Alex R. Chang

Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: Results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer)

BACKGROUND This placebo-controlled phase III study investigated the effect on survival of gefitinib as second-line or third-line treatment for patients with locally advanced or metastatic non-small-cell lung cancer. METHODS 1692 patients who were refractory to or intolerant of their latest chemotherapy regimen were randomly assigned in a ratio of two to one either gefitinib (250 mg/day) or placebo, plus best supportive care. The primary endpoint was survival in the overall population of patients and those with adenocarcinoma. The primary analysis of the population for survival was by intention to treat. This study has been submitted for registration with ClinicalTrials.gov, number 1839IL/709. FINDINGS 1129 patients were assigned gefitinib and 563 placebo. At median follow-up of 7.2 months, median survival did not differ significantly between the groups in the overall population (5.6 months for gefitinib and 5.1 months for placebo; hazard ratio 0.89 [95% CI 0.77-1.02], p=0.087) or among the 812 patients with adenocarcinoma (6.3 months vs 5.4 months; 0.84 [0.68-1.03], p=0.089). Preplanned subgroup analyses showed significantly longer survival in the gefitinib group than the placebo group for never-smokers (n=375; 0.67 [0.49-0.92], p=0.012; median survival 8.9 vs 6.1 months) and patients of Asian origin (n=342; 0.66 [0.48-0.91], p=0.01; median survival 9.5 vs 5.5 months). Gefitinib was well tolerated, as in previous studies. INTERPRETATION Treatment with gefitinib was not associated with significant improvement in survival in either coprimary population. There was pronounced heterogeneity in survival outcomes between groups of patients, with some evidence of benefit among never-smokers and patients of Asian origin.

Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer

Its All in the Delivery Pancreatic cancer is almost universally associated with a poor prognosis, in part because the tumors are resistant to chemotherapeutic drugs. Working with a mouse tumor model that displays many features of the human disease, Olive et al. (p. 1457, published online 21 May; see the Perspective by Olson and Hanahan) found that the tumors were poorly vascularized, a factor likely to impede drug delivery. Treatment of the mice with the chemotherapeutic drug gemcitabine in combination with a drug that depletes tumor-associated stromal tissue led to an increase in tumor vasculature, enhanced delivery of gemcitabine, and a delay in disease progression. Thus, drugs targeting the tumor stroma may merit investigation as a way to enhance the efficacy of conventional chemotherapy for pancreatic cancer. Pancreatic tumors are unresponsive to chemotherapy because their limited vasculature precludes efficient drug delivery. Pancreatic ductal adenocarcinoma (PDA) is among the most lethal human cancers in part because it is insensitive to many chemotherapeutic drugs. Studying a mouse model of PDA that is refractory to the clinically used drug gemcitabine, we found that the tumors in this model were poorly perfused and poorly vascularized, properties that are shared with human PDA. We tested whether the delivery and efficacy of gemcitabine in the mice could be improved by coadministration of IPI-926, a drug that depletes tumor-associated stromal tissue by inhibition of the Hedgehog cellular signaling pathway. The combination therapy produced a transient increase in intratumoral vascular density and intratumoral concentration of gemcitabine, leading to transient stabilization of disease. Thus, inefficient drug delivery may be an important contributor to chemoresistance in pancreatic cancer.

Heart Disease and Stroke Statistics—2018 Update: A Report From the American Heart Association

Each chapter listed in the Table of Contents (see next page) is a hyperlink to that chapter. The reader clicks the chapter name to access that chapter. Each chapter listed here is a hyperlink. Click on the chapter name to be taken to that chapter. Each year, the American Heart Association (AHA), in conjunction with the Centers for Disease Control and Prevention, the National Institutes of Health, and other government agencies, brings together in a single document the most up-to-date statistics related to heart disease, stroke, and the cardiovascular risk factors listed in the AHA’s My Life Check - Life’s Simple 7 (Figure1), which include core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure [BP], and glucose control) that contribute to cardiovascular health. The Statistical Update represents …

Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease

IMPORTANCE Proton pump inhibitors (PPIs) are among the most commonly used drugs worldwide and have been linked to acute interstitial nephritis. Less is known about the association between PPI use and chronic kidney disease (CKD). OBJECTIVE To quantify the association between PPI use and incident CKD in a population-based cohort. DESIGN, SETTING, AND PARTICIPANTS In total, 10,482 participants in the Atherosclerosis Risk in Communities study with an estimated glomerular filtration rate of at least 60 mL/min/1.73 m(2) were followed from a baseline visit between February 1, 1996, and January 30, 1999, to December 31, 2011. The data was analyzed from May 2015 to October 2015. The findings were replicated in an administrative cohort of 248,751 patients with an estimated glomerular filtration rate of at least 60 mL/min/1.73 m(2) from the Geisinger Health System. EXPOSURES Self-reported PPI use in the Atherosclerosis Risk in Communities study or an outpatient PPI prescription in the Geisinger Health System replication cohort. Histamine2 (H2) receptor antagonist use was considered a negative control and active comparator. MAIN OUTCOMES AND MEASURES Incident CKD was defined using diagnostic codes at hospital discharge or death in the Atherosclerosis Risk in Communities Study, and by a sustained outpatient estimated glomerular filtration rate of less than 60 mL/min/1.73 m(2) in the Geisinger Health System replication cohort. RESULTS Among 10,482 participants in the Atherosclerosis Risk in Communities study, the mean (SD) age was 63.0 (5.6) years, and 43.9% were male. Compared with nonusers, PPI users were more often of white race, obese, and taking antihypertensive medication. Proton pump inhibitor use was associated with incident CKD in unadjusted analysis (hazard ratio [HR], 1.45; 95% CI, 1.11-1.90); in analysis adjusted for demographic, socioeconomic, and clinical variables (HR, 1.50; 95% CI, 1.14-1.96); and in analysis with PPI ever use modeled as a time-varying variable (adjusted HR, 1.35; 95% CI, 1.17-1.55). The association persisted when baseline PPI users were compared directly with H2 receptor antagonist users (adjusted HR, 1.39; 95% CI, 1.01-1.91) and with propensity score-matched nonusers (HR, 1.76; 95% CI, 1.13-2.74). In the Geisinger Health System replication cohort, PPI use was associated with CKD in all analyses, including a time-varying new-user design (adjusted HR, 1.24; 95% CI, 1.20-1.28). Twice-daily PPI dosing (adjusted HR, 1.46; 95% CI, 1.28-1.67) was associated with a higher risk than once-daily dosing (adjusted HR, 1.15; 95% CI, 1.09-1.21). CONCLUSIONS AND RELEVANCE Proton pump inhibitor use is associated with a higher risk of incident CKD. Future research should evaluate whether limiting PPI use reduces the incidence of CKD.

Chemotherapy, chemoresistance and the changing treatment landscape for NSCLC

Management of patients with lung cancer continues to pose a considerable challenge to todays oncologist. While treatment may be curative in the early stages of the disease, the majority of patients are not diagnosed until the tumor has progressed beyond the primary site. Most patients face an intensive and invasive treatment regimen comprising surgery, radiotherapy, or chemotherapy, or combinations thereof depending on disease stage/performance status. Most will require chemotherapy even if their initial surgery is potentially curative; for those with advanced disease, chemotherapy may be their only treatment option. Moreover, the majority of patients will require multiple lines of therapy as their cancer cells acquire resistance to the chemotherapeutic agents to which they are exposed. Resistance to current chemotherapeutics available for the management of non-small cell lung cancer (NSCLC) represents one of the most significant barriers to improving long-term outcomes for this vulnerable patient group. Future management may lie in individualizing therapy through careful selection of appropriate agents based on the likelihood of response and the development of resistance. A number of biomarkers are emerging that predict response to current therapeutics; work is ongoing to develop appropriate algorithms based on such markers to guide treatment selection. In addition, novel chemotherapeutics are in development including new platinum analogs such as picoplatin (a cisplatin analog), ABT-751 (a sulfonamide) and tubulin binding agents (TBAs) such as the epothilones, providing hope for the future.

Gefitinib (IRESSA) in Patients of Asian Origin with Refractory Advanced Non-small Cell Lung Cancer: Subset Analysis from the ISEL Study

Introduction: The IRESSA Survival Evaluation in Lung Cancer (ISEL) phase III study compared the efficacy of gefitinib (IRESSA) versus placebo in patients with refractory advanced non-small cell lung cancer (NSCLC). Although a statistically significant difference in survival was not seen between gefitinib and placebo in the overall ISEL population, preplanned subset analyses demonstrated a significant survival benefit in patients who had never smoked and in patients of Asian origin. Methods: In ISEL, 1692 patients who were refractory to or intolerant of their latest chemotherapy were randomized to receive either gefitinib (250 mg/day) or placebo, plus best supportive care. Preplanned subgroup analyses included an assessment of patients who were of Asian origin (n = 342). Results: Two hundred thirty-five patients of Asian origin received gefitinib, and 107 received placebo. In these patients, treatment with gefitinib significantly improved survival compared with placebo (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.48, 0.91; p = 0.010; median survival, 9.5 versus 5.5 months). Patients of Asian origin also experienced statistically significant improvements in time to treatment failure with gefitinib compared with placebo (HR, 0.69; 95% CI, 0.52, 0.91; p = 0.0084; 4.4 versus 2.2 months), and objective response rates were higher with gefitinib than with placebo (12 versus 2%). Gefitinib was generally well tolerated in patients of Asian origin, with rash and diarrhea being the most common adverse events. No unexpected adverse events were observed. Conclusions: Treatment with gefitinib was associated with a significant improvement in survival in a subgroup of patients of Asian origin with previously treated refractory advanced NSCLC.

Kidney Failure Risk Projection for the Living Kidney Donor Candidate

BACKGROUND Evaluation of candidates to serve as living kidney donors relies on screening for individual risk factors for end-stage renal disease (ESRD). To support an empirical approach to donor selection, we developed a tool that simultaneously incorporates multiple health characteristics to estimate a persons probable long-term risk of ESRD if that person does not donate a kidney. METHODS We used risk associations from a meta-analysis of seven general population cohorts, calibrated to the population-level incidence of ESRD and mortality in the United States, to project the estimated long-term incidence of ESRD among persons who do not donate a kidney, according to 10 demographic and health characteristics. We then compared 15-year projections with the observed risk among 52,998 living kidney donors in the United States. RESULTS A total of 4,933,314 participants from seven cohorts were followed for a median of 4 to 16 years. For a 40-year-old person with health characteristics that were similar to those of age-matched kidney donors, the 15-year projections of the risk of ESRD in the absence of donation varied according to race and sex; the risk was 0.24% among black men, 0.15% among black women, 0.06% among white men, and 0.04% among white women. Risk projections were higher in the presence of a lower estimated glomerular filtration rate, higher albuminuria, hypertension, current or former smoking, diabetes, and obesity. In the model-based lifetime projections, the risk of ESRD was highest among persons in the youngest age group, particularly among young blacks. The 15-year observed risks after donation among kidney donors in the United States were 3.5 to 5.3 times as high as the projected risks in the absence of donation. CONCLUSIONS Multiple demographic and health characteristics may be used together to estimate the projected long-term risk of ESRD among living kidney-donor candidates and to inform acceptance criteria for kidney donors. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).

High dietary phosphorus intake is associated with all-cause mortality: results from NHANES III

BACKGROUND Elevated serum phosphorus is associated with all-cause mortality, but little is known about risk associated with dietary phosphorus intake. OBJECTIVE We investigated the association between phosphorus intake and mortality in a prospective cohort of healthy US adults (NHANES III; 1998-1994). DESIGN Study participants were 9686 nonpregnant adults aged 20-80 y without diabetes, cancer, or kidney or cardiovascular disease. Exposure to dietary phosphorus, which was assessed by using a 24-h dietary recall, was expressed as the absolute intake and phosphorus density (phosphorus intake divided by energy intake). All-cause and cardiovascular mortality was assessed through 31 December 2006. RESULTS Median phosphorus intake was 1166 mg/d (IQR: 823-1610 mg/d); median phosphorus density was 0.58 mg/kcal (0.48-0.70 mg/kcal). Individuals who consumed more phosphorus-dense diets were older, were less often African American, and led healthier lifestyles (smoking, physical activity, and Healthy Eating Index). In analyses adjusted for demographics, cardiovascular risk factors, kidney function, and energy intake, higher phosphorus intake was associated with higher all-cause mortality in individuals who consumed >1400 mg/d [adjusted HR (95% CI): 2.23 (1.09, 4.5) per 1-unit increase in ln(phosphorus intake); P = 0.03]. At <1400 mg/d, there was no association. A similar association was seen between higher phosphorus density and all-cause mortality at a phosphorus density amount >0.35 mg/kcal [adjusted HR (95% CI): 2.27 (1.19, 4.33) per 0.1-mg/kcal increase in phosphorus density; P = 0.01]. At <0.35 mg/kcal (approximately the fifth percentile), lower phosphorus density was associated with increased mortality risk. Phosphorus density was associated with cardiovascular mortality [adjusted HR (95% CI): 3.39 (1.43, 8.02) per 0.1 mg/kcal at >0.35 mg/kcal; P = 0.01], whereas no association was shown in analyses with phosphorus intake. Results were similar by subgroups of diet quality and in analyses adjusted for sodium and saturated fat intakes. CONCLUSIONS High phosphorus intake is associated with increased mortality in a healthy US population. Because of current patterns in phosphorus consumption in US adults, these findings may have important public health implications.

Efficacy of Oral Ondansetron in the Prevention of Emesis in Outpatients Receiving Cyclophosphamide-based Chemotherapy

Adequate control of nausea and vomiting in patients receiving chemotherapy is of great concern to both the patient and the physician. Uncontrolled nausea and vomiting frequently result in poor nutritional intake, metabolic derangements, deterioration of physical and mental condition, as well as the possible rejection of potentially beneficial treatment [1]. Many patients are more afraid of uncontrolled nausea and vomiting than of alopecia [2]. Research in the control of nausea and vomiting has increased in the past decade. Much of this research has focused on the control of nausea and vomiting associated with the use of highly emetogenic drugs such as cisplatin. Although cisplatin is one of the most emetogenic of all chemotherapy agents, many others produce considerable nausea and vomiting. Cytotoxic drugs are usually given in combination. Sixty to eighty percent of breast cancer patients receiving combinations of cyclophosphamide, methotrexate, and 5-fluorouracil or cyclophosphamide, doxorubicin, and 5-fluorouracil have nausea and vomiting [3-6]. Most patients receiving noncisplatin regimens are treated as outpatients. Effective control of nausea and vomiting in outpatients and in patients receiving either adjunctive or palliative therapy is of particular importance. Considerable advances in the control of chemotherapy-induced emesis have been made recently [7]. Drugs such as metoclopramide, phenothiazines, substituted benzamides, corticosteroids, and benzodiazepines are used singly or in combination [8-10]. Untoward side-effects such as sedation, dystonic reactions, restlessness, agitation, and hypotension produced by these medications remain an important clinical problem. Investigation in laboratory animals has shown that selective antagonism of serotonin, specifically, 5-hydroxytryptamine subtype-3 receptors, prevents cisplatin-induced emesis [11]. These receptors are located in the central nervous system and in the gastrointestinal tract [12, 13]. Ondansetron (GR38032F) is a 5-hydroxytryptamine subtype 3-receptor-antagonist that has previously been shown to be effective and safe in the control of chemotherapy-induced emesis when administered intravenously in patients receiving cisplatin [14]. However, oral administration of ondansetron has not been rigorously evaluated. We investigated the antiemetic efficacy and safety of oral ondansetron in outpatients receiving cyclophosphamide-based chemotherapy. Methods Study Design This study was a multicenter, randomized, double-blind, dose-comparison, stratified, placebo-controlled trial designed to evaluate the efficacy and safety of oral ondansetron (Zofran; Glaxo, Inc., Research Triangle Park, North Carolina) for the control of nausea and vomiting in patients receiving cyclophosphamide-based chemotherapy. Patients were randomly assigned to one of four treatment groups: 1 mg, 4 mg, and 8 mg of ondansetron, or placebo. The study was stratified to compare doxorubicin- with nondoxorubicin-containing regimens. All study medications were matched tablets prepackaged by the pharmacy (Glaxo Inc.) before shipment to study centers. Criteria for Entry Patients with histologically confirmed cancer were eligible for this clinical trial if they were chemotherapy naive, 18 years or older, had a Karnofsky performance status 60% or more, and were scheduled to receive cyclophosphamide-based chemotherapy. Women of childbearing age had a negative serum or urine -human chorionic gonadotropin-pregnancy test before entry. Patients were excluded if they had a serum alanine aminotransferase (ALT) level greater than twice the institutions upper limit of normal, had any retching or vomiting during the 24 hours before study entry, received any investigational agent in the previous 30-day period, or were scheduled to receive pelvic or abdominal radiation therapy during the 24 hours before or during the 72 hours after study entry. Concomitant administration of cisplatin, carboplatin, dacarbazine, nitrogen mustard, procarbazine, carmustine, or ifosfamide, or both made the patient ineligible. In addition, use of any antiemetic agents including phenothiazines, butyrophenones, lorazepam, cannabinoids, metoclopramide, corticosteroids, and trimethobenzamide during the previous 24 hours or during the 3-day study period excluded the patient. All patients gave written informed consent, and the protocol was reviewed and approved by the institutional review board of each participating center. Pretreatment and Follow-up Examinations Pretreatment evaluations were done within 7 days of study initiation. They included a complete medical history and physical examination, a complete blood count and serum chemical analysis, including blood urea nitrogen (BUN), creatinine, total bilirubin, lactic dehydrogenase, alkaline phosphatase, aspartate aminotransferase (AST), and ALT. Complete blood counts and all serum chemical analyses were repeated within 1 week of chemotherapy completion. Patients received cyclophosphamide ( 450 mg/m2) as a short ( 2 hours) infusion plus either doxorubicin ( 35 mg/m2) or methotrexate ( 30 mg/m2). Other low to moderately emetogenic chemotherapy was allowed, including 5-fluorouracil ( 400 mg/m2), vincristine, and etoposide ( 35 mg/m2). Antiemetic Schedule and Rescue Patients were randomized to one of four study groups (placebo or 1 mg, 4 mg, or 8 mg of ondansetron). The first dose of study medication was taken 30 minutes before the start of cyclophosphamide administration. Two additional doses of study drug were taken 4 and 8 hours after the start of the cyclophosphamide infusion. On study days 2 and 3, study drug was taken at approximately 7:00 am, 3:00 pm, and 10:00 pm. Patients repeated the dose of study medication if an episode of vomiting occurred within 30 minutes of ingesting any scheduled dose of medication. Patient compliance with the antiemetic schedule was assessed by a daily telephone call for 3 consecutive days beginning on study day 2, review of the patients diary, and pill counts. The study sponsor provided prochlorperazine tablets to investigators for use as rescue medication if patients had persistent nausea or vomiting. The approved Food and Drug Administration (FDA) package insert dose (10 mg, three times per day) was recommended. However, the rescue medication and regimen used was determined by the investigator. A patient could be withdrawn at any time; no minimum number of emetic episodes nor minimum degree of nausea needed to occur before a patient could be withdrawn. Study drug was discontinued if patients were rescued. Evaluation of Response Each patient was monitored by research personnel for the 3 days after chemotherapy. Patients were either seen in person or contacted by telephone. Patients were provided a diary for each study day and were instructed to record the time each study drug was taken, to record the time and total number of emetic episode(s), to record the assessment of nausea by a visual analog scale, and to record any adverse events. Emetic episodes and nausea were assessed independently. The primary efficacy parameter measured was the number of emetic episodes. An emetic episode was defined as a single vomit (productive of stomach contents) or retch (not productive of stomach contents) or any number of continuous vomits or retches or both separated by less than 1 minute. If more than 1 minute elapsed between vomits or retches, this was counted as two emetic episodes. A complete response was defined as no emetic episodes and no use of rescue medication during the 3-day study period. A major response was 1 to 2 emetic episodes in the 3-day period, and a minor response was 3 to 5 emetic episodes. Patients who had more than five emetic episodes or who were withdrawn due to the severity of nausea or vomiting or adverse events were deemed treatment failures. The secondary efficacy parameter analyzed was the severity of nausea. Before treatment and in the evening of each study day, patients assessed their own nausea. A 100-mm visual analog scale was used. Zero mm was no nausea and 100 mm was nausea as bad as it could be. Safety Assessments An adverse event was defined as any untoward medical occurrence in a patient (except nausea or vomiting) or an exacerbation of a preexisting medical condition. The investigator and patient were instructed to record all adverse events regardless of severity or assessment of the relation to the study drug. Blood samples to monitor hematology and blood chemistry variables were obtained within 7 days before chemotherapy and within 1 week after chemotherapy. Statistical Assessment All statistical tests were pairwise comparisons of the respective ondansetron dose groups to placebo. No adjustments for multiple comparisons between ondansetron doses were planned or done. As per protocol, patients with severe emesis were given rescue medication before the end of the study. Therefore, the number of emetic episodes occurring during the entire study period was not available for these patients; hence, a statistical analysis using means was not appropriate. The number of emetic episodes was analyzed in two ways, using nonparametric procedures. 1. Complete Response. The Cochran-Mantel-Haenszel Test (stratified by study center) was used to compare each ondansetron dose group to placebo with respect to the proportion of patients having a complete response (no emetic episodes, no use of rescue medication). 2. Number of Emetic Episodes. The van Elteren test [15, 16] (Wilcoxon rank-sum test stratified by study center) was used to compare each dose group to the placebo group. We compared the ondansetron dose groups to placebo with respect to nausea severity using the van Elteren test (Wilcoxon rank-sum test stratified by study center). Results A total of 349 cancer patients from 27 centers receiving their first cycle of chemotherapy were enrolled in this trial. Intravenous cyclophosphamide was given to 346 patients at a dose 450 mg/m2

UTILITY OF GATA3 IMMUNOHISTOCHEMISTRY IN DIFFERENTIATING UROTHELIAL CARCINOMA FROM PROSTATE ADENOCARCINOMA AND SQUAMOUS CELL CARCINOMAS OF THE UTERINE CERVIX, ANUS, AND LUNG

Distinguishing invasive high-grade urothelial carcinoma (UC) from other carcinomas occurring in the genitourinary tract may be difficult. The differential diagnosis includes high-grade prostatic adenocarcinoma, spread from an anal squamous cell carcinoma (SCC), or spread from a uterine cervical SCC. In terms of metastatic UC, the most common problem is differentiating spread of UC to the lung from a primary pulmonary SCC. Immunohistochemical analysis (IHC) for GATA binding protein 3 (GATA3), thrombomodulin (THROMBO), and uroplakin III was performed on a tissue microarray (TMA) containing 35 cases of invasive high-grade UC. GATA3 IHC was also performed on TMAs containing 38 high-grade (Gleason score ≥8) prostatic adenocarcinomas, representative tissue sections from 15 invasive anal SCCs, representative tissue sections from 19 invasive cervical SCCs, and TMAs with 12 invasive cervical carcinomas of the cervix [SCC (n=10), SCC with neuroendocrine features (n=1), and adenosquamous carcinoma (n=1)]. In addition, GATA3 IHC was performed on representative tissue sections from 15 pulmonary UC metastases and a TMA with 25 SCCs of the lung and 5 pulmonary non–small cell carcinomas with squamous features. GATA3, THROMBO, and uroplakin III were positive in 28 (80%), 22 (63%), and 21 (60%) cases of high-grade UC, respectively. All cases of GATA3-positive staining were nonfocal; 25 (89%) cases demonstrated moderate to strong staining, and 3 (11%) demonstrated weak staining. Of the 7 cases that failed to express GATA3, 5 were positive for THROMBO and/or uroplakin III, whereas 2 were negative for all 3 markers. None of the 38 high-grade prostatic adenocarcinomas was positive for GATA3. Weak GATA3 staining was present in occasional basal cells of benign prostate glands, in a few benign atrophic glands, and in urothelial metaplasia. Of the 15 cases of anal SCCs, 2 (7%) cases showed focal weak staining, and 1 (3%) showed focal moderate staining. Weak staining was also rarely observed in the benign anal squamous epithelium. Of the 31 uterine cervical carcinomas, 6 (19%) showed weak GATA3 staining (3 nonfocal and 3 focal), and 2 (6%) demonstrated focal moderate staining. Twelve (80%) of the metastatic UCs to the lung were positive for GATA3, with 11 cases showing diffuse moderate or strong staining and 1 case showing focal moderate staining. None of the pulmonary SCCs or non–small cell carcinomas with squamous features was GATA3 positive. GATA3 IHC is a sensitive marker for UC, and positive staining in UC is typically nonfocal and moderate or strong in intensity. GATA3 is also highly specific in excluding high-grade prostate adenocarcinoma. Although some cervical and anal SCCs can be GATA3 positive, unlike in UC, staining is more commonly focal and weak. GATA3 is also a useful maker when diagnosing metastatic UC to the lung.