Genome-wide association studies and Mendelian randomization analyses provide insights into the causes of early-onset colorectal cancer.

BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. CRC has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC. PATIENTS AND METHODS: We conducted a GWAS meta-analysis of 6176 EOCRC cases and 65 829 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample MR. RESULTS: We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, which were not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (odds ratio 1.80, 95% confidence interval 1.47-2.22) but show that most of the common genetic susceptibility was from noncoding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC-susceptibility genes, and in addition to pathways such as transforming growth factor (TGF) ß, suppressor of Mothers Against Decapentaplegic (SMAD), bone morphogenetic protein (BMP) and phosphatidylinositol kinase (PI3K) signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors-such as body fat percentage, waist circumference, waist-to-hip ratio, basal metabolic rate, and fasting insulin-higher alcohol drinking, and lower education attainment with increased EOCRC risk. CONCLUSIONS: Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk-stratify individuals for personalized screening strategies or other interventions.

Pembrolizumab monotherapy versus chemotherapy in platinum-pretreated, recurrent or metastatic nasopharyngeal cancer (KEYNOTE-122): an open-label, randomized, phase III trial.

BACKGROUND: Pembrolizumab previously demonstrated robust antitumor activity and manageable safety in a phase Ib study of patients with heavily pretreated, programmed death ligand 1 (PD-L1)-positive, recurrent or metastatic nasopharyngeal carcinoma (NPC). The phase III KEYNOTE-122 study was conducted to further evaluate pembrolizumab versus chemotherapy in patients with platinum-pretreated, recurrent and/or metastatic NPC. Final analysis results are presented. PATIENTS AND METHODS: KEYNOTE-122 was an open-label, randomized study conducted at 29 sites, globally. Participants with platinum-pretreated recurrent and/or metastatic NPC were randomly assigned (1 : 1) to pembrolizumab or chemotherapy with capecitabine, gemcitabine, or docetaxel. Randomization was stratified by liver metastasis (present versus absent). The primary endpoint was overall survival (OS), analyzed in the intention-to-treat population using the stratified log-rank test (superiority threshold, one-sided P = 0.0187). Safety was assessed in the as-treated population. RESULTS: Between 5 May 2016 and 28 May 2018, 233 participants were randomly assigned to treatment (pembrolizumab, n = 117; chemotherapy, n = 116); Most participants (86.7%) received study treatment in the second-line or later setting. Median time from randomization to data cut-off (30 November 2020) was 45.1 months (interquartile range, 39.0-48.8 months). Median OS was 17.2 months [95% confidence interval (CI) 11.7-22.9 months] with pembrolizumab and 15.3 months (95% CI 10.9-18.1 months) with chemotherapy [hazard ratio, 0.90 (95% CI 0.67-1.19; P = 0.2262)]. Grade 3-5 treatment-related adverse events occurred in 12 of 116 participants (10.3%) with pembrolizumab and 49 of 112 participants (43.8%) with chemotherapy. Three treatment-related deaths occurred: 1 participant (0.9%) with pembrolizumab (pneumonitis) and 2 (1.8%) with chemotherapy (pneumonia, intracranial hemorrhage). CONCLUSION: Pembrolizumab did not significantly improve OS compared with chemotherapy in participants with platinum-pretreated recurrent and/or metastatic NPC but did have manageable safety and a lower incidence of treatment-related adverse events.

Improved risk stratification of nasopharyngeal cancer by targeted sequencing of Epstein-Barr virus DNA in post-treatment plasma.

BACKGROUND: Quantitative measurement of plasma Epstein-Barr virus (EBV) DNA by real-time PCR at the end of primary treatment is a robust prognostic marker for nasopharyngeal carcinoma (NPC) patients. However, up to 40% of patients who would later develop disease recurrence had undetectable post-treatment plasma EBV DNA. Targeted sequencing for the entire EBV genome potentially allows a more comprehensive and unbiased detection of plasma EBV DNA and enables the use of other parameters such as fragment size as biomarkers. Hence, we explored if plasma EBV DNA sequencing might allow more accurate prognostication of NPC patients. PATIENTS AND METHODS: Plasma samples collected from 769 patients with stage IIB-IVB NPC at 6-8 weeks after radiotherapy were analysed using targeted sequencing for EBV DNA. RESULTS: The sensitivities of the PCR-based analysis, at a cut-off of any detectable levels of plasma EBV DNA, for prediction of local and distant recurrences were 42.3% and 85.3%, respectively. The sequencing-based analysis (involving quantitation and size profiling) achieved better performance for both local and distant recurrences than PCR. Using a cut-off of the proportion of plasma EBV DNA deduced by sequencing at 0.01%, the sensitivities of the sequencing-based analysis for local and distant recurrences were 88.5% and 97.1%, with the resultant negative predictive values of 99.1% and 99.4%, respectively. Among patients with undetectable EBV DNA on quantitative PCR, sequencing could further define a subgroup that enjoyed superior survival outcomes based on the proportion of plasma EBV DNA, with a 5-year progression-free survival (PFS) approaching 90%. On multivariate analysis, sequencing-based quantitative level of plasma EBV DNA was the independent prognostic factor with the highest hazard ratio for prediction of overall survival and PFS. CONCLUSION: NPC prognostication using post-treatment plasma EBV DNA could be enhanced through sequencing.

Proton pump inhibitor therapy and risk of knee replacement surgery: a general population-based cohort study.

OBJECTIVE: Proton pump inhibitors (PPIs) are among the most commonly used medications for patients with osteoarthritis (OA). Various types of PPIs have different impacts on lowering serum magnesium level that may affect knee OA progression. We aimed to compare the risk of clinically relevant endpoint of knee replacement (KR) among initiators of five different PPIs with that among histamine-2 receptor antagonist (H2RA) initiators. DESIGN: Among patients with knee OA (≥50 years) in The Health Improvement Network database in the UK we conducted five sequential propensity-score matched cohort studies to compare the risk of KR over 5-year among patients who initiated omeprazole (n = 2,672), pantoprazole (n = 664), lansoprazole (n = 3,747), rabeprazole (n = 751), or esomeprazole (n = 827) with those who initiated H2RA. RESULTS: The prevalence of PPI prescriptions among participants with knee OA increased from 12.7% in 2000-44.0% in 2017. Two-hundred-and-seventy-four KRs (30.8/1,000 person-years) occurred in omeprazole initiators and 230 KRs (25.4/1,000 person-years) in H2RA initiators. Compared with H2RA initiators, the risk of KR was 21% higher in omeprazole initiators (hazard ratio [HR] = 1.21,95% confidence interval [CI]:1.01-1.44). Similar results were observed when pantoprazole use was compared with H2RA use (HR = 1.38,95%CI:1.00-1.90). No such an increased risk of KR was observed among lansoprazole (HR = 1.06,95%CI:0.92-1.23), rabeprazole (HR = 0.97,95%CI:0.73-1.30), or esomeprazole (HR = 0.83,95%CI:0.60-1.15) initiators compared with that among H2RA initiators. CONCLUSIONS: In this population-based cohort study, initiation of omeprazole or pantoprazole use was associated with a higher risk of KR than initiation of H2RA use. This study raises concern regarding an unexpected risk of omeprazole and pantoprazole on accelerating OA progression.

Optimal symptom combinations to aid COVID-19 case identification: Analysis from a community-based, prospective, observational cohort.

OBJECTIVES: Diagnostic work-up following any COVID-19 associated symptom will lead to extensive testing, potentially overwhelming laboratory capacity whilst primarily yielding negative results. We aimed to identify optimal symptom combinations to capture most cases using fewer tests with implications for COVID-19 vaccine developers across different resource settings and public health. METHODS: UK and US users of the COVID-19 Symptom Study app who reported new-onset symptoms and an RT-PCR test within seven days of symptom onset were included. Sensitivity, specificity, and number of RT-PCR tests needed to identify one case (test per case [TPC]) were calculated for different symptom combinations. A multi-objective evolutionary algorithm was applied to generate combinations with optimal trade-offs between sensitivity and specificity. FINDINGS: UK and US cohorts included 122,305 (1,202 positives) and 3,162 (79 positive) individuals. Within three days of symptom onset, the COVID-19 specific symptom combination (cough, dyspnoea, fever, anosmia/ageusia) identified 69% of cases requiring 47 TPC. The combination with highest sensitivity (fatigue, anosmia/ageusia, cough, diarrhoea, headache, sore throat) identified 96% cases requiring 96 TPC. INTERPRETATION: We confirmed the significance of COVID-19 specific symptoms for triggering RT-PCR and identified additional symptom combinations with optimal trade-offs between sensitivity and specificity that maximize case capture given different resource settings.

Optimal symptom combinations to aid COVID-19 case identification: analysis from a community-based, prospective, observational cohort.

OBJECTIVES: Diagnostic work-up following any COVID-19 associated symptom will lead to extensive testing, potentially overwhelming laboratory capacity whilst primarily yielding negative results. We aimed to identify optimal symptom combinations to capture most cases using fewer tests with implications for COVID-19 vaccine developers across different resource settings and public health. METHODS: UK and US users of the COVID-19 Symptom Study app who reported new-onset symptoms and an RT-PCR test within seven days of symptom onset were included. Sensitivity, specificity, and number of RT-PCR tests needed to identify one case (test per case [TPC]) were calculated for different symptom combinations. A multi-objective evolutionary algorithm was applied to generate combinations with optimal trade-offs between sensitivity and specificity. FINDINGS: UK and US cohorts included 122,305 (1,202 positives) and 3,162 (79 positive) individuals. Within three days of symptom onset, the COVID-19 specific symptom combination (cough, dyspnoea, fever, anosmia/ageusia) identified 69% of cases requiring 47 TPC. The combination with highest sensitivity (fatigue, anosmia/ageusia, cough, diarrhoea, headache, sore throat) identified 96% cases requiring 96 TPC. INTERPRETATION: We confirmed the significance of COVID-19 specific symptoms for triggering RT-PCR and identified additional symptom combinations with optimal trade-offs between sensitivity and specificity that maximize case capture given different resource settings.

Early Detection of Cancer: Evaluation of MR Imaging Grading Systems in Patients with Suspected Nasopharyngeal Carcinoma.

BACKGROUND AND PURPOSE: We evaluated modifications to our contrast-enhanced MR imaging grading system for symptomatic patients with suspected nasopharyngeal carcinoma, aimed at improving discrimination of early-stage cancer and benign hyperplasia. We evaluated a second non-contrast-enhanced MR imaging grading system for asymptomatic patients from nasopharyngeal carcinoma plasma screening programs. MATERIALS AND METHODS: Dedicated nasopharyngeal MR imaging before (plain scan system) and after intravenous contrast administration (current and modified systems) was reviewed in patients from a nasopharyngeal carcinoma-endemic region, comprising 383 patients with suspected disease without nasopharyngeal carcinoma and 383 patients with nasopharyngeal carcinoma. The modified and plain scan systems refined primary tumor criteria, added a nodal assessment, and expanded the system from 4 to 5 grades. The overall combined sensitivity and specificity of the 3 systems were compared using the extended McNemar test (a χ2 value [Formula: see text]> 5.99 indicates significance). RESULTS: The current, modified, and plain scan MR imaging systems yielded sensitivities of 99.74%, 97.91%, and 97.65%, respectively, and specificities of 63.45%, 89.56% and 86.42%, respectively. The modified system yielded significantly better performance than the current ([Formula: see text] = 122) and plain scan ([Formula: see text] = 6.1) systems. The percentages of patients with nasopharyngeal carcinoma in grades 1-2, grade 3, and grades 4-5 for the modified and plain scan MR imaging systems were 0.42% and 0.44%; 6.31% and 6.96%; and 90.36% and 87.79%, respectively. No additional cancers were detected after contrast administration in cases of a plain scan graded 1-2. CONCLUSIONS: We propose a modified MR imaging grading system that improves diagnostic performance for nasopharyngeal carcinoma detection. Contrast was not valuable for low MR imaging grades, and the plain scan shows potential for use in screening programs.

Integrating postradiotherapy plasma Epstein-Barr virus DNA and TNM stage for risk stratification of nasopharyngeal carcinoma to adjuvant therapy.

BACKGROUND: After curative radiotherapy (RT) or chemoradiation (CRT), there is no validated tool to accurately identify patients for adjuvant therapy in nasopharyngeal carcinoma (NPC). Post-RT circulating plasma Epstein-Barr virus (EBV) DNA can detect minimal residual disease and is associated with recurrence and survival independent of TNM (tumor-lymph node-metastasis) stage. We aimed to develop and validate a risk model for stratification of NPC patients after completion of RT/CRT to observation or adjuvant therapy. PATIENTS AND METHODS: The prospective multicenter 0502 EBV DNA screening cohort (Hong Kong NPC Study Group 0502 trial) enrolled from 2006 to 2015 (n = 745) was used for model development. For internal validation, we pooled independent patient cohorts from prospective clinical studies enrolled from 1997 to 2006 (n = 340). For external validation, we used retrospective cohort of NPC patients treated at Sun Yat-sen University Cancer Center from 2009 to 2012 (n = 837). Eligible patients had histologically confirmed NPC of Union for International Cancer Control (UICC) 7th Edition stage II-IVB who completed curative RT/CRT with or without neoadjuvant chemotherapy, had post-RT EBV DNA tested within 120 days after RT and received no adjuvant therapy. The primary end point was overall survival (OS). We used recursive-partitioning analysis (RPA) to classify patients into groups of low, intermediate, and high risk of death. RESULTS: Combining post-RT EBV DNA level (0, 1-49, 50-499, and ≥500 copies/ml) and TNM stage (II, III, IVAB), RPA model classified patients into low-, intermediate-, and high-risk groups with 5-year OS of 89.4%, 78.5% and 37.2%, respectively. The RPA low-risk group had comparable OS to TNM stage II (5-year OS 88.5%) but identified more patients (64.8% versus stage II 28.1%) that could potentially be spared adjuvant therapy toxicity. The RPA model (c-index 0.712) showed better risk discrimination than either the TNM stage (0.604) or post-RT EBV DNA alone (0.675) with improved calibration and consistence. These results were validated in both internal and external cohorts. CONCLUSION: Combining post-RT EBV DNA and TNM stage improved risk stratification in NPC.

Complementary roles of MRI and endoscopic examination in the early detection of nasopharyngeal carcinoma.

BACKGROUND: Early-stage nasopharyngeal carcinoma (NPC) evades detection when the primary tumor is hidden from view on endoscopic examination. Therefore, in a prospective study of subjects being screened for NPC using plasma Epstein-Barr virus (EBV) DNA, we conducted a study to investigate whether magnetic resonance imaging (MRI) could detect endoscopically occult NPC. PATIENTS AND METHODS: Participants with persistently positive EBV DNA underwent endoscopic examination and biopsy when suspicious for NPC, followed by MRI blinded to the endoscopic findings. Participants with a negative endoscopic examination and positive MRI were recalled for biopsy or surveillance. Diagnostic performance was assessed by calculating sensitivity, specificity and accuracy, based on the histologic confirmation of NPC in the initial study or in a follow-up period of at least two years. RESULTS: Endoscopic examination and MRI were performed on 275 participants, 34 had NPC, 2 had other cancers and 239 without cancer were followed-up for a median of 36 months (24-60 months). Sensitivity, specificity and accuracy were 76.5%, 97.5% and 94.9%, respectively, for endoscopic examination and 91.2%, 97.5% and 96.7%, respectively, for MRI. NPC was detected only by endoscopic examination in 1/34 (2.9%) participants (a participant with stage I disease), and only by MRI in 6/34 (17.6%) participants (stage I = 4, II = 1, III = 1), two of whom had stage I disease and follow-up showing slow growth on MRI but no change on endoscopic examination for 36 months. CONCLUSION: MRI has a complementary role to play in NPC detection and can enable the earlier detection of endoscopically occult NPC.

Meeting report from the joint IARC-NCI international cancer seminar series: a focus on colorectal cancer.

Despite significant progress in our understanding of the etiology, biology and genetics of colorectal cancer, as well as important clinical advances, it remains the third most frequently diagnosed cancer worldwide and is the second leading cause of cancer death. Based on demographic projections, the global burden of colorectal cancer would be expected to rise by 72% from 1.8 million new cases in 2018 to over 3 million in 2040 with substantial increases anticipated in low- and middle-income countries. In this meeting report, we summarize the content of a joint workshop led by the National Cancer Institute and the International Agency for Research on Cancer, which was held to summarize the important achievements that have been made in our understanding of colorectal cancer etiology, genetics, early detection and treatment and to identify key research questions that remain to be addressed.

The Use of Post-ablation Stimulated Thyroglobulin in Predicting Clinical Outcomes in Differentiated Thyroid Carcinoma - What Cut-off Values Should We Use?

AIMS: Recently published international guidelines recommended using the stimulated thyroglobulin (sTg) post-radioactive iodine (RAI) ablation, in conjunction with tumour stage, as a risk stratification factor. The choice of cut-off values for sTg, namely 1 and 10 ng/ml, was, however, largely based on the functional sensitivities of the assays used, with relatively few published data addressing the prognostic impact of alternative cut-off values. Our study aims to provide data on the prognostic value of sTg at different levels of sensitivities and specificities. MATERIALS AND METHODS: We conducted a retrospective review of all adult cases of differentiated thyroid carcinoma receiving RAI ablation at our centre from 2008 to 2010. All patients had sTg measured at around 6 months post-ablation. The functional sensitivity of our assay was 0.5 ng/ml. The outcome was adverse clinical event, defined as cancer-related death, persistent macroscopic disease demonstrable on imaging (including radioisotope scan) and/or receiving further treatment for persistent or recurrent disease. A receiver operating characteristic (ROC) analysis was carried out. RESULTS: We identified 140 patients treated in the review period, with 106 of them suitable for further analysis. The reasons for exclusion included the presence of anti-thyroglobulin antibodies and medullary or anaplastic histological subtypes. Most (54.7%) had intermediate-risk disease as per the American Thyroid Association classification (2009). The median follow-up duration was 6.4 years; the minimum, excluding deaths, was 5.0 years. ROC analysis showed that the optimal cut-off value of sTg for predicting adverse clinical events was >1.0 ng/ml, associated with a sensitivity of 90.9%, a specificity of 81.0%, a positive predictive value of 55.6% and a negative predictive value of 97.1%. CONCLUSION: Based on ROC analysis of sensitivities and specificities, our data showed that a post-ablation sTg value of 1 ng/ml is the optimal cut-off in prognostication of adverse clinical events.

MR Imaging Criteria for the Detection of Nasopharyngeal Carcinoma: Discrimination of Early-Stage Primary Tumors from Benign Hyperplasia.

BACKGROUND AND PURPOSE: MR imaging can detect nasopharyngeal carcinoma that is hidden from endoscopic view, but for accurate detection carcinoma confined within the nasopharynx (stage T1) must be distinguished from benign hyperplasia of the nasopharynx. This study aimed to document the MR imaging features of stage T1 nasopharyngeal carcinoma and to attempt to identify features distinguishing it from benign hyperplasia. MATERIALS AND METHODS: MR images of 189 patients with nasopharyngeal carcinoma confined to the nasopharynx and those of 144 patients with benign hyperplasia were reviewed and compared in this retrospective study. The center, volume, size asymmetry (maximum percentage difference in area between the right and left nasopharyngeal halves), signal intensity asymmetry, deep mucosal white line (greater contrast enhancement along the deep tumor margin), and absence/distortion of the adenoidal septa were evaluated. Differences were assessed with logistic regression and the χ2 test. RESULTS: The nasopharyngeal carcinoma center was lateral, central, or diffuse in 134/189 (70.9%), 25/189 (13.2%), and 30/189 (15.9%) cases, respectively. Nasopharyngeal carcinomas involving the walls showed that a deep mucosal white line was present in 180/183 (98.4%), with a focal loss of this line in 153/180 (85%) cases. Adenoidal septa were absent or distorted in 111/111 (100%) nasopharyngeal carcinomas involving the adenoid. Compared with benign hyperplasia, nasopharyngeal carcinoma had a significantly greater volume, size asymmetry, signal asymmetry, focal loss of the deep mucosal white line, and absence/distortion of the adenoidal septa (P < .001). Although size asymmetry was the most accurate criterion (89.5%) for nasopharyngeal carcinoma detection, use of this parameter alone would have missed 11.9% of early-stage T1 nasopharyngeal carcinomas. CONCLUSIONS: MR imaging features can help distinguish stage T1 nasopharyngeal carcinoma from benign hyperplasia in most cases.

Identifying an early indicator of drug efficacy in patients with metastatic colorectal cancer-a prospective evaluation of circulating tumor cells, 18F-fluorodeoxyglucose positron-emission tomography and the RECIST criteria.

BACKGROUND: This study investigated the predictive and prognostic significance of assessing early drug response with both positron-emission computerized tomography (PET-CT) and circulating tumor cells (CTCs) in patients receiving first-line chemotherapy for metastatic colorectal cancer. PATIENTS AND METHODS: Eligible patients had PET-CT and CTC analysis at baseline and 4-6 weeks after starting chemotherapy, and then a CT scan at 10-12 weeks to assess the Response Evaluation Criteria In Solid Tumors (RECIST) response. Early response was defined as achieving a dual-endpoint consisting of PET-CT (30% drop in the sum of maximum standard uptake values-SUVmax-of target lesions) and CTC response (CTC < 3 cells/7.5 ml blood) at 4-6 weeks after starting chemotherapy. RESULTS: About 84 patients were enrolled with a median follow-up of 32.9 months (95% confidence interval, CI, 24.5 months-not reached, NR), and 70 patients (84.3%) completed all assessments. Achieving an early response based on the dual-endpoint was independently associated with progression-free survival (hazard ratio, HR = 0.452, 95% CI 0.267-0.765). The median progression-free survival of early responders was 7.41 months (95% CI, 6.05-9.11) compared with 5.37 months (95% CI, 4.68-6.24) in non-responders (log-rank, P = 0.0167). RECIST response at 10 weeks was independently associated with overall survival (OS) (HR = 0.484, 95% CI, 0.275-0.852). Early response based on the dual-endpoint could predict the subsequent RECIST response with a sensitivity, specificity and positive predictive value of 64%, 70% and 74%, respectively. CONCLUSIONS: Early response based on both PET-CT and CTC analysis has prognostic and probably predictive significance in patients undergoing first-line chemotherapy for metastatic colorectal cancer. Its utility as a new tool for assessing early drug response should be further validated.

Detection of Nasopharyngeal Carcinoma by MR Imaging: Diagnostic Accuracy of MRI Compared with Endoscopy and Endoscopic Biopsy Based on Long-Term Follow-Up.

BACKGROUND AND PURPOSE: Our previous nasopharyngeal carcinoma detection study, comparing MR imaging, endoscopy, and endoscopic biopsy, showed that MR imaging is a highly sensitive test that identifies nasopharyngeal carcinomas missed by endoscopy. However, at the close of that study, patients without biopsy-proved nasopharyngeal carcinoma nevertheless had shown suspicious abnormalities on endoscopy and/or MR imaging. The aim of this study was to determine whether there were any patients with undiagnosed nasopharyngeal carcinoma by obtaining long-term follow-up and to use these data to re-evaluate the diagnostic performance of MR imaging. MATERIALS AND METHODS: In the previous study, 246 patients referred to a hospital ear, nose, and throat clinic with suspected nasopharyngeal carcinoma, based on a wide range of clinical indications, had undergone MR imaging, endoscopy, and endoscopic biopsy, and 77 had biopsy-proved nasopharyngeal carcinoma. One hundred twenty-six of 169 patients without biopsy-proved nasopharyngeal carcinoma underwent re-examination of the nasopharynx after a minimum of 3 years, including 17 patients in whom a previous examination (MR imaging = 11; endoscopy = 7) had been positive for nasopharyngeal carcinoma, but the biopsy had been negative for it. Patients with nasopharyngeal carcinoma were identified by biopsy obtained in the previous and this follow-up study; patients without nasopharyngeal carcinoma were identified by the absence of a tumor on re-examination of the nasopharynx. The sensitivity and specificity of the previous investigations were updated and compared by using the Fisher exact test. RESULTS: One patient with a previous positive MR imaging finding was subsequently proved to have nasopharyngeal carcinoma. Nasopharyngeal carcinomas were not found in the remaining 125 patients at follow-up, and the previous positive findings for nasopharyngeal carcinoma on MR imaging and endoscopy were attributed to benign lymphoid hyperplasia. The diagnostic performances for the previous MR imaging, endoscopy, and endoscopic biopsy were 100%, 88%, and 94%, respectively, for sensitivity, and 92%, 94%, and 100%, respectively, for specificity; the differences between MR imaging and endoscopy were significant for sensitivity (P = .003) but not specificity (P = .617). CONCLUSIONS: MR imaging detected the 12% of nasopharyngeal carcinomas that were endoscopically invisible, including 1 cancer that remained endoscopically occult for several years. Lymphoid hyperplasia reduced the specificity of MR imaging.

Multicenter phase II study of the AKT inhibitor MK-2206 in recurrent or metastatic nasopharyngeal carcinoma from patients in the mayo phase II consortium and the cancer therapeutics research group (MC1079).

BACKGROUND: This study investigated the activity of MK-2206, an AKT inhibitor, in metastatic or recurrent nasopharyngeal carcinoma (NPC). METHOD: Oral MK-2206 at a dose of 200 mg was administered on days 1, 8, 15 and 22 of a 28-day cycle until progression. Plasma EBV DNA clearance during the first month of treatment was measured, and archived tumors were analyzed for the expression of AKT and PIK3CA mutation and PIK3CA amplification. The dual primary endpoint was objective response rate and 6-month progression-free survival (PFS) rate. RESULTS: 21 patients were enrolled and one patient achieved a partial response (5 %) and 11 had stable disease (52 %), with a median PFS of 3.5 months (95 % confidence interval, CI: 0.9-7.3). The 6-month PFS rate was 43 % (95 % CI: 22-66 %) and the median OS was 10 months (95 % CI: 5.9 months-not reached). Seven patients (33 %) experienced grade 3 toxicities which could be related to MK-2206. Macular-papular rash was the most common (n = 6), followed by hyperglycemia (n = 2) and fatigue (n = 1). In the 12 tumor samples analyzed, PIK3CA amplification was detected in one patient's primary NPC, who had SD lasting over 12 months. Patients with decreasing EBV DNA values over time were more likely to be alive and progression-free for at least 6 months than those without a decrease (p = 0.001). CONCLUSION: The study was terminated due to the limited activity observed in this heavily pre-treated group of patients. Further studies are needed to elucidate the optimal way of selecting patients for AKT inhibitors.

Reproductive factors, exogenous hormone use and risk of hepatocellular carcinoma among US women: results from the Liver Cancer Pooling Project.

BACKGROUND: Hepatocellular carcinoma (HCC) occurs less commonly among women than men in almost all regions of the world. The disparity in risk is particularly notable prior to menopause suggesting that hormonal exposures during reproductive life may be protective. Exogenous oestrogenic exposures such as oral contraceptives (OCs), however, have been reported to increase risk, suggesting that estrogens may be hepatocarcinogenic. To examine the effects of reproductive factors and exogenous hormones on risk, we conducted a prospective analysis among a large group of US women. METHODS: In the Liver Cancer Pooling Project, a consortium of US-based cohort studies, data from 799,500 women in 11 cohorts were pooled and harmonised. Cox proportional hazards regression models were used to generate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of reproductive factors and exogenous hormones with HCC (n=248). RESULTS: Bilateral oophorectomy was associated with a significantly increased risk of HCC (HR=2.67, 95% CI=1.22-5.85), which did not appear to be related to a shorter duration of exposure to endogenous hormones or to menopausal hormone therapy use. There was no association between OC use and HCC (HR=1.12, 95% CI=0.82-1.55). Nor were there associations with parity, age at first birth, age at natural menopause, or duration of fertility. CONCLUSIONS: The current study suggests that bilateral oophorectomy increases the risk of HCC but the explanation for the association is unclear. There was no association between OC use and HCC risk. Examination of endogenous hormone levels in relation to HCC may help to clarify the findings of the current study.