Accounting for Delayed Entry in Analyses of Overall Survival in Clinico-Genomic Databases.

BACKGROUND: Clinico-genomic databases favor inclusion of long-term survivors, leading to potentially biased overall survival (OS) analyses. Risk set adjustments relying on the independent delayed entry assumption may mitigate this bias. We aimed to determine whether this assumption is satisfied in a dataset of patients with advanced non-small cell lung cancer (aNSCLC), and to give guidance for clinico-genomic OS analyses when the assumption is not satisfied. METHODS: We analyzed the association of timing of next-generation sequencing (NGS) testing with real-world OS (rwOS) in patient data from a United States-based nationwide longitudinal deidentified electronic health records-derived database. Estimates of rwOS using risk set adjustment were compared with estimates computed with respect to all patients, regardless of NGS testing. RESULTS: The independent delayed entry assumption was not satisfied in this database, and later sequencing had a negative association with the hazard of death after sequencing. In a model adjusted for relevant characteristics, each month delay in sequencing was associated with a 2% increase in the hazard of death. However, until the median survival time, estimates of OS using risk set adjustment are similar to estimates computed for all patients, regardless of NGS testing. CONCLUSIONS: rwOS analyses in clinico-genomic databases should assess the independent delayed entry assumption. Comparisons versus broader population may be useful to evaluate the rwOS differences between calculations using risk set adjustment and patient cohorts where the bias relates to overrepresentation of long survivors. IMPACT: This study illustrates practices that can increase the interpretability of findings from OS analyses in clinico-genomic databases.

Bayesian additional evidence for decision making under small sample uncertainty.

BACKGROUND: Statistical inference based on small datasets, commonly found in precision oncology, is subject to low power and high uncertainty. In these settings, drawing strong conclusions about future research utility is difficult when using standard inferential measures. It is therefore important to better quantify the uncertainty associated with both significant and non-significant results based on small sample sizes. METHODS: We developed a new method, Bayesian Additional Evidence (BAE), that determines (1) how much additional supportive evidence is needed for a non-significant result to reach Bayesian posterior credibility, or (2) how much additional opposing evidence is needed to render a significant result non-credible. Although based in Bayesian analysis, a prior distribution is not needed; instead, the tipping point output is compared to reasonable effect ranges to draw conclusions. We demonstrate our approach in a comparative effectiveness analysis comparing two treatments in a real world biomarker-defined cohort, and provide guidelines for how to apply BAE in practice. RESULTS: Our initial comparative effectiveness analysis results in a hazard ratio of 0.31 with 95% confidence interval (0.09, 1.1). Applying BAE to this result yields a tipping point of 0.54; thus, an observed hazard ratio of 0.54 or smaller in a replication study would result in posterior credibility for the treatment association. Given that effect sizes in this range are not extreme, and that supportive evidence exists from a similar published study, we conclude that this problem is worthy of further research. CONCLUSIONS: Our proposed method provides a useful framework for interpreting analytic results from small datasets. This can assist researchers in deciding how to interpret and continue their investigations based on an initial analysis that has high uncertainty. Although we illustrated its use in estimating parameters based on time-to-event outcomes, BAE easily applies to any normally-distributed estimator, such as those used for analyzing binary or continuous outcomes.

Real-world association of HER2/ERBB2 concordance with trastuzumab clinical benefit in advanced esophagogastric cancer.

Aim: To assess concordance between HER2 status measured by traditional methods and ERBB2 amplification measured by next-generation sequencing and its association with first-line trastuzumab clinical benefit in patients with advanced esophagogastric cancer. Methods: Retrospective analysis of HER2/ERBB2 concordance using a deidentified USA-based clinicogenomic database. Clinical outcomes were assessed for patients with HER2+ advanced esophagogastric cancer who received first-line trastuzumab. Results: Overall HER2/ERBB2 concordance was 87.5%. Among patients who received first-line trastuzumab, concordant HER2/ERBB2 was associated with longer time to treatment discontinuation (adjusted hazard ratio [aHR]: 0.63; 95% CI: 0.43-0.90) and overall survival (aHR: 0.51; 95% CI: 0.33-0.79). ERBB2 copy number ≥25 (median) was associated with longer time to treatment discontinuation (aHR: 0.56; 95% CI: 0.35-0.88) and overall survival (aHR: 0.52; 95% CI: 0.30-0.91). Conclusion: HER2/ERBB2 concordance and higher ERBB2 copy number predicted clinical benefit from trastuzumab.

Lay abstract Trastuzumab is a drug that has been shown to prolong survival in some patients with advanced esophagogastric cancer whose tumor expresses a protein biomarker called HER2. There are different methods for assessing whether a patient's tumor expresses HER2, including but not limited to traditional methods such as immunohistochemistry and in situ hybridization and novel methods such as next-generation sequencing, which detects alterations in the gene (ERBB2) that encodes the HER2 protein. In our study, we assessed concordance between HER2 status (HER2-positive or HER2-negative) measured by traditional methods and ERBB2 amplification measured by next-generation sequencing, to determine whether there was an association between concordance and clinical benefit in patients with advanced esophagogastric cancer treated with trastuzumab. Our results suggest that, when HER2 positivity is detected through traditional methods, both ERBB2 concordance (i.e., agreement that a patient's tumor had the biomarker) and a higher ERBB2 copy number (the amount of the ERBB2 gene expressed by the tumor) were associated with longer time to treatment discontinuation and overall survival in patients with advanced esophagogastric cancer treated with first-line trastuzumab.

Real-world use of procalcitonin and other biomarkers among sepsis hospitalizations in the United States: A retrospective, observational study.

BACKGROUND: Sepsis management guidelines endorse use of biomarkers to support clinical assessment and treatment decisions in septic patients. The impact of biomarkers on improving patient outcomes remains uncertain. METHODS: Retrospective observational study of adult sepsis discharges between January 1, 2012, and December 31, 2015, from Premier Healthcare Database hospitals. Sepsis was defined by an All Patients Refined Diagnosis-Related Group code of 720 (septicemia and disseminated infections). Use of four biomarker strategies was evaluated based on hospital records: (i) >1 procalcitonin (PCT), (ii) 1 PCT, (iii) no PCT but ≥1 C-reactive protein (CRP) and/or lactate and (iv) no sepsis biomarkers. Associations between biomarker use and clinical and cost outcomes were examined. The primary outcome was impact of biomarker strategy on hospital costs per day. RESULTS: Among 933,591 adult sepsis discharges during the study period, 731,392 (78%) had biomarker tests ordered. In multivariable analyses, discharges with >1 PCT had higher hospital costs per day ($1,904; 95% confidence interval [CI] $1,896-$1,911) compared with discharges with no sepsis biomarkers ($1,606; 95% CI $1,658-$1,664). Discharges with >1 PCT also had greater illness severity and antimicrobial exposure compared with other biomarker-use groups. The adjusted odds of dying during hospital stay compared with being discharged were significantly lower for sepsis discharges with >1 PCT (0.64; 95% CI 0.61-0.67) and 1 PCT (0.88; 95% CI 0.85-0.91) compared with no sepsis biomarker use. The proportion of discharges with ≥1 PCT increased almost six-fold during the study; use of other biomarkers remained constant. CONCLUSIONS: Between 2012 and 2015, PCT use among sepsis discharges increased six-fold while lactate and CRP use remained unchanged. PCT use was associated with decreased odds of in-hospital mortality but increased hospital costs per day. Serial biomarker monitoring may be associated with improved patient outcomes in the most critically ill septic patients.

Real-world treatment patterns for patients receiving second-line and third-line treatment for advanced non-small cell lung cancer: A systematic review of recently published studies.

Most patients with advanced non-small cell lung cancer (NSCLC) have a poor prognosis and receive limited benefit from conventional treatments, especially in later lines of therapy. In recent years, several novel therapies have been approved for second- and third-line treatment of advanced NSCLC. In light of these approvals, it is valuable to understand the uptake of these new treatments in routine clinical practice and their impact on patient care. A systematic literature search was conducted in multiple scientific databases to identify observational cohort studies published between January 2010 and March 2017 that described second- or third-line treatment patterns and clinical outcomes in patients with advanced NSCLC. A qualitative data synthesis was performed because a meta-analysis was not possible due to the heterogeneity of the study populations. A total of 12 different study cohorts in 15 articles were identified. In these cohorts, single-agent chemotherapy was the most commonly administered treatment in both the second- and third-line settings. In the 5 studies that described survival from the time of second-line treatment initiation, median overall survival ranged from 4.6 months (95% CI, 3.8-5.7) to 12.8 months (95% CI, 10.7-14.5). There was limited information on the use of biomarker-directed therapy in these patient populations. This systematic literature review offers insights into the adoption of novel therapies into routine clinical practice for second- and third-line treatment of patients with advanced NSCLC. This information provides a valuable real-world context for the impact of recently approved treatments for advanced NSCLC.

Lung Cancer Survival Among Chinese Americans, 2000 to 2010.

PURPOSE: Despite being the leading cause of cancer death, no prior studies have characterized survival patterns among Chinese Americans diagnosed with lung cancer. This study was conducted to identify factors associated with survival after lung cancer in a contemporary cohort of Chinese patients with lung cancer. METHODS: The study design is a prospective descriptive analysis of population-based California Cancer Registry data. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) for overall mortality. Participants were Chinese American residents diagnosed with first primary invasive lung cancer from 2000 to 2010 (2,216 men and 1,616 women). RESULTS: Among Chinese men, decreased mortality was associated with care at a National Cancer Institute cancer center (HR, 0.85; 95% CI, 0.73 to 0.99) and adenocarcinoma versus small-cell carcinoma (HR, 0.78; 95% CI, 0.65 to 0.92). Women had better survival compared with men (HR, 0.82; 95% CI, 0.75 to 0.89), with mortality associated with never married versus currently married status (HR, 1.36; 95% CI, 1.11 to 1.66), lower versus higher neighborhood socioeconomic status (HR, 1.38; 95% CI, 1.10 to 1.72 comparing lowest to highest quintile), care at a cancer center (HR, 0.80; 95% CI, 0.67 to 0.96), and squamous cell relative to small-cell carcinoma (HR, 1.60; 95% CI, 1.04 to 2.48). CONCLUSION: Focusing on factors associated with marital status, community socioeconomic status, and characteristics unique to National Cancer Institute-designated cancer centers may help to identify potential strategies for improving the length of survival for Chinese Americans.

The incidence of metastatic basal cell carcinoma (mBCC) in Denmark, 1997-2010.

BACKGROUND: Few data exist on the occurrence of metastatic basal cell carcinoma (mBCC). OBJECTIVE: To identify all cases of mBCC in Denmark over a 14-year period. METHODS: We searched the Danish National Patient Registry covering all Danish hospitals, the Danish Cancer Registry, the National Pathology Registry and the Causes of Death Registry during the period 1997 to 2010 for potential cases of mBCC registered according to the International classification of diseases ICD-10 and the International Systemized Nomenclature of Medicine (SNOMED). RESULTS: We identified 126,627 patients with a history of primary basal cell carcinoma (BCC) in the registries during the 14-year study period. Using case identifications from the four registries, a total of 170 potential mBCC cases were identified. However, after a pathology review, only five cases could be confirmed, of which three were basosquamous carcinomas. The 14-year cumulative incidence proportion of mBCC was 0.0039% (95% CI 0.0016-0.0083) among individuals with a history of previous BCC (n = 126,627) and 0.0001% (95% CI 0.0000-0.0002) in the general population. CONCLUSION: MBCC is a rare disease and only a small proportion of potential cases identified in automated clinical databases or registries can be confirmed by pathology and medical record review.

Incidence trends of lung cancer by immigration status among Chinese Americans.

BACKGROUND: Lung cancer is the leading cause of cancer-related death among Chinese Americans. A detailed examination of incidence trends by immigration status and histology may inform the etiology of lung cancer in this growing population. METHODS: California Cancer Registry data were enhanced with data on patient nativity. Lung cancer incidence rates for Chinese males and females were computed for the years 1990-2010, and rates by immigration status and histology were computed for 1990-2004. Trends were assessed with annual percentage change (APC) statistics (two-sided P values) based on linear regression. RESULTS: A total of 8,167 lung cancers were diagnosed among California Chinese from 1990 to 2010. Overall incidence increased nonstatistically among U.S.-born males (APC, 2.1; 95% CI, -4.9 to 9.7), but decreased significantly among foreign-born (APC, -1.7; 95% CI, -2.9 to -0.6). Statistically significant decreasing trends were observed for non-small cell lung cancer (NSCLC), specifically the squamous cell and large cell carcinoma subtypes among foreign-born males. Among females, incidence decreased nonsignificantly among U.S.-born (APC, -2.8; 95% CI, -9.1 to 4.0) but was stable among foreign-born (APC, -0.4; 95% CI, -1.7 to 1.0). A statistically significant decreasing trend was observed for squamous cell among foreign-born females. CONCLUSIONS: These data provide critical evidence base to inform screening, research, and public health priorities in this growing population. IMPACT: Given the low smoking prevalence among Chinese Americans, especially females, and few known lung cancer risk factors in U.S. never-smoker populations, additional research of etiologic genetic or biologic factors may elucidate knowledge regarding lung cancer diagnosed in never smokers.

Metastatic basal cell carcinoma: prognosis dependent on anatomic site and spread of disease.

PURPOSE: This review provides a description of the epidemiology and survival outcomes for cases with metastatic basal cell carcinoma (mBCC) based on published reports (1981-2011). METHODS: A literature search (MEDLINE via PubMed) was conducted for mBCC case reports published in English: 1981-2011. There were 172 cases that met the following criteria: primary BCC located on skin, metastasis confirmed by pathology and metastasis not resulting from direct tumour spread. From these, 100 mBCC cases with explicit information on follow-up time were selected for analysis. Survival analysis was conducted using Kaplan-Meier methods. RESULTS: Among 100 mBCC cases selected for analysis, including one case with Gorlin syndrome, 50% had regional metastases (RM) and 50% had distant metastases (DM). Cases with DM were younger at mBCC diagnosis (mean age, 58.0 versus 66.3 years for RM; P=0.0013). Among 93 (of 100) cases with treatment information for metastatic disease, more DM cases received chemotherapy (36.2% versus 6.5% for RM), but more RM cases underwent surgery (87.0% versus 40.4% for DM). Among all 100 cases, median survival after mBCC diagnosis was 54 months (95% confidence interval (CI), 24-72), with shorter survival in DM (24 months; 95% CI, 12-35) versus RM cases (87 months; 95% CI, 63-not evaluable). CONCLUSION: Cases with RM and DM mBCC may have different clinical courses and outcomes. Based on published reports, DM cases were younger at mBCC diagnosis, with shorter median survival than RM cases. This study provides a historical context for emerging mBCC treatments.

Feasibility of linking population-based cancer registries and cancer center biorepositories.

PURPOSE: Biospecimen-based research offers tremendous promise as a way to increase understanding of the molecular epidemiology of cancers. Population-based cancer registries can augment this research by providing more clinical detail and long-term follow-up information than is typically available from biospecimen annotations. In order to demonstrate the feasibility of this concept, we performed a pilot linkage between the California Cancer Registry (CCR) and the University of California, Davis Cancer Center Biorepository (UCD CCB) databases to determine if we could identify patients with records in both databases. METHODS: We performed a probabilistic data linkage between 2180 UCD CCB biospecimen records collected during the years 2005-2009 and all CCR records for cancers diagnosed from 1988-2009 based on standard data linkage procedures. RESULTS: The 1040 UCD records with a unique medical record number, tissue site, and pathology date were linked to 3.3 million CCR records. Of these, 844 (81.2%) were identified in both databases. Overall, record matches were highest (100%) for cancers of the cervix and testis/other male genital system organs. For the most common cancers, matches were highest for cancers of the lung and respiratory system (93%), breast (91.7%), and colon and rectum (89.5%), and lower for prostate (72.9%). CONCLUSIONS: This pilot linkage demonstrated that information on existing biospecimens from a cancer center biorepository can be linked successfully to cancer registry data. Linkages between existing biorepositories and cancer registries can foster productive collaborations and provide a foundation for virtual biorepository networks to support population-based biospecimen research.

CK20 and CK7 protein expression in colorectal cancer: demonstration of the utility of a population-based tissue microarray.

The ability to use archival tissue to test externally valid hypotheses of carcinogenesis is dependent on the availability of population-based samples of cancer tissue. Tissue microarrays (TMAs) provide an efficient format for developing population-based samples of tissue. A TMA was constructed consisting of archival tissue from patients diagnosed with invasive colorectal cancer in the state of Hawaii in 1995. The population representativeness of the TMA was evaluated by comparing patient and clinical characteristics of TMA cases to that of all cases of colorectal carcinoma diagnosed statewide in 1995. Cytokeratin 20 (CK20) and cytokeratin 7 (CK7) immunohistochemistry was used to validate the utility of the TMA, and the expression of these proteins was correlated with patient and tumor characteristics. The TMA comprised tissue specimens from 286 patients representing 47% of all invasive cases diagnosed statewide in 1995. TMA cases were comparable to all invasive colorectal cases statewide with respect to age, sex, race/ethnicity, anatomic site, and survival. There were some differences between TMA cases and all cases with respect to tumor stage, histological classification, and treatment. There were significant differences in the relative expression of CK20 and CK7 proteins between malignant and normal tissues and by tumor stage. Advanced cancers were more likely to have CK20+/cytokeratin 7+ (CK7+) profiles than early-stage cancers, which were predominantly CK20+/cytokeratin 7- (CK7-). CK7+ expression was not correlated with anatomic location of carcinomas. This well-characterized TMA offers a powerful tool for testing hypotheses regarding colorectal carcinogenesis, including the identification of potential markers of neoplastic development and progression.

Family history of heart disease and cardiovascular disease risk-reducing behaviors.

BACKGROUND: Family history is an important cardiovascular disease (CVD) risk factor. Preventive behaviors, including lifestyle modifications, can attenuate CVD risk. We studied the association between family history-based heart disease (HD) risk and CVD risk-reducing behaviors. METHODS: Using data from the 2001 Healthstyles survey, we compared frequencies of CVD risk-reducing behaviors among adults without known CVD in categories defined by family history-based HD risk. We classified respondents' HD risk as average (no first-degree relatives with HD), moderate (one relative), or high (> or = two relatives). Behaviors studied included lifestyle modifications, cholesterol measurement, and aspirin use. RESULTS: Of 3383 respondents without known CVD, 28% were classified as being at moderate risk and 15% as being at high risk for HD based on family history. Adjusted odds ratios indicated that moderate- and high-risk respondents were more likely to report having cholesterol measured within the previous 5 years (OR = 1.39, 95% Confidence Interval [CI] = 1.16-1.67 and 1.29, 95% CI = 1.01-1.64, respectively), and aspirin use to reduce CVD risk (OR = 1.49, 95% CI = 1.23-1.79 and 1.67, 95% CI = 1.33-2.09, respectively) than average-risk respondents. CONCLUSION: Almost one half of respondents reported a family history of HD. Aspirin use and cholesterol measurement (i.e., behaviors that health-care providers might suggest) were more likely to be reported by moderate- and high-risk respondents than were lifestyle changes. Family history merits further investigation as a public health tool to identify persons with increased HD risk who might benefit from enhanced prevention strategies.

Fluoroquinolone use and Clostridium difficile-associated diarrhea.

We performed a case-control study to evaluate the association between antibiotic use and Clostridium difficile-associated diarrhea (CDAD), matching for admission unit and time at risk for CDAD. A multivariable regression model showed that treatment with fluoroquinolones (odds ratio 12.7; 95% confidence interval 2.6 to 61.6) was the strongest risk factor for CDAD.

Endocrine tumors of the uterine cervix: incidence, demographics, and survival with comparison to squamous cell carcinoma.

OBJECTIVE: The aim was to describe the epidemiology of endocrine tumors of the cervix in comparison with invasive squamous cell carcinomas using population-based data reported to the Surveillance, Epidemiology and End-Results (SEER) program. METHODS: Retrospective analysis of actively followed cases reported to SEER from 1973 to 1998. Incidence, demographic characteristics, and survival were compared for endocrine and squamous tumors. RESULTS: There were 239 cases of endocrine tumors and 18,458 cases of invasive squamous cell carcinoma of the cervix included in the study. Mean age at diagnosis was 49 years for endocrine tumors versus 52 years for squamous cell carcinoma (P < 0.01). Endocrine tumors were more likely to present at a later FIGO stage (P < 0.01), and to have lymph node involvement at diagnosis (57 vs 18%, P < 0.01) compared to squamous cell carcinoma. Observed median survival for women with endocrine tumors was 22 months versus 10 years for women with squamous cell carcinoma. Age and FIGO stage-adjusted hazards of death were 1.84 times greater for endocrine tumors than for squamous cell carcinoma (95% CI 1.52-2.23). At all stages of disease, survival was worse for women with endocrine tumors compared to women with squamous cell carcinomas. CONCLUSIONS: Endocrine tumors of the cervix are extremely aggressive and survival is poor regardless of stage at diagnosis.

Primary malignant neoplasms of the appendix: a population-based study from the surveillance, epidemiology and end-results program, 1973-1998.

BACKGROUND: Cancer of the appendix is an uncommon disease that is rarely suspected rarely before surgery. Although several case series of these tumors have been published, little research has been anchored in population-based data on cancer of the appendix. METHODS: This analysis included all actively followed cases of appendiceal neoplasms reported to the National Cancer Institute's Surveillance, Epidemiology and End-Results (SEER) program between 1973 and 1998. Tumors were classified as "colonic type" adenocarcinoma, mucinous adenocarcinoma, signet ring cell carcinoma, goblet cell carcinoid, and "malignant carcinoid" (SEER only collects data on carcinoids specifically classified as malignant). We compared incidence, overall survival and survival rates by extent of disease at diagnosis. RESULTS: Between 1973 and 1998, 2117 appendiceal malignancies were reported to the SEER program, of which 1645 cases were included in the analysis. Age-adjusted incidence of cancer of the appendix was 0.12 cases per 1,000,000 people per year. Demographic characteristics of patients with goblet cell carcinoid tumors were midway between those of patients with malignant carcinoid and all types of adenocarcinomas. After controlling for age and extent of disease at diagnosis, the overall survival rate for patients diagnosed between 1983 and 1997 (n = 1061) was significantly worse for those with signet ring cell carcinoma than for those with any other tumor type (P < 0.01). In addition, overall survival rates were better for patients with malignant carcinoid (P = 0.01). CONCLUSIONS: Demographic characteristics of patients with cancer of the appendix vary by histology. Except for signet ring cell carcinoma and malignant carcinoid, the extent of disease at time of diagnosis is a more important predictor of survival than histology.

Severity-of-illness markers as predictors of nosocomial infection in adult intensive care unit patients.

BACKGROUND: Patients admitted to intensive care units (ICUs) are at high risk for acquiring nosocomial infections. We examined the association between markers of severity of illness at ICU admission and the development of ICU-attributable nosocomial infections. METHODS: Retrospective cohort study of 851 patients admitted to the medical or surgical ICU in an urban teaching hospital from January 1997 to January 1998. Logistic regression analysis was used to identify predictors of nosocomial infection, including the Acute Physiology, Age, Chronic Health Evaluation III severity-of-illness scoring system. RESULTS: Patients receiving mechanical ventilation on day 1 of ICU admission (OR, 1.99; 95% CI, 1.29-3.06) and patients transferred to the ICU from another unit within the same hospital (OR, 2.04; 95% CI, 1.24-3.34) were twice as likely to acquire an ICU-attributable nosocomial infection compared with patients admitted from other sources. The day-1 Acute Physiology, Age, Chronic Health Evaluation III score was not a significant predictor of nosocomial infection. CONCLUSION: The need for mechanical ventilation on ICU day 1 and transfer to the ICU from another unit are independent predictors of ICU-attributable nosocomial infections. Up to 50% of ICU patients who develop nosocomial infections could be easily identified at ICU admission, allowing for targeted use of preventive strategies to reduce the risk of nosocomial infections.