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1.  Retraction 
doi:10.1002/ijc.30271
PMCID: PMC5221671  PMID: 27534920
2.  Retraction 
doi:10.1002/ijc.30270
PMCID: PMC5221694  PMID: 27534921
3.  Age-specific risk factor profiles of adenocarcinomas of the esophagus: a pooled analysis from the international BEACON consortium 
Esophageal (EA) and esophagogastric junction (EGJA) adenocarcinoma have been steadily increasing in frequency in younger people, however the etiology of these cancers is poorly understood. We therefore investigated associations of body- mass index (BMI), cigarette smoking, alcohol consumption, gastroesophageal reflux, and use of non-steroidal anti-inflammatory drugs (NSAIDs) in relation to age-specific risks of EA and EGJA. We pooled individual participant data from eight population-based, case-control studies within the international Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON). The analysis included 1,363 EA patients, 1,472 EGJA patients, and 5,728 control participants. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for age-specific (<50, 50–59, 60–69, ≥70 years) cancer outcomes, as well as interactions by age. BMI, smoking status and pack-years, recurrent gastroesophageal reflux, and frequency of gastroesophageal reflux were positively associated with EA and EGJA in each age group. Early-onset EA (<50 years) had stronger associations with recurrent gastroesophageal reflux (OR=8.06, 95%CI: 4.52, 14.37; Peffect modification=0.01) and BMI (ORBMI ≥30 vs. <25=4.19, 95%CI: 2.23, 7.87; Peffect modification=0.04), relative to older age groups. In contrast, inverse associations of NSAID use were strongest in the oldest age group (≥70 years), although this apparent difference was not statistically significant. Age-specific associations with EGJA showed similar, but slightly weaker patterns and no statistically significant differences by age were observed. Our study provides evidence that associations between obesity and gastroesophageal reflux are stronger among earlier onset EA cancers.
doi:10.1002/ijc.29688
PMCID: PMC4607633  PMID: 26175109
risk factors; esophageal cancer; case-control studies; obesity; age of onset
4.  HIV and human herpesvirus 8 co-infection across the globe: systematic review and meta-analysis 
HIV-infection is an important risk factor for developing Kaposi sarcoma (KS), but it is unclear whether HIV-positive persons are also at increased risk of co-infection with human herpesvirus 8 (HHV-8), the infectious cause of KS. We systematically searched literature up to 12/2012 and included studies reporting HHV-8 seroprevalence for HIV-positive and HIV-negative persons. We used random-effects meta-analysis to combine odds ratios (ORs) of the association between HIV and HHV-8 seropositivity and conducted random-effects meta-regression to identify sources of heterogeneity. We included 93 studies with 58,357 participants from 32 countries in sub-Saharan Africa, North and South America, Europe, Asia, and Australia. Overall, HIV-positive persons were more likely to be HHV-8 seropositive than HIV-negative persons (OR 1.99, 95% confidence interval [CI] 1.70 - 2.34) with considerable heterogeneity among studies (I2 84%).The association was strongest in men who have sex with men (MSM, OR 3.95, 95% CI 2.92 - 5.35), patients with hemophilia (OR 3.11, 95%CI 1.19 - 8.11) and children (OR 2.45, 95% CI 1.58 - 3.81), but weaker in heterosexuals who engage in low-risk (OR 1.42, 95% CI 1.16 - 1.74) or high-risk sexual behavior (OR 1.66, 95% CI 1.27 - 2.17), persons who inject drugs (OR 1.66, 95% CI 1.28-2.14), and pregnant women (OR 1.68, 95% CI 1.15 - 2.47), p-value for interaction <0.001. In conclusion, HIV-infection was associated with an increased HHV-8 seroprevalence in all population groups examined. A better understanding of HHV-8 transmission in different age and behavioral groups is needed to develop strategies to prevent HHV-8 transmission.
doi:10.1002/ijc.29687
PMCID: PMC4607648  PMID: 26175054
HIV; Human herpesvirus 8; co-infection; meta-analysis
5.  The High Prevalence of Undiagnosed Prostate Cancer at Autopsy: Implications for Epidemiology and Treatment of Prostate Cancer in the Prostate-Specific Antigen-Era 
Widespread prostate-specific antigen (PSA) screening detects many cancers that would have otherwise gone undiagnosed. To estimate the prevalence of unsuspected prostate cancer, we reviewed 19 studies of prostate cancer discovered at autopsy among 6024 men. Among men aged 70-79, tumor was found in 36% of Caucasians and 51% of African-Americans. This enormous prevalence, coupled with the high sensitivity of PSA screening, has led to the marked increase in the apparent incidence of prostate cancer. The impact of PSA screening on clinical practice is well-recognized, but its effect on epidemiologic research is less appreciated. Before screening, a larger proportion of incident prostate cancers had lethal potential and were diagnosed at advanced stage. However, in the PSA era, overall incident prostate cancer mainly is indolent disease, and often reflects the propensity to be screened and biopsied. Studies must therefore focus on cancers with lethal potential, and include long follow-up to accommodate the lead time induced by screening. Moreover, risk factor patterns differ markedly for potentially lethal and indolent disease, suggesting separate etiologies and distinct disease entities. Studies of total incident or indolent prostate cancer are of limited clinical utility, and the main focus of research should be on prostate cancers of lethal potential.
doi:10.1002/ijc.29408
PMCID: PMC4485977  PMID: 25557753
Prostate cancer; autopsy; PSA-screening; epidemiology; lethal prostate cancer
6.  Regulation of non small-cell lung cancer stem cell like cells by neurotransmitters and opioid peptides 
Non small-cell lung cancer (NSCLC) is the leading type of lung cancer and has a poor prognosis. We have shown that chronic stress promoted NSCLC xenografts in mice via stress neurotransmitter-activated cAMP signaling downstream of beta-adrenergic receptors and incidental beta-blocker therapy was reported to improve clinical outcomes in NSCLC patients. These findings suggest that psychological stress promotes NSCLC whereas pharmacologically or psychologically induced decreases in cAMP may inhibit NSCLC. Cancer stem cells are thought to drive the development, progression and resistance to therapy of NSCLC. However, their potential regulation by stress neurotransmitters has not been investigated. In the current study, epinephrine increased the number of cancer stem cell like cells (CSCs) from three NSCLC cell lines in spheroid formation assays while enhancing intracellular cAMP and the stem cell markers sonic hedgehog (SHH), aldehyde dehydrogenase-1 (ALDH-1) and Gli1, effects reversed by GABA or dynorphin B via Gαi-mediated inhibition of cAMP formation. The growth of NSCLC xenografts in a mouse model of stress reduction was significantly reduced compared with mice maintained under standard conditions. Stress reduction reduced serum levels of corticosterone, norepinephrine and epinephrine while the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and opioid peptides increased. Stress reduction significantly reduced cAMP, VEGF, p-ERK, p-AKT, p-CREB, p-SRc, SHH, ALDH-1 and Gli1 in xenograft tissues whereas cleaved caspase-3 and p53 were induced. We conclude that stress neurotransmitters activate CSCs in NSCLC via multiple cAMP-mediated pathways and that pharmacologically or psychologically induced decreases in cAMP signaling may improve clinical outcomes in NSCLC patients.
doi:10.1002/ijc.29646
PMCID: PMC4600645  PMID: 26088878
non small-cell lung cancer; cancer stem cell like cells; cancer stem cell markers; cAMP signaling; neurotransmitters; opioid peptides
7.  Association of Breast Cancer Risk loci with Breast Cancer Survival 
The survival of breast cancer patients is largely influenced by tumor characteristics, such as TNM stage, tumor grade and hormone receptor status. However, there is growing evidence that inherited genetic variation might affect the disease prognosis and response to treatment. Several lines of evidence suggest that alleles influencing breast cancer risk might also be associated with breast cancer survival. We examined the associations between 35 breast cancer susceptibility loci and the disease over-all survival (OS) in 10,255 breast cancer patients from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3) of which 1,379 died, including 754 of breast cancer. We also conducted a meta-analysis of almost 35,000 patients and 5,000 deaths, combining results from BPC3 and the Breast Cancer Association Consortium (BCAC) and performed in silico analyses of SNPs with significant associations. In BPC3, the C allele of LSP1-rs3817198 was significantly associated with improved OS (HRper-allele=0.70; 95% CI: 0.58–0.85; Ptrend=2.84×10−4; HRheterozygotes=0.71; 95% CI: 0.55–0.92; HRhomozygotes=0.48; 95% CI: 0.31–0.76; P2DF=1.45×10−3). In silico, the C allele of LSP1-rs3817198 was predicted to increase expression of the tumor suppressor cyclin-dependent kinase inhibitor 1C (CDKN1C). In the meta-analysis, TNRC9-rs3803662 was significantly associated with increased death hazard (HRMETA =1.09; 95% CI: 1.04–1.15; Ptrend=6.6×10−4; HRheterozygotes=0.96 95% CI: 0.90–1.03; HRhomozygotes= 1.21; 95% CI: 1.09–1.35; P2DF=1.25×10−4). In conclusion, we show that there is little overlap between the breast cancer risk single nucleotide polymorphisms (SNPs) identified so far and the SNPs associated with breast cancer prognosis, with the possible exceptions of LSP1-rs3817198 and TNRC9-rs3803662.
doi:10.1002/ijc.29446
PMCID: PMC4615576  PMID: 25611573
breast cancer; SNP; survival; BPC3; meta-analysis
8.  Serological response to Helicobacter pylori infection among Latin American populations with contrasting risks of gastric cancer 
International journal of cancer  2015;137(12):3000-3005.
Gastric cancer is a rare outcome of chronic Helicobacter pylori infection. Serologic profiles may reveal bacterial, environmental and/or host factors associated with cancer risk. We therefore compared specific anti-H. pylori antibodies among populations with at least 2-fold differences in gastric cancer mortality from Mexico, Colombia and Chile. Our study included 1,776 adults (mean age 42 years) from three nationally representative surveys, equally divided between residents of high- and low-risk areas. Antibodies to 15 immunogenic H. pylori antigens were measured by fluorescent bead-based multiplex assays; results were summarized to identify overall H. pylori seropositivity. We used logistic regression to model associations between antibody seroreactivity and regional cancer risk (high vs. low), adjusting for country, age and sex. Both risk areas had similar H. pylori seroprevalence. Residents in high- and low-risk areas were seroreactive to a similar number of antigens (means 8.2 vs. 7.9, respectively; adjusted-odds ratio, OR: 1.02, p=0.05). Seroreactivities to Catalase and the known virulence proteins CagA and VacA were each significantly (p<0.05) associated with residence in high-risk areas, but ORs were moderate (1.26, 1.42, and 1.41, respectively) and their discriminatory power was low (ROC area under curve <0.6). The association of Catalase was independent from effects of either CagA or VacA. Sensitivity analyses for antibody associations restricted to H. pylori-seropositive individuals generally replicated significant associations. Our findings suggest that humoral responses to H. pylori are insufficient to distinguish high and low gastric cancer risk in Latin America. Factors determining population variation of gastric cancer burden remain to be identified.
doi:10.1002/ijc.29678
PMCID: PMC4817269  PMID: 26178251
Gastric cancer; H. pylori; Latin America; Serology
9.  Home pesticide exposures and risk of childhood leukemia: Findings from the Childhood Leukemia International Consortium 
Some previous studies have suggested that home pesticide exposure before birth and during a child's early years may increase the risk of childhood leukemia. To further investigate this, we pooled individual level data from 12 case-control studies in the Childhood Leukemia International Consortium (CLIC). Exposure data were harmonized into compatible formats. Pooled analyses were undertaken using multivariable unconditional logistic regression. The odds ratio (ORs) for acute lymphoblastic leukaemia (ALL) associated with any pesticide exposure shortly before conception, during pregnancy and after birth were 1.39 (95% confidence interval (CI) 1.25, 1.55) (using (2,785 cases, 3635 controls), 1.43 (95% CI 1.32, 1.54) (5,055 cases, 7,370 controls) and 1.36 (95% CI 1.23, 1.51) (4,162 cases 5,179 controls), respectively. Corresponding ORs for risk of acute myeloid leukaemia (AML) were 1.49 (95% CI 1.02, 2.16) (173 cases, 1,789 controls), 1.55 (95% CI 1.21, 1.99) (344 cases, 4,666 controls) and 1.08 (95% CI 0.76, 1.53) (198 cases, 2,655 controls) respectively. There was little difference by type of pesticide used. The relative similarity in ORs between leukaemia types, time periods and pesticide types may be explained by similar exposure patterns and effects across the time periods in ALL and AML, participants’ exposure to multiple pesticides, or recall bias. Although some recall bias is likely, until a better study design can be found to investigate associations between home pesticide use and childhood leukaemia in an equally large sample, it would appear prudent to limit the use of home pesticides before and during pregnancy, and during childhood.
doi:10.1002/ijc.29631
PMCID: PMC4572913  PMID: 26061779
pesticide; acute lymphoblastic leukemia acute myeloid leukemia; childhood; pooled analysis; case-control study
10.  Lynch Syndrome and Cervical Cancer 
Carriers of germline mutations in DNA mismatch repair (MMR) genes are at increased risk of several cancers including colorectal and gynecologic cancers (Lynch syndrome). There is no substantial evidence that these mutations are associated with an increased risk of cervical cancer. A total of 369 families with at least one carrier of a mutation in a MMR gene (133 MLH1, 174 MSH2, 35 MSH6, and 27 PMS2) were ascertained via population cancer registries or via family cancer clinics in Australia, New Zealand, Canada, and USA. Personal and family histories of cancer were obtained from participant interviews. Modified segregation analysis was used to estimate the hazard ratio (incidence rates for carriers relative to those for the general population), and age-specific cumulative risks of cervical cancer for carriers. A total of 65 cases of cervical cancer were reported (including 10 verified by pathology reports). The estimated incidence was 5.6–fold (95% CI: 2.3–13.8; p=0.001) higher for carriers than for the general population with a corresponding cumulative risk to 80 years of 4.5% (95% CI: 1.9–10.7%) compared with 0.8% for the general population. The mean age at diagnosis was 43.1 years (95% CI: 40.0–46.2), 3.9 years younger than the reported USA population mean of 47.0 years (p=0.02). Women with MMR gene mutations were found to have an increased risk of cervical cancer. Due to limited pathology verification we cannot be certain that a proportion of these cases were not lower uterine segment endometrial cancers involving the endocervix, a recognized cancer of Lynch syndrome.
doi:10.1002/ijc.29641
PMCID: PMC4573262  PMID: 26077226
11.  Clostridium Perfringens Enterotoxin C-terminal domain labeled to fluorescent Dyes for in vivo visualization of micro-metastatic chemotherapy-resistant ovarian cancer 
Identification of micro-metastatic disease at the time of surgery remains extremely challenging in ovarian cancer patients. We used fluorescence microscopy, an in vivo imaging system and a fluorescence stereo microscope to evaluate fluorescence distribution in claudin-3 and -4 overexpressing ovarian tumors, floating tumor clumps isolated from ascites and healthy organs. To do so, mice harboring chemotherapy-naïve and chemotherapy-resistant human ovarian cancer xenografts or patient-derived xenografts (PDX) were treated with the carboxi-terminal binding domain of the Clostridium Perfringens Enterotoxin (c-CPE) conjugated to FITC (FITC-c-CPE) or the near-infrared (NIR) fluorescent tag IRDye CW800 (CW800-c-CPE) either intraperitoneal (IP) or intravenous (IV). We found tumor fluorescence to plateau at 30 minutes after IP injection of both the FITC-c-CPE and the CW800-c-CPE peptides and to be significantly higher than in healthy organs (p<0.01). After IV injection of CW800-c-CPE, tumor fluorescence plateaued at 6 hours while the most favorable tumor to background fluorescence ratio (TBR) was found at 48 hours in both mouse models. Importantly, fluorescent c-CPE was highly sensitive for the in vivo visualization of peritoneal micro-metastatic tumor implants and the identification of ovarian tumor spheroids floating in malignant ascites that were otherwise not detectable by conventional visual observation. The use of the fluorescent c-CPE peptide may represent a novel and effective optical approach at the time of primary debulking surgery for the real-time detection of micro-metastatic ovarian disease overexpressing the claudin-3 and -4 receptors or the identification of residual disease at the time of interval debulking surgery after neoadjuvant chemotherapy treatment.
doi:10.1002/ijc.29632
PMCID: PMC4573336  PMID: 26060989
ovarian cancer; Clostridium Perfringens Enterotoxin; IRDye CW800; real-time imaging; residual disease
12.  Soluble levels of CD27 and CD30 are associated with risk of non-Hodgkin lymphoma in three Chinese prospective cohorts 
International journal of cancer  2015;137(11):2688-2695.
Prospective studies conducted in Western populations have suggested that alterations in soluble CD27 (sCD27) and soluble CD30 (sCD30), two markers indicative of B-cell activation, are associated with risk of non-Hodgkin lymphoma (NHL). Given that the characteristics of NHL in East Asia differ from the West, and mechanistic commonalities between these populations with respect to the role of intermediate endpoint biomarkers in lymphomagenesis have not been explored, we conducted a pooled nested case-control study from three prospective studies of Chinese men and women including 218 NHL cases and 218 individually matched controls. Compared to the lowest quartile, ORs (95% CIs) for the 2nd, 3rd, and 4th quartiles of sCD27 were 1.60 (0.83-3.09), 1.94 (0.98-3.83), and 4.45 (2.25-8.81), respectively (ptrend = 0.000005). The corresponding ORs for sCD30 were 1.74 (0.85-3.58), 1.86 (0.94-3.67), and 5.15 (2.62-10.12) (ptrend = 0.0000002). These associations remained statistically significant in individuals diagnosed with NHL 10 or more years after blood draw. Notably, the magnitude of the associations with NHL risk was very similar to those in Western populations in previous studies. These findings of the similar association between sCD27 or sCD30 and NHL risk across different populations support an important underlying mechanism of B-cell activation in lymphomagenesis.
doi:10.1002/ijc.29637
PMCID: PMC4898881  PMID: 26095604
CD27; CD30; immune markers; non-Hodgkin lymphoma; East Asians; prospective study
13.  Distinct and shared three‐dimensional chromosome organization patterns in lymphocytes, monoclonal gammopathy of undetermined significance and multiple myeloma 
International Journal of Cancer  2016;140(2):400-410.
The consistent appearance of specific chromosomal translocations in multiple myeloma has suggested that the positioning of chromosomes in the interphase nucleus might play a role in the occurrence of particular chromosomal rearrangements associated with malignant transformation. Using fluorescence in situ hybridization, we have determined the positions of selected chromosome pairs (18 and 19, 9 and 22, 4 and 14, 14 and 16, 11 and 14) in interphase nuclei of myeloma cells compared to normal lymphocytes of treatment‐naïve patients. All chromosome pairs were arranged in a nonrandom pattern. Chromosomes commonly involved in myeloma‐associated translocations (4 and 14, 14 and 16, 11 and 14) were found in close spatial proximity, and this is correlated with the occurrence of overlapping chromosome territories. The spatial distribution of chromosomes may increase the possibility of chromosomal translocations in multiple myeloma.
What's new?
The positioning of chromosomes in the interphase nucleus might play a role in the occurrence of chromosomal rearrangements associated with malignant transformation. Here, the authors examined the nuclei of myeloma cells and control lymphocytes from treatment‐naïve patients using conventional 3D imaging and super‐resolution microscopy. Common and distinct chromosome positions were found in lymphocytes and myeloma cells with respect to neighborhood relationships and tendency to overlap. Chromosomes commonly involved in myeloma‐associated translocations were found in close spatial proximity, which correlated with the occurrence of overlapping chromosome territories. The spatial distribution of chromosomes may increase the possibility of translocations in multiple myeloma.
doi:10.1002/ijc.30461
PMCID: PMC5132008  PMID: 27711972
3D‐SIM; chromosome territory; myeloma; monoclonal gammopathy of undetermined significance
14.  Investigating the possible causal role of coffee consumption with prostate cancer risk and progression using Mendelian randomization analysis 
International Journal of Cancer  2016;140(2):322-328.
Coffee consumption has been shown in some studies to be associated with lower risk of prostate cancer. However, it is unclear if this association is causal or due to confounding or reverse causality. We conducted a Mendelian randomisation analysis to investigate the causal effects of coffee consumption on prostate cancer risk and progression. We used two genetic variants robustly associated with caffeine intake (rs4410790 and rs2472297) as proxies for coffee consumption in a sample of 46,687 men of European ancestry from 25 studies in the PRACTICAL consortium. Associations between genetic variants and prostate cancer case status, stage and grade were assessed by logistic regression and with all‐cause and prostate cancer‐specific mortality using Cox proportional hazards regression. There was no clear evidence that a genetic risk score combining rs4410790 and rs2472297 was associated with prostate cancer risk (OR per additional coffee increasing allele: 1.01, 95% CI: 0.98,1.03) or having high‐grade compared to low‐grade disease (OR: 1.01, 95% CI: 0.97,1.04). There was some evidence that the genetic risk score was associated with higher odds of having nonlocalised compared to localised stage disease (OR: 1.03, 95% CI: 1.01, 1.06). Amongst men with prostate cancer, there was no clear association between the genetic risk score and all‐cause mortality (HR: 1.00, 95% CI: 0.97,1.04) or prostate cancer‐specific mortality (HR: 1.03, 95% CI: 0.98,1.08). These results, which should have less bias from confounding than observational estimates, are not consistent with a substantial effect of coffee consumption on reducing prostate cancer incidence or progression.
What's new?
Does coffee consumption reduce prostate cancer risk? It's biologically plausible that it could, but studies showing a link have relied on observational evidence, which could be affected by confounding factors. These authors set out to isolate coffee's contribution. They focused on two genetic variants that correspond with caffeine intake, and used them as proxies for coffee drinking. Alleles are not affected by behavior or demographic factors, nor can behavior changes after diagnosis change whether a person carries an allele. The authors found no correlation between either of the alleles and prostate cancer risk, suggesting drinking coffee may not protect against prostate cancer.
doi:10.1002/ijc.30462
PMCID: PMC5132137  PMID: 27741566
prostate cancer; coffee; Mendelian randomization
15.  Childhood body mass index growth trajectories and endometrial cancer risk 
International Journal of Cancer  2016;140(2):310-315.
Previously, we found that excess weight already in childhood has positive associations with endometrial cancer; however, associations with changes in body mass index (BMI) during childhood are not well understood. Therefore, we examined whether growth in childhood BMI is associated with endometrial cancer and its sub‐types. A cohort of 155,505 girls from the Copenhagen School Health Records Register with measured weights and heights at the ages of 6–14 years and born 1930–1989 formed the analytical population. BMI was transformed to age‐specific z scores. Using linear spline multilevel models, each girl's BMI growth trajectory was estimated as the deviance from the average trajectory for three different growth periods (6.25–7.99, 8.0–10.99, 11.0–14.0 years). Via a link to health registers, 1,020 endometrial cancer cases were identified, and Cox regressions were performed. A greater gain in BMI during childhood was positively associated with endometrial cancer but no differences between the different growth periods were detected in models adjusted for baseline BMI. The hazard ratios for the associations with overall growth during childhood per 0.1 z score increase were 1.15 (95% confidence interval [CI]: 1.07–1.24) for all endometrial cancers, 1.12 (95% CI: 1.04–1.21) for estrogen‐dependent cancers, 1.16 (95% CI: 1.06–1.26) for endometrioid adenocarcinomas and 1.46 (95% CI: 1.16–1.84) for non‐estrogen‐dependent cancers. Growth in BMI in early life is positively linked to later endometrial cancer risk. We did not identify any sensitive childhood growth period, which suggests that excess gain in BMI during the entire childhood period should be avoided.
What's new?
High body mass index (BMI) early in life is linked to an increased risk of endometrial cancer in adulthood. Potentially influencing that association are the amount by which BMI increases in childhood, as well as the timing of BMI increase. Here, analyses of data from the Copenhagen School Health Records Register for girls ages 6 to 14 shows that endometrial cancer risk is increased by greater BMI gain across ages, while the specific age at which BMI increases occurs has little impact. Excess BMI gain at any time during childhood could set the stage for endometrial carcinogenesis.
doi:10.1002/ijc.30464
PMCID: PMC5132154  PMID: 27718528
body weights and measures; child; endometrial neoplasms; growth and development; obesity
16.  Epstein‐Barr virus mRNA profiles and viral DNA methylation status in nasopharyngeal brushings from nasopharyngeal carcinoma patients reflect tumor origin 
International Journal of Cancer  2016;140(1):149-162.
Undifferentiated nasopharyngeal carcinoma (NPC) is 100% associated with Epstein‐Barr virus (EBV) as oncogenic driver. NPC is often diagnosed late due to initial vague complaints and obscured location. Prior studies suggest that measurement of EBV DNA load and RNA transcripts in nasopharyngeal (NP) brushings is useful for minimally invasive NPC diagnosis. However, whether these EBV markers relate to local virus replication or reflect tumor origin remains to be demonstrated. To resolve this, we analysed EBV‐DNA characteristics and quantified latent and lytic viral RNA transcripts in NP brushings and matching frozen NP‐biopsy specimens from patients suspected of having NPC.
We observed non‐fragmented and Cp‐promotor methylated EBV‐DNA in both NP brushings and biopsies suggestive of tumor origin. Using quantitative RT‐PCR we determined expression levels of 7 critical latent (EBER1, Qp‐EBNA1, EBNA2, BART, LMP1, LMP2, BARF1) and 5 lytic (Zta, Rta, TK, PK and VCA‐p18) RNA transcripts. Although latent and early lytic RNA transcripts were frequently detected in conjunction with high EBV viral load, in both brushings and biopsies the latent transcripts prevailed and reflected a typical NPC‐associated latency‐II transcription profile without EBNA2. Late lytic RNA transcripts were rare and detected at low levels mainly in NP brushings, suggestive of abortive viral reactivation rather than complete virus replication. EBV‐IgA serology (EBNA1, VCA, Zta) did not correlate to the level of viral reactivation in situ.
Overall, viral RNA profiling, DNA fragmentation and methylation analysis in NP brushings and parallel biopsies indicate that NP brush sampling provides a true and robust indicator of NPC tumor presence.
What's new?
Nasopharyngeal carcinoma (NPC) often is diagnosed at late stages, in part because physical examination of the nasopharyngeal (NP) space is difficult. Moreover, despite a strong association with Epstein‐Barr virus (EBV) infection, optimal EBV‐based diagnostic modalities for NPC are lacking. Here, EBV DNA load, methylation status and EBV latent and lytic RNA profiles obtained from NP brush biopsy were found to be robustly indicative of tumor presence at the site of initiation. EBV (immediate) early mRNAs were frequently detected, suggesting local abortive viral reactivation. Using the described EBV markers, NP brushing may be a practical minimally invasive approach for NPC diagnosis.
doi:10.1002/ijc.30418
PMCID: PMC5129462  PMID: 27600027
nasopharyngeal brushing; EBV viral load; EBV RNA profiles; viral DNA methylation; EBV IgA serology
17.  Phase II study of the effectiveness and safety of trastuzumab and paclitaxel for taxane‐ and trastuzumab‐naïve patients with HER2‐positive, previously treated, advanced, or recurrent gastric cancer (JFMC45‐1102) 
International Journal of Cancer  2016;140(1):188-196.
Paclitaxel is a standard second‐line gastric cancer treatment in Japan. Trastuzumab could be active as second‐line chemotherapy for taxane/trastuzumab‐naïve patients with epidermal growth factor 2 (HER2)‐positive advanced gastric cancer. Patients aged ≥20 years with HER2‐positive, previously treated (except for trastuzumab and taxane), unresectable or recurrent gastric adenocarcinoma underwent combined trastuzumab (first and subsequent doses of 8 and 6 mg kg−1, respectively, every 3 weeks) and paclitaxel (days 1, 8, 15, every 4 weeks) treatment. Study endpoints were best overall response, progression‐free survival, overall survival, and safety. From September 2011 to March 2012, 47 Japanese patients were enrolled. Forty patients discontinued treatment after a median of 128.5 (range 4–486) days. Complete and partial responses were obtained in one and 16 patients (response rate of 37% [95% CI 23–52]), respectively. Median progression‐free survival and overall survival were 5.1 (95% CI 3.8–6.5) and 17.1 (95% CI 13.5–18.6) months, respectively. Grade 3/4 adverse events were neutropenia (32.6%), leukopenia (17.4%), anemia (15.2%) and hypoalbuminemia (8.7%). There was no clinically significant cardiotoxicity or cumulative toxicity. Three (disturbed consciousness, pulmonary fibrosis, and rapid disease progression) grade 5 events occurred. In conclusion, trastuzumab combined with paclitaxel was well tolerated and was a promising regimen for patients with HER2‐positive, previously treated, advanced or recurrent gastric cancer.
What's new?
Second‐line chemotherapy can provide important survival benefits in patients with advanced or recurrent gastric cancer, and trastuzumab, a HER2‐targeting monoclonal antibody, could be especially useful in second‐line therapy, though its safety and effectiveness are yet to be fully explored. Here, combined trastuzumab‐paclitaxel therapy was assessed in Japanese patients with salvage line HER2‐positive advanced/recurrent gastric cancer. Trastuzumab‐naïve HER2‐positive patients showed high response rates and experienced prolonged survival on the trastuzumab plus paclitaxel regimen. The combination also was generally well tolerated. The findings indicate that HER2‐positive patients treated with paclitaxel can benefit further from the addition of trastuzumab.
doi:10.1002/ijc.30383
PMCID: PMC5129528  PMID: 27521503
human epidermal growth factor receptor; paclitaxel; recurrence; stomach neoplasms; trastuzumab
18.  Alcohol consumption and prostate cancer incidence and progression: A Mendelian randomisation study 
International Journal of Cancer  2016;140(1):75-85.
Prostate cancer is the most common cancer in men in developed countries, and is a target for risk reduction strategies. The effects of alcohol consumption on prostate cancer incidence and survival remain unclear, potentially due to methodological limitations of observational studies. In this study, we investigated the associations of genetic variants in alcohol‐metabolising genes with prostate cancer incidence and survival. We analysed data from 23,868 men with prostate cancer and 23,051 controls from 25 studies within the international PRACTICAL Consortium. Study‐specific associations of 68 single nucleotide polymorphisms (SNPs) in 8 alcohol‐metabolising genes (Alcohol Dehydrogenases (ADHs) and Aldehyde Dehydrogenases (ALDHs)) with prostate cancer diagnosis and prostate cancer‐specific mortality, by grade, were assessed using logistic and Cox regression models, respectively. The data across the 25 studies were meta‐analysed using fixed‐effect and random‐effects models. We found little evidence that variants in alcohol metabolising genes were associated with prostate cancer diagnosis. Four variants in two genes exceeded the multiple testing threshold for associations with prostate cancer mortality in fixed‐effect meta‐analyses. SNPs within ALDH1A2 associated with prostate cancer mortality were rs1441817 (fixed effects hazard ratio, HRfixed = 0.78; 95% confidence interval (95%CI):0.66,0.91; p values = 0.002); rs12910509, HRfixed = 0.76; 95%CI:0.64,0.91; p values = 0.003); and rs8041922 (HRfixed = 0.76; 95%CI:0.64,0.91; p values = 0.002). These SNPs were in linkage disequilibrium with each other. In ALDH1B1, rs10973794 (HRfixed = 1.43; 95%CI:1.14,1.79; p values = 0.002) was associated with prostate cancer mortality in men with low‐grade prostate cancer. These results suggest that alcohol consumption is unlikely to affect prostate cancer incidence, but it may influence disease progression.
What's new?
Alcohol may spur prostate cancer progression, though it does not appear to affect incidence, according to new analysis. Variation in genes involved in alcohol metabolism affect how much the body is exposed to carcinogenic metabolites. These authors examined 68 genetic variants in alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) genes, seeking a link with prostate cancer risk. While they found no evidence that these variants alter prostate cancer incidence, they did show that SNPs in the ALDH1A2 gene affect prostate cancer mortality. From a public health standpoint, these results suggest reducing alcohol consumption could slow prostate cancer disease progression.
doi:10.1002/ijc.30436
PMCID: PMC5111609  PMID: 27643404
alcohol; prostate cancer; alcohol metabolising genes; Mendelian randomisation
19.  Identification of novel BRCA founder mutations in Middle Eastern breast cancer patients using capture and Sanger sequencing analysis 
International Journal of Cancer  2016;139(5):1091-1097.
Ethnic differences of breast cancer genomics have prompted us to investigate the spectra of BRCA1 and BRCA2 mutations in different populations. The prevalence and effect of BRCA 1 and BRCA 2 mutations in Middle Eastern population is not fully explored. To characterize the prevalence of BRCA mutations in Middle Eastern breast cancer patients, BRCA mutation screening was performed in 818 unselected breast cancer patients using Capture and/or Sanger sequencing. 19 short tandem repeat (STR) markers were used for founder mutation analysis. In our study, nine different types of deleterious mutation were identified in 28 (3.4%) cases, 25 (89.3%) cases in BRCA 1 and 3 (10.7%) cases in BRCA 2. Seven recurrent mutations identified accounted for 92.9% (26/28) of all the mutant cases. Haplotype analysis was performed to confirm c.1140 dupG and c.4136_4137delCT mutations as novel putative founder mutation, accounting for 46.4% (13/28) of all BRCA mutant cases and 1.6% (13/818) of all the breast cancer cases, respectively. Moreover, BRCA 1 mutation was significantly associated with BRCA 1 protein expression loss (p = 0.0005). Our finding revealed that a substantial number of BRCA mutations were identified in clinically high risk breast cancer from Middle East region. Identification of the mutation spectrum, prevalence and founder effect in Middle Eastern population facilitates genetic counseling, risk assessment and development of cost‐effective screening strategy.
What's new?
Genetic testing for BRCA mutations reveals the ethnic diversity of prevalence and spectrum of BRCA1/BRCA2 mutations in breast cancer. Compared with other populations, however, little is known about ethnic differences in breast cancer genomics in populations in the Middle East region. Here, BRCA mutation screening was carried out in 818 Middle Eastern breast cancer patients. The authors identify two putative founder mutations—together accounting for more than 46% of BRCA cases—and a particular spectrum of deleterious BRCA mutations, which may be unique to the population. The findings could impact genetic counseling in Middle Eastern populations.
doi:10.1002/ijc.30143
PMCID: PMC5111783  PMID: 27082205
breast cancer; mutation; BRCA 1; BRCA 2
20.  Apoptotic variants as predictors of risk of oropharyngeal cancer recurrence after definitive radiotherapy 
Single nucleotide polymorphisms (SNPs) in the promoter region of FAS and FASLG may alter their transcriptional activity. Thus, we determined the associations between four FAS and FASLG promoter variants (FAS1377G>A, rs2234767; 670A>G, rs1800682; FASLG844T>C, rs763110; and 124A>G, rs5030772) and the risk of recurrence of squamous cell carcinoma of the oropharynx (SCCOP). We evaluated the associations between FAS and FASLG genetic variants and the risk of recurrence in a cohort of 1008 patients. The log-rank test and multivariate Cox models were used to evaluate the associations. Compared with patients with common homozygous genotypes of FAS670 and FASLG844 polymorphisms, patients with variant genotypes had lower disease-free survival rates (log-rank P < 0.0001 and P < 0.0001, respectively) and an approximately 3-fold higher risk of SCCOP recurrence (HR, 3.2;95% CI, 2.2–4.6; and HR, 3.1; 95% CI, 2.2–4.4, respectively) after multivariate adjustment. Furthermore, among patients with HPV16-positive tumors, those with variant genotypes of these two polymorphisms had lower disease-free survival rates (log-rank, P < 0.0001 and P < 0.0001, respectively) and a higher recurrence risk than did patients with common homozygous genotypes (HR, 12.9; 95% CI, 3.8–43.6; and HR, 8.1; 95% CI, 3.6–18.6, respectively), whereas no significant associations were found for FAS1377 and FASLG124 polymorphisms. Our findings suggest that FAS670 and FASLG844 polymorphisms modulate the risk of recurrence of SCCOP, particularly in patients with HPV16-positive tumors. Larger studies are needed to validate these results.
doi:10.1002/ijc.29604
PMCID: PMC4575831  PMID: 25976983
FAS and FASLG; recurrence; genetic variants; biomarkers; apoptosis; human papillomavirus; head and neck cancer; oropharyngeal cancer
21.  Adolescent and mid-life diet and subsequent risk of thyroid cancer in the NIH-AARP Diet and Health Study 
Although thyroid cancer is suspected to have a nutritional etiology, prospective studies examining the relationship between diet and thyroid cancer are lacking. During 1996–1997, NIH-AARP Diet and Health Study participants, ages 51–72 years, completed a 37-item food frequency questionnaire about diet at ages 12–13 years (adolescence) and 10 years before baseline (mid-life). Over a median 10 years of follow-up, 325 individuals (143 men and 182 women) were diagnosed with thyroid cancer. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for intakes of foods and food groups comparing the highest to the lowest quartiles. Adolescent intakes of chicken/turkey (HR=1.59, 95% CI: 0.97–2.60; Ptrend<0.01) and sweet baked goods (HR=1.59, 95% CI: 1.09–2.34; Ptrend =0.04) were positively associated with thyroid cancer risk, while intake of butter/margarine was inversely associated with risk (HR=0.64, 95% CI: 0.44–0.91; Ptrend<0.02). Similar to adolescent diet, mid-life intake of sweet baked goods was non-significantly associated with an increased risk of thyroid cancer (HR=1.39, 95% CI: 0.96–2.00; Ptrend =0.11), but intake of butter/margarine was inversely associated with risk (HR=0.66, 95% CI: 0.46–0.95; Ptrend=0.03). Among men, higher adolescent consumption of canned tuna was positively associated with risk of thyroid cancer (HR=1.69, 95% CI: 1.01–2.83; Ptrend=0.03), and greater mid-life intake of broccoli was associated with a twofold increased risk (HR=2.13, 95% CI: 1.13–3.99; Ptrend <0.01). This large prospective study suggests that several components of the adolescent and mid-life diet, including iodine-rich foods and goitrogens, may influence thyroid cancer risk.
doi:10.1002/ijc.29600
PMCID: PMC4575832  PMID: 25974060
adolescence; diet; nutrients; prospective study; thyroid cancer
22.  A quantitative microscopic approach to predict local recurrence based on in vivo intraoperative imaging of sarcoma tumor margins 
The goal of resection of soft tissue sarcomas located in the extremity is to preserve limb function while completely excising the tumor with a margin of normal tissue. With surgery alone, one-third of patients with soft tissue sarcoma of the extremity will have local recurrence due to microscopic residual disease in the tumor bed. Currently, a limited number of intraoperative pathology-based techniques are used to assess margin status; however, few have been widely adopted due to sampling error and time constraints. To aid in intraoperative diagnosis, we developed a quantitative optical microscopy toolbox, which includes acriflavine staining, fluorescence microscopy, and analytic techniques called sparse component analysis and circle transform to yield quantitative diagnosis of tumor margins. A series of variables were quantified from images of resected primary sarcomas and used to optimize a multivariate model. The sensitivity and specificity for differentiating positive from negative ex vivo resected tumor margins was 82% and 75%. The utility of this approach was tested by imaging the in vivo tumor cavities from 34 mice after resection of a sarcoma with local recurrence as a bench mark. When applied prospectively to images from the tumor cavity, the sensitivity and specificity for differentiating local recurrence was 78% and 82%. For comparison, if pathology was used to predict local recurrence in this data set, it would achieve a sensitivity of 29% and a specificity of 71%. These results indicate a robust approach for detecting microscopic residual disease, which is an effective predictor of local recurrence.
doi:10.1002/ijc.29611
PMCID: PMC4575838  PMID: 25994353
Optical fluorescence imaging; Intraoperative imaging; Soft Tissue Sarcoma; Image analysis; Logistic models
23.  Short-term Natural History of High-Risk Human Papillomavirus Infection in Mid-Adult Women Sampled Monthly (Short title: Short-term HPV Natural History in Mid-Adult Women) 
Characterizing short-term HPV detection patterns and viral load may inform HPV natural history in mid-adult women. From 2011–2012, we recruited women aged 30–50 years. Women submitted monthly self-collected vaginal samples for high-risk HPV DNA testing for 6 months. Positive samples were tested for type-specific HPV DNA load by real-time PCR. HPV type-adjusted linear and Poisson regression assessed factors associated with 1) viral load at initial HPV detection and 2) repeat type-specific HPV detection. One-hundred thirty-nine women (36% of 387 women with ≥4 samples) contributed 243 type-specific HR HPV infections during the study; 54% of infections were prevalent and 46% were incident. Incident (versus prevalent) detection and past pregnancy were associated with lower viral load, whereas current smoking was associated with higher viral load. In multivariate analysis, current smoking was associated with a 40% (95%CI:5%–87%) increase in the proportion of samples that were repeatedly positive for the same HPV type, whereas incident (versus prevalent) detection status and past pregnancy were each associated with a reduction in the proportion of samples repeatedly positive (55%,95%CI:38%–67% and 26%,95%CI:10%–39%, respectively). In a separate multivariate model, each log10 increase in viral load was associated with a 10% (95%CI:4%–16%) increase in the proportion of samples repeatedly positive. Factors associated with repeat HPV detection were similar to those observed in longer-term studies, suggesting that short-term repeat detection may relate to long-term persistence. The negative associations between incident HPV detection and both viral load and repeat detection suggest that reactivation or intermittent persistence was more common than new acquisition.
doi:10.1002/ijc.29602
PMCID: PMC4591913  PMID: 25976733
human papillomavirus; viral load; natural history; women
24.  Dairy intake after prostate cancer diagnosis in relation to disease-specific and total mortality 
Information regarding post-diagnostic dairy intake and prostate cancer survival is limited. We evaluated intake of total, high-fat and low-fat dairy after prostate cancer diagnosis in relation to disease-specific and total mortality. We included 926 men from the Physicians’ Health Study diagnosed with non-metastatic prostate cancer between 1982 and 2000 who completed a diet questionnaire a median of 5 years after diagnosis and were followed thereafter for a median of 10 years to assess mortality. Cox proportional hazards regression was used to estimate associations between dairy intake and prostate cancer specific and all-cause mortality. During 8,903 person-years of follow-up, 333 men died, 56 due to prostate cancer. Men consuming ≥3 servings/day of total dairy products had a 76% higher risk of total mortality and a 141% higher risk of prostate cancer-specific mortality compared to men who consumed less than 1 dairy product/ day (relative risk (RR) = 1.76, 95% confidence interval (CI): 1.21, 2.55, Ptrend < 0.001 for total mortality; RR = 2.41, 95%CI: 0.96, 6.02, Ptrend = 0.04 for prostate cancer specific mortality). The association between high-fat dairy and mortality risk appeared to be stronger than that of low-fat dairy, but the difference between them was not statistically significant (P for difference = 0.57 for prostate cancer-specific mortality and 0.56 for total mortality). Among men without metastases when diagnosed, higher intake of dairy foods after prostate cancer diagnosis may be associated with increased prostate cancer-specific and all-cause mortality.
doi:10.1002/ijc.29608
PMCID: PMC4754664  PMID: 25989745
dairy products; prostate cancer; all-cause mortality; Physicians’ Health Study
25.  A prospective study of dietary patterns and cancer mortality among Blacks and Whites in the REGARDS cohort 
International journal of cancer  2016;139(10):2221-2231.
Marked racial differences exist in dietary patterns and obesity, as well as cancer mortality. This study aims to assess whether dietary patterns are associated with cancer mortality overall and by race. We identified 22,041 participants from the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. Dietary patterns were categorized into: Convenience (Chinese and Mexican foods, pasta, pizza), Plant-based (fruits, vegetables), Southern (added fats, fried foods, sugar-sweetened beverages), Sweets/Fats (sugary foods) and Alcohol/Salads (alcohol, green-leafy vegetables, salad dressing). Using Cox regression, we examined the association between quartiles of dietary patterns and cancer mortality, adjusted for potential confounders, overall among all participants and stratified by race. A total of 873 cancer deaths were observed over the 10-year observation period: 582 (66.7%) in Whites and 291 (33.3%) in Blacks. Greater adherence to the Southern dietary pattern was associated with an increased risk of cancer mortality (4th vs. 1st quartile HR: 1.67; 95% CI: 1.32–2.10) overall, especially among Whites (4th vs. 1st quartile HR: 1.59; 95% CI: 1.22–2.08). The convenience (HR: 0.73; 95% CI: 0.56–0.94) and Plant-based (HR: 0.72; 95% CI: 0.55–0.93) dietary patterns were associated with up to a 28% reduced risk of cancer mortality, but only among Whites. Greater adherence to the Southern dietary pattern increased the risk of cancer mortality, while greater adherence to the convenience and Plant-based diets reduced the risk of cancer mortality among Whites. Racial differences were observed in the association between dietary patterns and cancer mortality, but warrant further study.
doi:10.1002/ijc.30287
PMCID: PMC5041524  PMID: 27459634
diet; cancer; mortality; racial disparities; prospective cohort

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