Outcomes of older patients with follicular lymphoma using individual data from 5922 patients in 18 randomized controlled trials.

Limited data exist to describe the clinical features and outcomes for elderly patients with follicular lymphoma (FL). The Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) group performed a prospectively planned pooled analysis of individual patient data from first-line randomized controlled trials (RCTs) and examined associations between age (≤70 vs >70 years), clinical characteristics, and FL outcomes. We identified 18 multicenter clinical RCTs in the FLASH database that enrolled elderly patients (>70 years). Primary end points were early disease outcomes, CR24 and CR30, and progression-free survival (PFS) at 24 months (PFS24). Secondary end points were PFS and overall survival (OS). We identified 5922 previously untreated FL patients from 18 RCTs. Patients age >70 years (vs ≤70 years) more commonly had elevated lactate dehydrogenase, hemoglobin <12 g/dL, ECOG PS ≥2, and elevated ß2-microglobulin. Median follow-up was 5.6 years. Patients >70 years did not differ from patients ≤70 years in rates of CR24, CR30, or PFS24. With a median OS of 14.6 years for all patients, median OS was 7.4 and 15.7 years for patients >70 and ≤70 years of age, respectively (hazard ratio = 2.35; 95% confidence interval = 2.03-2.73; P < .001). Age >70 years was a significant predictor of OS and PFS due to higher rates of death without progression, but not PFS24, CR24, or CR30. FL patients >70 years treated on trials have similar early disease outcomes to younger patients. There is no disease-specific outcome difference between age groups. Age alone should not disqualify patients from standard treatments or RCTs.

Development of cutaneous squamous cell carcinoma after prolonged exposure to pegylated liposomal doxorubicin and hand-foot syndrome: a newly recognized toxicity.

Pegylated liposomal doxorubicin (PLD) can be administered for prolonged periods with minimal toxicity. The risk of cutaneous squamous cell carcinoma (SCC) with this therapy has not been reported. We describe cutaneous SCC of the plantar foot in two patients exposed to high doses of PLD. A 50-year-old man with angiosarcoma received a total PLD dose of 1350 mg/m2 and developed cutaneous SCC of bilateral plantar feet. A 45-year-old woman with cutaneous T-cell lymphoma was treated with a total PLD dose of 1142 mg/m2 with subsequent diagnosis of cutaneous SCC of the right plantar foot. No risk factors for SCC of the plantar foot were identified in either patient. Cutaneous SCC is likely an unreported side effect of prolonged exposure to PLD. An extended duration of hand-foot syndrome from other anti-cancer drugs may also share this risk. Regular complete skin examination with early intervention for suspicious lesions is indicated in this patient population.

Colorectal Lymphoma: A Contemporary Case Series.

BACKGROUND: Colon and rectal lymphomas are rare and can occur in the context of posttransplant lymphoproliferative disorder. Evidence-based management guidelines are lacking. OBJECTIVE: The purpose of this study was to characterize the presentation, diagnosis, and management of colorectal lymphoma and to identify differences within the transplant population. DESIGN: This was a retrospective review of patients evaluated for colorectal lymphoma between 2000 and 2017. Patients were identified through clinical note queries. SETTINGS: Four hospitals within a single health system were included. PATIENTS: Fifty-two patients (64% men; mean age = 64 y; range, 26-91 y) were identified. No patient had <3 months of follow-up. Eight patients (15%) had posttransplant lymphoproliferative disorder. MAIN OUTCOME MEASURES: Overall survival, recurrence, and complications in treatment pathway were measured. RESULTS: Most common presentations were rectal bleeding (27%), abdominal pain (23%), and diarrhea (23%). The most common location was the cecum (62%). Most frequent histologies were diffuse large B-cell lymphoma (48%) and mantle cell lymphoma (25%). Posttransplant lymphoproliferative disorder occurred in the cecum (n = 4) and rectum (n = 4). Twenty patients (38%) were managed with chemotherapy; 25 patients (48%) underwent primary resection. Mass lesions had a higher risk of urgent surgical resection (35% vs 8%; p = 0.017). Three patients (15%) treated with chemotherapy presented with perforation requiring emergency surgery. Overall survival was 77 months (range, 25-180 mo). Patients with cecal involvement had longer overall survival (96 vs 26 mo; p = 0.038); immunosuppressed patients had shorter survival (16 vs 96 mo; p = 0.006). Survival in patients treated with surgical management versus chemotherapy was similar (67 vs 105 mo; p = 0.62). LIMITATIONS: This was a retrospective chart review, with data limited by the contents of the medical chart. This was a small sample size. CONCLUSIONS: Colorectal lymphoma is rare, with variable treatment approaches. Patients with noncecal involvement and chronic immunosuppression had worse overall survival. Patients with mass lesions, particularly cecal masses, are at higher risk to require urgent intervention, and primary resection should be considered. See Video Abstract at http://links.lww.com/DCR/A929.

Arterial elasticity as a risk factor for early cardiovascular disease among testicular cancer survivors treated with platinum-based chemotherapy: a cross-sectional pilot study.

PURPOSE: Testicular cancer survivors who have received platinum-based chemotherapy are at risk for premature cardiovascular disease. The etiology of this risk is not well understood. This pilot study explores the impact of platinum-based chemotherapy on endothelial function. METHODS: Testicular cancer survivors <30 years old at the time of diagnosis who received platinum-based chemotherapy between 2002 and 2012, as well as 17 similarly aged male controls, were identified. Consented subjects underwent vascular assessment using the HDI/PulseWave CR-2000 Cardiovascular Profiling System and the Endo-PAT2000 system. Biomarkers and functional test markers were compared among cases, controls, and a group of historical controls using two sided two-sampled t-tests and Wilcoxon rank-sum tests. RESULTS: Thirteen survivors with a median age of 30.2 years and body mass index of 27.3 were enrolled, along with 17 healthy controls with a median age of 27.1 years and body mass index of 24.8. Median time from chemotherapy was 4.7 (range: 0.8-14) years. There was no statistical difference in reactive hyperemia peripheral arterial tonometry ratio between cases and controls (p = 0.574). There was no statistical difference in small or large artery elasticity between cases and controls (p = 0.086) or between cases and historical controls (p = 0.729). There was also no statistical difference in the blood levels of circulating endothelial cells, von Willebrand factor, and vascular cell adhesion molecules. There was a trend toward increased metabolic syndrome in cases (15%) as compared to recruited controls (6%), though this difference was not statistically significant (p = 0.565). CONCLUSION: Testicular cancer survivors have no clinically significant difference in endothelial function compared to controls 4 years after the completion of chemotherapy. Further research is needed to explore the secondary modifiable causes that may contribute to the risk of premature cardiovascular disease.

Linking permafrost thaw to shifting biogeochemistry and food web resources in an arctic river.

Rapidly, increasing air temperatures across the Arctic are thawing permafrost and exposing vast quantities of organic carbon, nitrogen, and phosphorus to microbial processing. Shifts in the absolute and relative supplies of these elements will likely alter patterns of ecosystem productivity and change the way carbon and nutrients are delivered from upland areas to surface waters such as rivers and lakes. The ultra-oligotrophic nature of surface waters across the Arctic renders these ecosystems particularly susceptible to changes in productivity and food web dynamics as permafrost thaw alters terrestrial-aquatic linkages. The objectives of this study were to evaluate decadal-scale patterns in surface water chemistry and assess potential implications of changing water chemistry to benthic organic matter and aquatic food webs. Data were collected from the upper Kuparuk River on the North Slope of Alaska by the U.S. National Science Foundation's Long-Term Ecological Research program during 1978-2014. Analyses of these data show increases in stream water alkalinity and cation concentrations consistent with signatures of permafrost thaw. Changes are also documented for discharge-corrected nitrate concentrations (+), discharge-corrected dissolved organic carbon concentrations (-), total phosphorus concentrations (-), and δ13 C isotope values of aquatic invertebrate consumers (-). These changes show that warming temperatures and thawing permafrost in the upland environment are leading to shifts in the supply of carbon and nutrients available to surface waters and consequently changing resources that support aquatic food webs. This demonstrates that physical, geochemical, and biological changes associated with warming permafrost are fundamentally altering linkages between upland and aquatic ecosystems in rapidly changing arctic environments.

A pilot study evaluating chemotherapy tolerability for breast cancer patients who have received prior treatment and chest radiation for Hodgkin Lymphoma.

MICROABSTRACT: Women treated with chest radiation for Hodgkin lymphoma (HL) have significantly higher risk of developing breast cancer, and little is known about how these patients tolerate chemotherapy for breast cancer. This small retrospective study identified 15 patients, noting that these patients tolerate proposed chemotherapy regimens for breast cancer in rates similar to those without prior HL and therapeutic radiation. PURPOSE: Women treated for Hodgkin lymphoma (HL) with chest radiation have significantly higher risk of developing breast cancer, and little is known about how these patients tolerate chemotherapy for breast cancer. METHODS: Women with breast cancer diagnosed from 1986-2015 after radiation for HL were identified from hospitals and clinics in St. Paul and Minneapolis, Minnesota. Patient, tumor and treatment characteristics, and clinical outcomes were abstracted from medical records and summarized using descriptive statistics. Chemotherapy was defined as tolerated if all scheduled doses and cycles were completed without deviation from the initial plan, with lack of grade 3 or higher toxicity attributable to chemotherapy in categories including blood, cardiac, gastrointestinal, fatigue and pain. RESULTS: Forty-two patients with breast cancer and prior radiation for HL were identified, 15 of which received chemotherapy for breast cancer. We noted 75% tolerability of taxane-based and 100% tolerability of anthracycline-based chemotherapy, suggesting that most patients with prior radiation for HL tolerate chemotherapy for breast cancer. A subset of patients (N = 7) in this study were also treated with chemotherapy for HL prior to breast cancer diagnosis, and 86% (6 of 7) also tolerated chemotherapy for breast cancer. CONCLUSIONS: Treatment of breast cancer is strongly influenced by prior treatment of HL. Although this study was small and did not meet statistical significance, the data suggest that these patients tolerate proposed chemotherapy regimens for breast cancer in rates similar to those without prior HL and therapeutic radiation. Larger studies comparing specific chemotherapy dosing schedules are needed to address this complicated population.

Patterns of growth factor usage and febrile neutropenia among older patients with diffuse large B-cell non-Hodgkin lymphoma treated with CHOP or R-CHOP: the Intergroup experience (CALGB 9793; ECOG-SWOG 4494).

Patterns of myeloid growth factor (GF) usage and febrile neutropenia (FN) were examined in patients >60 years of age with diffuse large B-cell non-Hodgkin lymphoma (DLBCL) enrolled on CALGB 9793/ECOG-SWOG 4494, receiving initial therapy with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or rituximab + CHOP (R-CHOP). Myeloid GFs were administered to 256/520 (49%) patients. Indications for use were: prevent dose reduction/dose delay (81%, 207/256); treat FN or non-febrile neutropenia (NFN) (19%, 48/256). One or more FN episodes occurred in 41% (212/520) of patients, with FN most often in cycle 1 (38% of episodes). In multivariate analysis, risk factors for FN included age >65 years (odds ratio (OR) = 2.6, 95% CI: [1.4, 4.9]) and anemia (hemoglobin <12 g/dl) (OR =2.2, 95% confidence intervals (CI): [1.4, 3.5]. Myeloid GF use was common in this older DLBCL population receiving CHOP-based therapy, as was FN, especially during cycle one. Risk factors predictive for FN should be used prospectively to identify patients for whom myeloid GFs are best utilized.

Thirty-Month Complete Response as a Surrogate End Point in First-Line Follicular Lymphoma Therapy: An Individual Patient-Level Analysis of Multiple Randomized Trials.

Purpose Follicular lymphoma (FL) is an indolent cancer, with effective but rarely curative treatment options. As a standard study end point for first-line FL therapy, progression-free survival (PFS) requires extended follow-up (median PFS, > 7 years). To provide patients with earlier access to newer therapies, an earlier end point to expedite clinical trials is needed. Our objective was to formally assess the complete response rate at 30 months (CR30) after initiation of induction therapy as a potential surrogate end point for PFS in first-line FL therapy. Patients and Methods We analyzed individual patient data from 13 randomized multicenter trials of induction and maintenance regimens in first-line FL therapy published after 1990 and with sufficient data to evaluate whether CR30 could predict treatment effects on PFS. Correlation of the CR30 odds ratio with the PFS hazard ratio was evaluated by both linear regression (R2WLS) and bivariate copula (R2Copula) models. Prespecified criteria for surrogacy required either R2WLS or R2Copula ≥ 0.80, with a lower-bound 95% CI > 0.60. Results Data from eight induction and five maintenance randomized trials in 3,837 evaluable patients were analyzed. The prespecified surrogacy threshold was met, with an R2WLS of 0.88 (95% CI, 0.77 to 0.96) and an R2Copula of 0.86 (95% CI, 0.72 to 1.00). Multiple sensitivity and supplemental analyses supported the robustness of the findings. A minimum 11% absolute improvement in CR30 from a 50% control rate predicted a significant treatment effect on PFS (hazard ratio, 0.69). Conclusion This large, prospective, pooled analysis of randomized chemotherapy, immunotherapy, and chemoimmunotherapy trials demonstrates that CR30 is a surrogate end point for PFS in first-line FL treatment trials. Use of this end point may expedite therapeutic development with the intent of bringing novel therapies to this patient population years before PFS results are mature.

Personalized risk prediction for event-free survival at 24 months in patients with diffuse large B-cell lymphoma.

We recently defined event-free survival at 24 months (EFS24) as a clinically relevant outcome for patients with DLBCL. Patients who fail EFS24 have very poor overall survival, while those who achieve EFS24 have a subsequent overall survival equivalent to that of the age- and sex-matched general population. Here, we develop and validate a clinical risk calculator (IPI24) for EFS24. Model building was performed on a discovery dataset of 1,348 patients with DLBCL and treated with anthracycline-based immunochemotherapy. A multivariable model containing age, Ann Arbor stage, normalized serum LDH, ALC, ECOG performance status, bulky disease, and sex was identified. The model was then applied to an independent validation dataset of 1,177 DLBCL patients. The IPI24 score estimates the probability of failing to achieve the EFS24 endpoint for an individual patient. The IPI24 model showed superior discriminatory ability (c-statistic = 0.671) in the validation dataset compared to the IPI (c-statistic = 0.649) or the NCCN-IPI (c-statistic = 0.657). After recalibration of the model on the combined dataset, the median predicted probability of failing to achieve EFS24 was 36% (range, 12-88%), and the IPI24 showed an EFS24 gradient in all IPI groups. The IPI24 also identified a significant percentage of patients with high risk disease, with over 20% of patients having a 50% or higher risk of failing to achieve EFS24. The IPI24 provides an individual patient level probability of achieving the clinically relevant EFS24 endpoint. It can be used via electronic apps.

Lymphoma of the hands in a patient with rheumatoid arthritis: case report.

The correlation of rheumatoid arthritis and lymphoma-and more generally, autoimmune disease and malignancy-has long been observed. Here, we present the case of a woman with rheumatoid arthritis who developed lymphoma limited to her hands.

Insights and issues with simulating terrestrial DOC loading of Arctic river networks.

Terrestrial carbon dynamics influence the contribution of dissolved organic carbon (DOC) to river networks in addition to hydrology. In this study, we use a biogeochemical process model to simulate the lateral transfer of DOC from land to the Arctic Ocean via riverine transport. We estimate that, over the 20th century, the pan-Arctic watershed has contributed, on average, 32 Tg C/yr of DOC to river networks emptying into the Arctic Ocean with most of the DOC coming from the extensive area of boreal deciduous needle-leaved forests and forested wetlands in Eurasian watersheds. We also estimate that the rate of terrestrial DOC loading has been increasing by 0.037 Tg C/yr2 over the 20th century primarily as a result of climate-induced increases in water yield. These increases have been offset by decreases in terrestrial DOC loading caused by wildfires. Other environmental factors (CO2 fertilization, ozone pollution, atmospheric nitrogen deposition, timber harvest, agriculture) are estimated to have relatively small effects on terrestrial DOC loading to Arctic rivers. The effects of the various environmental factors on terrestrial carbon dynamics have both offset and enhanced concurrent effects on hydrology to influence terrestrial DOC loading and may be changing the relative importance of terrestrial carbon dynamics on this carbon flux. Improvements in simulating terrestrial DOC loading to pan-Arctic rivers in the future will require better information on the production and consumption of DOC within the soil profile, the transfer of DOC from land to headwater streams, the spatial distribution of precipitation and its temporal trends, carbon dynamics of larch-dominated ecosystems in eastern Siberia, and the role of industrial organic effluents on carbon budgets of rivers in western Russia.

Coastal eutrophication as a driver of salt marsh loss.

Salt marshes are highly productive coastal wetlands that provide important ecosystem services such as storm protection for coastal cities, nutrient removal and carbon sequestration. Despite protective measures, however, worldwide losses of these ecosystems have accelerated in recent decades. Here we present data from a nine-year whole-ecosystem nutrient-enrichment experiment. Our study demonstrates that nutrient enrichment, a global problem for coastal ecosystems, can be a driver of salt marsh loss. We show that nutrient levels commonly associated with coastal eutrophication increased above-ground leaf biomass, decreased the dense, below-ground biomass of bank-stabilizing roots, and increased microbial decomposition of organic matter. Alterations in these key ecosystem properties reduced geomorphic stability, resulting in creek-bank collapse with significant areas of creek-bank marsh converted to unvegetated mud. This pattern of marsh loss parallels observations for anthropogenically nutrient-enriched marshes worldwide, with creek-edge and bay-edge marsh evolving into mudflats and wider creeks. Our work suggests that current nutrient loading rates to many coastal ecosystems have overwhelmed the capacity of marshes to remove nitrogen without deleterious effects. Projected increases in nitrogen flux to the coast, related to increased fertilizer use required to feed an expanding human population, may rapidly result in a coastal landscape with less marsh, which would reduce the capacity of coastal regions to provide important ecological and economic services.

Pilot study of vascular health in survivors of Hodgkin lymphoma.

BACKGROUND: Vascular-related toxicities have been reported among survivors of Hodgkin lymphoma (HL), but their genesis is not well understood. PROCEDURE: Fasting blood samples from 25 previously irradiated HL survivors were analyzed for biomarkers that can reveal underlying inflammation and/or endothelial cell activation: high-sensitivity C-reactive protein (hsCRP), triglycerides, total cholesterol, high-density lipoprotein (HDL), apolipoprotein ß, lipoprotein (a), fibrinogen, circulating endothelial cells (CECs), and vascular cell adhesion molecule-1 (VCAM-1) expression. Values were compared to subjects in the Coronary Artery Risk Development in Young Adults (CARDIA) study. CECs and VCAM-1 were compared to healthy controls. RESULTS: Survivors (76% male), median age 17.6 years (5-33) at diagnosis, 33.0 years (19-55) at follow-up, included stages IA (n = 6), IIA (n = 10), IIB (n = 2), IIIA (n = 4), and IVA (n = 3) patients. Twenty-four received at least chest radiation therapy (RT) (median dose 3,150 cGy; range: 175-4,650 cGy), one received neck only; 14 (56%) had a history of anthracycline exposure (median dose: 124 mg/m(2) range: 63-200 mg/m2). Compared to CARDIA subjects, mean hsCRP (3.0 mg/L ± 2.0 vs. 1.6 ± 1.9), total cholesterol (194.1 mg/dl ± 33.2 vs. 179.4 ± 32.9), lipoprotein (a) (34.2 mg/dl ± 17.5 vs. 13.8 ± 17.5), and fibrinogen (342.0 mg/dl ± 49.1 vs. 252.6 ± 48.4) were significantly elevated. CECs (2.3 cells/ml ± 1.5 vs. 0.34 ± 1.4) were significantly elevated compared to controls. No difference in VCAM-1 expression (51.1% ± 36.8 vs. 42.3 ± 35.6) was detected. CONCLUSION: HL survivors exposed to RT have evidence of vascular inflammation, dyslipidemia, and injury suggestive of early atherogenesis.

Castleman disease and associated autoimmune disease.

PURPOSE OF REVIEW: Castleman disease can occur in association with autoimmune connective tissue disease and confound the clinical picture, resulting in delayed diagnosis and suboptimal treatment. This review focuses on the intersection of Castleman disease and autoimmunity with an emphasis on shared pathology and mutually beneficial treatments. RECENT FINDINGS: Targeting CD-20, interleukin-6, and the nuclear factor-κB pathway has shown promise in achieving long-term remission in patients with Castleman disease and associated autoimmune features. SUMMARY: Advances in understanding of pathogenic cell types and cytokines in Castleman disease have allowed the development of targeted therapies successful in the treatment of both Castleman disease and associated autoimmune disease.

Quality of life appears similar between survivors of indolent and aggressive non-Hodgkin lymphoma.

Few studies have examined the quality of life (QOL) in survivors of non-Hodgkin lymphoma (NHL). A total of 109 patients with NHL (58 aggressive [AGG], 51 indolent [IND]) completed two health-related QOL assessments using the Medical Outcomes Study 36-Item Short-Form Healthy Survey (MOS SF-36) and the Functional Assessment in Cancer Therapy - Fatigue (FACT-F). Scores between IND and AGG were compared using a two-sample t-test. Multiple linear regression was performed to account for any potentially explanatory variables. Overall, 70.6% had received chemotherapy and 55% had received immunotherapy. Some 17.6% of the IND group had received no therapy. The overall physical and mental component QOL scores of the SF-36 did not differ between survivors. Physical function in survivors of IND was significantly better when compared with that of AGG NHL. Our study reports a similar overall QOL between survivors of IND and AGG NHL. Physical function, however, may be more impaired in survivors of AGG NHL.

A phase III study of anti-B4-blocked ricin as adjuvant therapy post-autologous bone marrow transplant: CALGB 9254.

Anti-B4-blocked ricin (anti-B4-bR) is a potent immunotoxin directed against the CD19 antigen. Previous phase I and II studies suggested a possible role for anti-B4-bR as consolidation after high-dose chemotherapy and autologous stem cell transplant. Cancer and Leukemia Group B (CALGB) 9254 is a phase III study which randomized 157 patients with B-cell lymphoma in complete remission following autologous transplant to treatment with anti-B4-bR or observation. With a median follow-up time for patients of 5.8 years, the median event-free survival for protocol treatment and observation are 2.1 and 2.9 years, respectively (p = 0.275). The median overall survival for treatment and observation are 6.1 years and not reached, respectively (p = 0.063). Therefore, no differences were found in event-free survival and overall survival between protocol treatment and observation, although there was a trend toward improved survival with observation. These data fail to support a role for anti-B4-bR as consolidative therapy after bone marrow transplant in patients with B-cell lymphoma.

Primary CNS plasmablastic lymphoma: report of a case with CSF cytology, flow cytometry, radiology, histological correlation, and review of the literature.

Plasmablastic lymphoma (PBL) is a rare subtype of diffuse large B cell lymphoma and commonly presents as an oral mass in HIV patients. Extraoral PBL has been reported, including one case of primary central nervous system PBL (PCNSPBL). The cytological features of PBL have been described, including cerebrospinal fluid (CSF) cytology findings for secondary CNS involvement by PBL. The etiology of PCNSPBL is still unknown. We report here the CSF cytology of a PCNSPBL, which shows a hypercellular specimen composed of markedly atypical, singly dispersed plasmacytoid cells with frequent abnormal mitoses and binucleation. The neoplastic cells are positive for CD138. Flow cytometry of the CSF specimen demonstrates a monoclonal neoplastic cell population, which is CD138 positive, kappa light chain positive, lambda light chain negative, and CD19 negative. Molecular analysis and immunohistochemical stains on a tissue biopsy confirmed the diagnosis and reveal concurrent infections with Epstein-Barr virus and human polyomavirus JC virus. Clinical and radiological correlations are reported, and the literature is reviewed. To the best of our knowledge, this is the first case report for CSF cytology of a PCNSPBL, demonstrating the utility of the cytological examination in the triage and diagnosis of this disease. Because of its dismal prognosis, it is critical for cytopathologists to be aware of the entity and recognize the neoplastic cells in CSF specimen. This report also emphasizes the importance of clinical and radiological correlation in the diagnosis of this lethal disease.

Nitrous oxide emission from denitrification in stream and river networks.

Nitrous oxide (N(2)O) is a potent greenhouse gas that contributes to climate change and stratospheric ozone destruction. Anthropogenic nitrogen (N) loading to river networks is a potentially important source of N(2)O via microbial denitrification that converts N to N(2)O and dinitrogen (N(2)). The fraction of denitrified N that escapes as N(2)O rather than N(2) (i.e., the N(2)O yield) is an important determinant of how much N(2)O is produced by river networks, but little is known about the N(2)O yield in flowing waters. Here, we present the results of whole-stream (15)N-tracer additions conducted in 72 headwater streams draining multiple land-use types across the United States. We found that stream denitrification produces N(2)O at rates that increase with stream water nitrate (NO(3)(-)) concentrations, but that <1% of denitrified N is converted to N(2)O. Unlike some previous studies, we found no relationship between the N(2)O yield and stream water NO(3)(-). We suggest that increased stream NO(3)(-) loading stimulates denitrification and concomitant N(2)O production, but does not increase the N(2)O yield. In our study, most streams were sources of N(2)O to the atmosphere and the highest emission rates were observed in streams draining urban basins. Using a global river network model, we estimate that microbial N transformations (e.g., denitrification and nitrification) convert at least 0.68 Tg·y(-1) of anthropogenic N inputs to N(2)O in river networks, equivalent to 10% of the global anthropogenic N(2)O emission rate. This estimate of stream and river N(2)O emissions is three times greater than estimated by the Intergovernmental Panel on Climate Change.