of miRNAs (n = 13) were deregulated in the same way in the two types of bladder tumors, irrespective of pathological stage : three miRNAs were upregulated (miR-200b, miR-182 and miR-138) and the other 10 miRNAs were downregulated (miR-1, miR-133a, miR-133b, miR-145, miR-143, miR-204, miR-921, miR-1281, miR-199a and miR-199b). A 3-miRNA signature (miR-9, miR-182 and miR-200b) was found to be related to MIBC tumor aggressiveness and was associated with both recurrence-free and overall survival in univariate analysis with a trend to significance in the multivariate analysis (p = 0.05). Our results suggested a promising individual prognostic value of these new markers.
University of Kiel1, Max Delbrück Center for Molecular Medicine2, International Agency for Research on Cancer3, Icahn School of Medicine at Mount Sinai4, Aarhus University5, Aarhus University Hospital6, French Institute of Health and Medical Research7, South University8, German Cancer Research Center9, National and Kapodistrian University of Athens10, Academy of Athens11, Harvard University12, Prevention Institute13, Imperial College London14, University Medical Center Utrecht15, Utrecht University16, Karolinska Institutet17, Andalusian School of Public Health18, University of Gothenburg19, Lund University20, Umeå University21, University of Cambridge22, Cancer Epidemiology Unit23
TL;DR: Evidence of an association between obesity, particularly abdominal obesity, and risk of HCC and GBC is provided and public health recommendations to reduce the prevalence of obesity and weight gain in adulthood for HCCand GBC prevention in Western populations are supported.
Abstract: General obesity has been positively associated with risk of liver and probably with biliary tract cancer, but little is known about abdominal obesity or weight gain during adulthood. We used multivariable Cox proportional hazard models to investigate associations between weight, body mass index, waist and hip circumference, waist-to-hip and waist-to-height ratio (WHtR), weight change during adulthood and risk of hepatocellular carcinoma (HCC), intrahepatic (IBDC) and extrahepatic bile duct system cancer [EBDSC including gallbladder cancer (GBC)] among 359,525 men and women in the European Prospective Investigation into Cancer and Nutrition study. Hepatitis B and C virus status was measured in a nested casecontrol subset. During a mean follow-up of 8.6 years, 177 cases of HCC, 58 cases of IBDC and 210 cases of EBDSC, including 76 cases of GBC, occurred. All anthropometric measures were positively associated with risk of HCC and GBC. WHtR showed the strongest association with HCC [relative risk (RR) comparing extreme tertiles 3.51, 95% confidence interval (95% CI): 2.095.87; ptrend < 0.0001] and with GBC (RR: 1.56, 95% CI: 1.122.16 for an increment of one unit in WHtR). Weight gain during adulthood was also positively associated with HCC when comparing extreme tertiles (RR: 2.48, 95% CI: 1.494.13; <0.001). No statistically significant association was observed between obesity and risk of IBDC and EBDSC. Our results provide evidence of an association between obesity, particularly abdominal obesity, and risk of HCC and GBC. Our findings support public health recommendations to reduce the prevalence of obesity and weight gain in adulthood for HCC and GBC prevention in Western populations.
TL;DR: The magnitude of the excess risk has decreased with increasing attained age or time since exposure, and the excess thyroid cancer risk associated with childhood exposure has persisted for >50 years after exposure.
Abstract: Thyroid cancer risk following exposure to ionizing radiation in childhood and adolescence is a topic of public concern. To characterize the long-term temporal trend and age-at-exposure variation in the radiation-induced risk of thyroid cancer, we analyzed thyroid cancer incidence data for the period from 1958 through 2005 among 105,401 members of the Life Span Study cohort of Japanese atomic-bomb survivors. During the follow-up period, 371 thyroid cancer cases (excluding those with microcarcinoma with a diameter 50 years after exposure.
TL;DR: The higher incidence of breast cancer in developed countries has been tempered by reductions in mortality, largely attributable to mammographic screening programmes and advances in adjuvant therapy, but the need for biomarkers which are fit for purpose is expected to increase.
Abstract: The higher incidence of breast cancer in developed countries has been tempered by reductions in mortality, largely attributable to mammographic screening programmes and advances in adjuvant therapy. Optimal systemic management requires consideration of clinical, pathological and biological parameters. Oestrogen receptor alpha (ERα), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER2) are established biomarkers evaluated at diagnosis, which identify cardinal subtypes of breast cancer. Their prognostic and predictive utility effectively guides systemic treatment with endocrine, anti-HER2 and chemotherapy. Hence, accurate and reliable determination remains of paramount importance. However, the goals of personalized medicine and targeted therapies demand further information regarding residual risk and potential benefit of additional treatments in specific circumstances. The need for biomarkers which are fit for purpose, and the demands placed upon them, is therefore expected to increase. Technological advances, in particular high-throughput global gene expression profiling, have generated multi-gene signatures providing further prognostic and predictive information. The rational integration of routinely evaluated clinico-pathological parameters with key indicators of biological activity, such as proliferation markers, also provides a ready opportunity to improve the information available to guide systemic therapy decisions. The additional value of such information and its proper place in patient management is currently under evaluation in prospective clinical trials. Expanding the utility of biomarkers to lower resource settings requires an emphasis on cost effectiveness, quality assurance and possible international variations in tumor biology; the potential for improved clinical outcomes should be justified against logistical and economic considerations.
TL;DR: Cancer control in Zimbabwe, as elsewhere in sub‐Saharan Africa, involves meeting the challenge of emerging cancers associated with westernization of lifestyles (large bowel, breast and prostate), while the incidence of cancersassociated with poverty and infection shows little decline, and the residual burden of the AIDS‐associated cancers remains significant.
Abstract: Incidence rates of different cancers have been calculated for the black population of Harare, Zimbabwe for a 20-year period (1991–2010) coinciding with continuing social and lifestyle changes, and the peak, and subsequent wane, of the HIV-AIDS epidemic. The overall risk of cancer increased during the period in both sexes, with rates of cervix and prostate cancers showing particularly dramatic increases (3.3% and 6.4% annually, respectively). By 2004, prostate cancer had become the most common cancer of men. The incidence of cancer of the esophagus, formerly the most common cancer of men, has remained relatively constant, whereas rates of breast and cervix cancers, the most common malignancies of women, have shown significant increases (4.9% and 3.3% annually, respectively). The incidence of Kaposi sarcoma increased to a maximum around 1998–2000 and then declined in all age groups, and in both sexes The incidence of squamous cell cancers of the conjunctiva is relatively high, with temporal trends similar to those of Kaposi sarcoma. Non-Hodgkin lymphoma, the fifth most common cancer of men and fourth of women, showed a steady increase in incidence throughout the period (6.7–6.9% annually), although rates in young adults (15–39) have decreased since 2001. Cancer control in Zimbabwe, as elsewhere in sub-Saharan Africa, involves meeting the challenge of emerging cancers associated with westernization of lifestyles (large bowel, breast and prostate), while the incidence of cancers associated with poverty and infection (liver, cervix and esophagus) shows little decline, and the residual burden of the AIDS-associated cancers remains significant.
TL;DR: This review discusses some of the major, potentially targetable, molecular pathways associated with head and neck carcinogenesis and discusses the general mechanism underlying the functional components for each signaling pathway, how these components are aberrantly regulated in HNSCC and their potential as therapeutic targets.
Abstract: The 20th century saw great advances in anatomy-based (surgery and radiotherapy) and chemotherapy approaches for treating head and neck squamous cell carcinoma (HNSCC) and improving quality of life (QoL). However, despite these advances, the survival rate in HNSCC remains at ∼50%. Front-line treatments often cause severe toxicity and debilitating long-term impacts on QoL. In recent decades, dramatic advances have been made in our knowledge of fundamental tumor biology and signaling pathways that contribute to oncogenesis and cancer progression. These insights are presenting unprecedented opportunities to develop more effective and less toxic treatments that are specific to particular molecular targets. This review discusses some of the major, potentially targetable, molecular pathways associated with head and neck carcinogenesis. We present the general mechanism underlying the functional components for each signaling pathway, discuss how these components are aberrantly regulated in HNSCC and describe their potential as therapeutic targets. We have restricted our discussion to "drug-able targets" such as oncogenes including those associated with HPV, tumor hypoxia and microRNAs and present these changes in the context of HNSCC patient care. The specific targeting of these pathways to achieve cancer control/remission and reduce toxicity is now challenging conventional treatment paradigms in HNSCC. This new "biologic era" is transforming our ability to target causal pathways and improve survival outcomes in HNSCC.