SARS-CoV-2 serosurvey across multiple waves of the COVID-19 pandemic in New York City between 2020-2023.

Sero-monitoring provides context to the epidemiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and changes in population immunity following vaccine introduction. Here, we describe results of a cross-sectional hospital-based study of anti-spike seroprevalence in New York City (NYC) from February 2020 to July 2022, and a follow-up period from August 2023 to October 2023. Samples from 55,092 individuals, spanning five epidemiological waves were analyzed. Prevalence ratios (PR) were obtained using Poisson regression. Anti-spike antibody levels increased gradually over the first two waves, with a sharp increase during the 3rd wave coinciding with SARS-CoV-2 vaccination in NYC resulting in seroprevalence levels >90% by July 2022. Our data provide insights into the dynamic changes in immunity occurring in a large and diverse metropolitan community faced with a new viral pathogen and reflects the patterns of antibody responses as the pandemic transitions into an endemic stage.

SARS-CoV-2 BA.1 and BA.2 breakthrough infections boost antibody responses to early Omicron subvariants but not BQ.1.1 or XBB.1.5.

Subvariants of the Omicron lineage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) efficiently escape neutralizing antibody responses induced by both vaccination and infection with antigenically distinct variants. Here, we describe the potency and breadth of neutralizing and binding antibody responses against a large panel of variants following an Omicron BA.1 or BA.2 breakthrough infection in a heterogeneous cohort of individuals with diverse exposure histories. Both BA.1 and BA.2 breakthrough infections significantly boost antibody levels and broaden antibody reactivity. However, this broader immunity induced by BA.1 and BA.2 breakthrough infections does not neutralize Omicron BQ and XBB subvariants efficiently. While these subvariants are not neutralized well by post-breakthrough sera, suggesting escape, binding non-neutralizing antibody responses are sustained. In summary, our data suggest that while BA.1 and BA.2 breakthrough infections broaden the immune response to SARS-CoV-2 spike, the induced neutralizing antibody response is still outpaced by viral evolution.

SARS-CoV-2-infection- and vaccine-induced antibody responses are long lasting with an initial waning phase followed by a stabilization phase.

It is thought that mRNA-based vaccine-induced immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) wanes quickly, based mostly on short-term studies. Here, we analyzed the kinetics and durability of the humoral responses to SARS-CoV-2 infection and vaccination using >8,000 longitudinal samples collected over a 3-year period in New York City. Upon primary immunization, participants with pre-existing immunity mounted higher antibody responses faster and achieved higher steady-state antibody titers than naive individuals. Antibody kinetics were characterized by two phases: an initial rapid decay, followed by a stabilization phase with very slow decay. Booster vaccination equalized the differences in antibody concentration between participants with and without hybrid immunity, but the peak antibody titers decreased with each successive antigen exposure. Breakthrough infections increased antibodies to similar titers as an additional vaccine dose in naive individuals. Our study provides strong evidence that SARS-CoV-2 antibody responses are long lasting, with initial waning followed by stabilization.

Stage IV Colorectal Cancer at Initial Presentation versus Progression during and after Treatment, Differences in Management: Management Differences for Initial Presentation versus Progression of Disease after Initial Treatment.

Stage IV colorectal cancer is a prevalent disease and understanding the appropriate treatment options is important. Medical oncologic treatment remains the mainstay of treatment in cases where curative resection is not possible. Surgical intervention is indicated if the primary tumor and associated metastases are amenable to curative resection or if obstructive, bleeding, or perforative complications arise from the tumor. New endoscopic techniques can provide palliation and benefit for patients who cannot undergo surgery and may speed time to chemotherapy initiation. Recently, immunotherapy has shown promise at managing, controlling, and regressing advanced disease, in some cases converting it to curative with resection. For patients that progress while on treatment, continued medical therapy remains the mainstay of treatment. Further research into the benefits of asymptomatic primary tumor resection without curative intent needs to be performed. Colorectal cancer, and more specifically metastatic colorectal cancer, continues to have improved 1- and 5-year survival rates and likely will continue to do so over the coming months and years.

A 52-Year-Old Woman with Abdominal Pain and Vomiting.

A 52-Year-Old Woman with Abdominal Pain and VomitingA 52-year-old woman presented for evaluation of abdominal pain, nausea, and vomiting after consuming a large calzone. How do you approach the evaluation, and what is the diagnosis?

Seasonal Variations and Factors that Influence Diverticular Bleeding in the United States of America.

BACKGROUND: Seasonal variation in hospitalizations for diverticulitis has a sinusoidal pattern, peaking in summer. Little is known about seasonal, regional trends, and risk factors associated with hospital admissions regarding diverticular bleeding in the United States. STUDY DESIGN: Cross-sectional population database review using the healthcare cost and utilization project's national inpatient sample. METHODS: Patients that had diagnoses of diverticulitis with bleeding or diverticulosis with bleeding admitted from January 1, 2015, through December 31, 2017, were identified and stratified by month and season. Then, the potential effects of region, age, gender, race, and patient risk factors on seasonal admissions for diverticular bleeding were explored, and data were analyzed in SAS and presented in Excel using chi-square and Kruskal-Wallis for categorical and continuous variables, respectively. RESULTS: Of the 54191 hospitalized cases for diverticular bleeding, the peak and the lowest seasons were spring and summer (25.5% vs. 24.2%, P<0.0001). A significant seasonal pattern in comorbidities was also identified, and those with diabetes (P<0.0001), hypertension (HTN) (P<0.0001), obesity (P<0.0001), and those on anticoagulants (P=0.016) all had more bleeding events in the spring. This was noted across US regions, gender, race, and age. Eventually, the southern region had the most admissions for diverticular bleeding at 40.9% (P<0.0001). CONCLUSION: A better understanding of these seasonal and regional trends may provide a mechanism to identify a potential trigger for diverticular bleeding events. This helps identify individuals at greatest risk for hospitalization, as well as prepare hospitals to allocate supplies appropriately during the seasons.

Associations of maternal preterm birth with subsequent risk for type 2 diabetes in women from the women's health initiative.

Preterm birth has been associated with insulin resistance and beta-cell dysfunction, a hallmark characteristic of type 2 diabetes. However, studies investigating the relationship between a personal history of being born preterm and type 2 diabetes are sparse. We sought to investigate the potential association between a personal history of being born preterm and risk for type 2 diabetes in a racially and ethnically diverse population. Baseline and incident data (>16 years of follow-up) from the Women's Health Initiative (n = 85,356) were used to examine the association between personal history of being born preterm (born 1910-1940s) and prevalent (baseline enrollment; cross-sectional) or incident (prospective cohort) cases of type 2 diabetes. Logistic and Cox proportional hazards regression models were used to estimate odds and hazards ratios. Being born preterm was significantly, positively associated with odds for prevalent type 2 diabetes at enrollment (adjOR = 1.79, 95% CI 1.43-2.24; P < 0.0001). Stratified regression models suggested the positive associations at baseline were consistent across race and ethnicity groups. However, being born preterm was not significantly associated with risk for incident type 2 diabetes. Regression models stratified by age at enrollment suggest the relationship between being born preterm and type 2 diabetes persists only among younger age groups. Preterm birth was associated with higher risk of type 2 diabetes but only in those diagnosed with type 2 diabetes prior to study enrollment, suggesting the association between preterm birth and type 2 diabetes may exist at earlier age of diagnosis but wane over time.

Site of vulnerability on SARS-CoV-2 spike induces broadly protective antibody against antigenically distinct Omicron subvariants.

The rapid evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variants has emphasized the need to identify antibodies with broad neutralizing capabilities to inform future monoclonal therapies and vaccination strategies. Herein, we identified S728-1157, a broadly neutralizing antibody (bnAb) targeting the receptor-binding site (RBS) that was derived from an individual previously infected with WT SARS-CoV-2 prior to the spread of variants of concern (VOCs). S728-1157 demonstrated broad cross-neutralization of all dominant variants, including D614G, Beta, Delta, Kappa, Mu, and Omicron (BA.1/BA.2/BA.2.75/BA.4/BA.5/BL.1/XBB). Furthermore, S728-1157 protected hamsters against in vivo challenges with WT, Delta, and BA.1 viruses. Structural analysis showed that this antibody targets a class 1/RBS-A epitope in the receptor binding domain via multiple hydrophobic and polar interactions with its heavy chain complementarity determining region 3 (CDR-H3), in addition to common motifs in CDR-H1/CDR-H2 of class 1/RBS-A antibodies. Importantly, this epitope was more readily accessible in the open and prefusion state, or in the hexaproline (6P)-stabilized spike constructs, as compared with diproline (2P) constructs. Overall, S728-1157 demonstrates broad therapeutic potential and may inform target-driven vaccine designs against future SARS-CoV-2 variants.

Seasonal and Geographic Variation in Peptic Ulcer Disease and Associated Complications in the United States of America.

BACKGROUND: Hospitalization for peptic ulcer disease (PUD) has been described outside of North America as peaking in the fall and winter. However, no recent literature has so far investigated the seasonal fluctuations and complications of PUD in the USA. Study Design: Cross-sectional population database review. METHODS: Patients with a diagnosis of either acute gastric or acute duodenal ulcers from January 1, 2015, through December 31, 2017, were identified in the Healthcare Cost and Utilization Project's National Inpatient Sample. The proportion of admissions with either hemorrhage or perforation was determined for each season and further subdivided into geographic regions. RESULTS: Of 18829 hospitalizations for PUD, admissions were the highest in the fall (25.9%) while being the lowest in the summer (23.9%). Complications, hemorrhage or perforation, were the highest and the lowest in the fall and spring, respectively (75.7% vs. 73.6%; P=0.060 for comparing all 4 seasons). Geographically, the West had the highest rate of peptic ulcer hemorrhage (64.5%, P=0.004), while the northeast had the highest rate of perforation (14.3%, P=0.003). Hemorrhage was more common in males, those who used aspirin, nonsteroidal anti-inflammatory drugs, or anticoagulants, and diabetics (P<0.05). Perforation was less common in males, those with diabetes, obesity, or hypertension (HTN), or those using aspirin or anticoagulants (P<0.05). Helicobacter pylori infection was more associated with perforation in the fall and winter months. CONCLUSION: Seasonal and regional trends in hospitalizations due to PUD may help identify modifiable risk factors, which can improve diagnostic and treatment outcomes for patients by allowing for more targeted identification of vulnerable populations.

COVID-19 and U.S. Disputes Over Authority, 2020-2021: Implications for the Constructionist Analysis of Social Problems.

COVID-19 is very different from the cases typically studied by constructionist analysts of social problems: it emerged quickly, spread widely, and affected many aspects of social life. As such, it offers important opportunities to reconsider the constructionist model. We focus on three issues-metrics, masks, and vaccines-where COVID-19 disputes about authority led to different alliances among several categories of claimsmakers. Our point is that COVID-19 discourse seems far messier than most of the narratives presented by constructionist analysts, and we identify several lessons from this unusual contemporary case that might help us strengthen existing social problems theory.

Birthweight and subsequent risk for thyroid and autoimmune conditions in postmenopausal women.

The objective of this study was to determine the association between birthweight and risk of thyroid and autoimmune conditions in a large sample of postmenopausal women. Baseline data from the Women's Health Initiative (n = 80,806) were used to examine the associations between birthweight category (<6 lbs., 6-7 lbs. 15 oz, 8-9 lbs. 15 oz, and ≥10 lbs.) and prevalent thyroid (underactive and overactive thyroid and goiter) and autoimmune (lupus, rheumatoid arthritis (RA), multiple sclerosis, ulcerative colitis/Crohn's disease) conditions. Follow-up questionnaire data were used to examine the associations between birthweight and incident underactive and overactive thyroid, lupus, and RA. Logistic and Cox proportional hazards regression models were used to estimate crude and adjusted odds (OR) and hazards ratios (HR), respectively. Overall, women born weighing ≥10 lbs. had an increased risk for underactive thyroid [OR 1.14 (95% CI 1.02, 1.28)] and incident lupus [HR 1.51 (95% CI 1.12, 2.03)] and a decreased risk for overactive thyroid [OR 0.67 (95% CI 0.50, 0.92)] compared to women born weighing 6-7.99 lbs., after adjustment for adult BMI, demographic variables, and lifestyle factors. Further, women born weighing <6 lbs. were at increased risk for underactive thyroid [OR 1.13 (95% CI 1.04, 1.22)]. Birthweight was not associated with other thyroid or autoimmune disorders. High birthweight was associated with later-life thyroid and autoimmune conditions while low birthweight was associated with underactive thyroid. Preconception and prenatal interventions aimed at reducing the risk of both high and low birthweights may reduce the burden of later-life thyroid and autoimmune conditions.

Medical emergencies on a medium-sized urban university campus with collegiate-based EMS.

ObjectiveThis study aimed to identify the types and frequency of acute medical events at a university with a collegiate-based emergency medical services (CBEMS) agency. Participants: Patients who requested assistance from the studied CBEMS agency, which provides emergency medical services coverage at a medium-sized urban university. Methods: This retrospective chart review examined requests for emergency service from August 2010-July 2017. Data abstracted include the type of medical event, frequency, call times/dates, and locations of reported medical events. Results: The studied agency received an average 889.4 (SD +/-68.6 calls) per year with the most common falling under the categories of "Substance Abuse" (231.7 calls/year, SD +/-15.7) and "Minor Trauma" (207.1 calls/year, SD+/-37.8). Most requests for acute medical attention occurred between the hours of 1800-0600 on Fridays and Saturdays. Implications/Conclusions: These results suggest that universities can potentially predict patterns and prepare for the types of acute medical issues that occur on campus.

Implementation of an Alcohol Medical Amnesty Policy at an Urban University With a Collegiate-Based Emergency Medical Services Agency.

PURPOSE: Medical amnesty policies (MAPs) at universities attempt to encourage students to seek emergency medical care by reducing disciplinary sanctions. This study analyzed how a MAP affected requests for emergency medical help to a collegiate-based emergency medical services (CBEMS) agency for alcohol-related issues. METHODS: This before-and-after study analyzed CBEMS call data for the 6 semesters prior to and after MAP implementation. Extracted data included patient demographics, dispatch time, and requests for advanced life support (ALS) resources. RESULTS: Following MAP introduction, increases were observed in alcohol-related calls/day in the fall semesters (0.84 vs. 0.93; p < 0.01). The median time of calls decreased; 1:20 a.m. versus 12:59 a.m. (median difference 21 minutes, p < 0.001). Finally, ALS was requested less often (9.0% vs. 3.7%; odds ratio 0.39; p < 0.01). CONCLUSIONS: MAP implementation at a university with a CBEMS is associated with a higher call volume, requests for service that occur earlier in the evening, and reduction in ALS requests for alcohol-related emergencies.

Evaluation of polarization rotation in the scattering responses from individual semiconducting oxide nanorods.

We investigate the interaction of visible light with the solid matters of semiconducting oxide nanorods (NRs) of zinc oxide (ZnO), indium tin oxide (ITO), and zinc tin oxide (ZTO) at the single nanomaterial level. We subsequently identify an intriguing, material-dependent phenomenon of optical rotation in the electric field oscillation direction of the scattered light by systematically controlling the wavelength and polarization direction of the incident light, the NR tilt angle, and the analyzer angle. This polarization rotation effect in the scattered light is repeatedly observed from the chemically pure and highly crystalline ZnO NRs, but absent on the chemically doped NR variants of ITO and ZTO under all measurement circumstances. We further elucidate that the phenomenon of polarization rotation detected from single ZnO NRs is affected by the NR tilt angle, while the phenomenon itself occurs irrespective of the wavelength and incident polarization direction of the visible light. Combined with the widespread optical and optoelectronic use of the semiconducting oxide nanomaterials, these efforts may provide much warranted fundamental bases to tailor material-specific, single nanomaterial-driven, optically modulating functionalities which, in turn, can be beneficial for the realization of high-performance integrated photonic circuits and miniaturized bio-optical sensing devices.

NCCAM/NCI Phase 1 Study of Mistletoe Extract and Gemcitabine in Patients with Advanced Solid Tumors.

PURPOSE: European Mistletoe (Viscum album L.) extracts (mistletoe) are commonly used for cancer treatment in Europe. This phase I study of gemcitabine (GEM) and mistletoe in advanced solid cancers (ASC) evaluated: (1) safety, toxicity, and maximum tolerated dose (MTD), (2) absolute neutrophil count (ANC) recovery, (3) formation of mistletoe lectin antibodies (ML ab), (4) cytokine plasma concentrations, (5) clinical response, and (6) pharmacokinetics of GEM. DESIGN: increasing mistletoe and fixed GEM dose in stage I and increasing doses of GEM with a fixed dose of mistletoe in stage II. Dose limiting toxicities (DLT) were grade (G) 3 nonhematologic and G4 hematologic events related to platelets and granulocytes only [corrected]; MTD was reached with 2 DLTs in one dosage level. Response in stage IV ASC was assessed with descriptive statistics. Statistical analyses examined clinical response/survival and ANC recovery. RESULTS: DLTs were G4 neutropenia, G4 thrombocytopenia, G4 acute renal failure, and G3 cellulitis, attributed to mistletoe. GEM 1300 mg/m(2) [corrected] and mistletoe 250 mg combined were the MTD. Of 44 patients, 24 developed nonneutropenic fever and flu-like syndrome. GEM pharmacokinetics were unaffected by mistletoe. All patients developed ML3 IgG antibodies. ANC showed a trend to increase between baseline and cycle 2 in stage I dose escalation. 6% of patients showed partial response, 42% stable disease. Median survival was 200 days. Compliance with mistletoe injections was high. CONCLUSION: GEM plus mistletoe is well tolerated. No botanical/drug interactions were observed. Clinical response is similar to GEM alone.

Mechanistic and Treatment Implications of DeltaNp63 Expression in a Rare Case of Metastatic Hidradenocarcinoma.

Hidradenocarcinomas are rare, aggressive adnexal tumors of sweat gland origin that demonstrate a high potential for local recurrence, metastasis and poor outcome. These neoplasms can derive from preexisting clear cell hidradenomas, but more commonly appear de novo with the molecular events responsible for the pathogenesis currently unknown. Molecular markers of pathogenesis as well as effective forms of adjuvant chemotherapy are missing due to the lack of accurate diagnosis, paucity of cases and confusion with other visceral solid tumors. Here, we report a 37-year-old man who presented with a rapidly growing, painful palpable mass located in the right inguinal area. The patient was a nonsmoker, did not consume alcohol and had a medical history remarkable only for a lower abdominal superficial skin lesion in the same area that had been excised 11 years earlier. Although initially slow growing, the lesion eventually expanded, was surgically excised and was diagnosed as a hidradenoma. There was no family history of malignancy and the patient had not experienced any constitutional symptoms. We probed the immunohistochemical status and detected negative staining for the estrogen, progesterone and Her2 receptors, while strong, diffuse nuclear staining was seen in the majority of cells consistent with p53 overexpression. Similarly, strong nuclear reactivity was seen with p63 and p73 antibodies. The p63 gene contains 2 separate promoters which express at least 6 major transcripts that lead to 2 fundamentally different classes of proteins; 3 isoforms (TAp63alpha, beta and gamma) encode proteins that induce apoptosis, whereas the other 3 isoforms (DeltaNp63alpha, beta and gamma) may exert inhibitory effects on p53. Interest in p63 stems from this 'two genes in one'-concept. Importantly, the nuclear presence of DeltaNp63 was detected widespread throughout the tumor. We have identified a subtype of hidradenocarcinomas that express DeltaNp63 and uncovered an unforeseen commonality with triple-negative breast tumors. To our knowledge, this is the first report of a sweat gland tumor that displayed expression of both DeltaNp63 and p73 and demonstrated a triple-negative receptor status. Such a link between 2 seemingly disparate tumor types indicates a mutual pathway of tumorigenesis and suggests the potential for common therapeutic regimens.

Necrotizing enterocolitis in neutropenia and chemotherapy: a clinical update and old lessons relearned.

Neutropenic enterocolitis (NE) must be recognized in patients with fever, neutropenia, and abdominal pain. Classically, NE has been described in patients with hematologic malignancies treated with intensive chemotherapy. Current interest in NE has increased due to recent cases associated with newer, more intensive chemotherapy in solid tumors. This review discusses pathology, clinical presentation, and treatment of NE. Ultrasonography or CT scans are the best radiographic studies to confirm the diagnosis. Management options, including antimicrobial therapy, surgery, and supportive care, are discussed. Chemotherapy incorporating the taxane family of drugs (paclitaxel and docetaxel) associated with NE is also reviewed with observations regarding the earlier onset of the disease in the first weeks following chemotherapy. Even with currently recommended therapy, a high mortality rate, approximating 45%, can occur. Best outcomes for NE rely upon understanding of risks for the condition, prompt empiric therapy with broad-spectrum antimicrobial agents, systemic antifungal therapy, and meticulous attention to supportive care.

A phase I pharmacologic and pharmacogenetic trial of sequential 24-hour infusion of irinotecan followed by leucovorin and a 48-hour infusion of fluorouracil in adult patients with solid tumors.

PURPOSE: In preclinical studies, sequential exposure to irinotecan (CPT-11) then fluorouracil (5-FU) is superior to concurrent exposure or the reverse sequence; a 24-hour infusion of CPT-11 may be better tolerated than shorter infusions. EXPERIMENTAL DESIGN: CPT-11 was first given at four levels (70-140 mg/m(2)/24 hours), followed by leucovorin 500 mg/m(2)/0.5 hours and 5-FU 2,000 mg/m(2)/48 hours on days 1 and 15 of a 4-week cycle. 5-FU was then increased in three cohorts up to 3,900 mg/m(2)/48 hours. RESULTS: Two patients had dose-limiting toxicity during cycle 1 at 140/3,900 of CPT-11/5-FU (2-week delay for neutrophil recovery; grade 3 nausea despite antiemetics); one of six patients at 140/3,120 had dose-limiting toxicity (grade 3 diarrhea, grade 4 neutropenia). Four of 22 patients with colorectal cancer had partial responses, two of which had prior bolus CPT-11/5-FU. The mean 5-FU plasma concentration was 5.1 micromol/L at 3,900 mg/m(2)/48 hours. The end of infusion CPT-11 plasma concentration averaged 519 nmol/L at 140 mg/m(2)/24 hours. Patients with UDP-glucuronosyltransferase (UGT1A1; TA)6/6 promoter genotype had a lower ratio of free to glucuronide form of SN-38 than in patients with >/=1 (TA)7 allele. Thymidylate synthase genotypes for the 28-base promoter repeat were 2/2 (13%), 2/3 (74%), 3/3 (13%); all four responders had a 2/3 genotype. CONCLUSIONS: Doses (mg/m(2)) of CPT-11 140/24 hours, leucovorin 500/0.5 hours and 5-FU 3,120/48 hours were well tolerated.

A phase I and pharmacologic study of weekly gemcitabine in combination with infusional 5-fluorodeoxyuridine and oral calcium leucovorin.

PURPOSE: Since preclinical studies have shown more than additive cytotoxicity and DNA damage with the combination of gemcitabine and 5-fluoro-2'-deoxyuridine (FUDR), we studied this combination in a phase I trial. METHODS: Gemcitabine alone was given in cycle 1 as a 24-h, 2-h or 1-h i.v. infusion weekly for 3 of 4 weeks; if tolerated, a 24-h i.v. infusion of FUDR was added with oral leucovorin. The cycle was aborted for grade 3 thrombocytopenia, grade 4 neutropenia, and grade 2 or worse nonhematologic toxicity. RESULTS: During cycle 1, six of eight patients who received 150 or 100 mg/m2 over 24 h had dose-limiting neutropenia, thrombocytopenia, fatigue or mucositis. Six of seven patients treated with 1000 mg/m2 over 2 h required a gemcitabine dose reduction for cycle 2 (thrombocytopenia, neutropenia, fatigue). Of 25 assessable patients who received gemcitabine 1000 mg/m2 over 1 h, 7 did not complete cycle 1 due to thrombocytopenia (n=6) or diarrhea (n=1). Of 42 patients entered, 27 received at least one course of gemcitabine/FUDR (5-19.5 mg/m2 over 24 h) without appreciable toxicity. Due to a shortage of FUDR, the protocol was closed early. Gemcitabine plasma concentrations averaged 0.061 micro M (24 h), 16.3 micro M (2 h), and 31.9 micro M (1 h). In 21 paired bone marrow mononuclear cell samples obtained before treatment and during FUDR infusion, thymidylate synthase ternary complex was only seen during FUDR infusion. CONCLUSIONS: Gemcitabine 100-150 mg/m2 over 24 h was poorly tolerated, whereas toxicity was acceptable with 800-1000 mg/m2 over 1 h. Inhibition of the target enzyme was demonstrated at all FUDR doses.