Urinary biomarkers of kidney tubule injury, risk of acute kidney injury, and mortality in patients with acute ischaemic stroke treated at a stroke care unit.

BACKGROUND AND PURPOSE: Urinary liver-type fatty-acid binding protein (L-FABP), which is a biomarker of kidney tubule injury, has been studied extensively and established as a risk marker of acute kidney injury (AKI). The aim of this study was to investigate whether kidney tubule injury is associated with the development of AKI and mortality in patients with acute ischaemic stroke. METHODS: Acute ischaemic stroke patients hospitalized in the stroke care unit (SCU) within 24 h after symptom onset were prospectively investigated. AKI was defined on the basis of Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Baseline urinary L-FABP was measured on admission. We evaluated the associations among urinary L-FABP, incidence of AKI, and 90-day mortality adjusted for renal function, albuminuria and other potentially predictive variables, using multivariable analysis. RESULTS: In total, 527 acute ischaemic stroke patients (342 men, median age 74 years) were enrolled in the study. Twenty-seven patients (5.1%) experienced AKI within 7 days of admission. In the univariate analysis, high urinary L-FABP level had positive associations with AKI [53.8 µg/g creatinine (Cr) vs. 3.9 µg/g Cr; P < 0.001] and 90-day mortality (15.5 µg/g Cr vs. 4.0 µg/g Cr; P < 0.001). In the multivariate analysis, elevated urinary L-FABP level (per 10-µg/g Cr increase) was independently associated with AKI (odds ratio 1.225, 95% confidence interval (CI) 1.083-1.454; P = 0.003) and 90-day mortality (hazard ratio 1.091, 95% CI 1.045-1.138; P < 0.001). CONCLUSION: Urinary biomarkers of kidney tubule injury are independently associated with the development of AKI and 90-day mortality in patients with acute ischaemic stroke treated at the SCU.

Does preoperative enteral nutrition reduce the incidence of surgical complications in patients with Crohn's disease? A case-matched study.

AIM: Currently, the notion that preoperative optimization with enteral nutrition (EN) reduces the incidence of complication after surgery in Crohn's disease (CD) patients is being debated. This case-matched study was to evaluate the impact of preoperative EN on surgical outcomes in patients with CD. METHOD: Twenty-four patients received EN therapy with an elemental diet (1800-2400 kcal/day) for at least 2 weeks before the planned surgery (EN group). A further 24 patients who underwent surgery without receiving preoperative EN or parenteral nutrition formed a control group based on four matched criteria: age (≤/>40 years), the use of preoperative medications (corticosteroids/azathioprine/biologics), disease behaviour (inflammatory/stricturing/penetrating) and main surgical procedure (ileal resection/ileocolonic resection/colectomy). The incidence of complications observed within 30 days after surgery was compared between the two groups. Septic complications were defined as anastomotic leak, intra-abdominal abscess, entero-cutaneous fistula or wound infection. RESULTS: In the EN group, the median serum albumin level significantly increased, while C-reactive protein (CRP) significantly decreased during the preoperative EN (albumin, from 3.0 mg/dl to 3.1 mg/dl, P = 0.04; CRP, from 3.05 mg/dl to 2.52 mg/dl, P = 0.02). The incidence of postoperative septic complications was significantly lower in the EN group compared with the control group (4% vs 25%, P = 0.04). The occurrence rate of overall complications was lower in the EN group (21% vs 29%, P = 0.51), but not statistically significant. CONCLUSION: In patients with CD, preoperative optimization with EN reduced the overall rate of postoperative complications and significantly decreased postoperative septic complications.

The relationship between stroke severity and prior direct oral anticoagulant therapy in patients with acute ischaemic stroke and non-valvular atrial fibrillation.

BACKGROUND AND PURPOSE: Anticoagulant treatment with a vitamin K antagonist (VKA) has been reported to reduce stroke severity when patients with atrial fibrillation (AF) suffer acute ischaemic stroke (AIS). Direct oral anticoagulant (DOAC) therapy also has the potential to reduce the initial severity of AIS. However, the effect of DOAC therapy on the severity of AIS is not well known. The aim of the present study was to investigate the effect of DOACs on initial stroke severity in patients with AIS and non-valvular AF. METHODS: From March 2011 to July 2016, consecutive patients with AIS having non-valvular AF were recruited. The effects of prior DOAC treatment on severity were assessed by multivariate logistic regression analyses. RESULTS: A total of 484 patients [208 women; median age 79 (interquartile range, 71-85) years; National Institutes of Health Stroke Scale (NIHSS) score 9 (interquartile range, 3-20)] were enrolled. Of these, 352 (73%) were on no anticoagulant medication, 54 (11%) were undertreated with a VKA, 35 (7%) were sufficiently treated (admission prothrombin time-international normalized ratio: ≥2.0 for patients <70 years old and ≥1.6 for ≥70 years old) with a VKA and 43 (9%) were on a DOAC. The initial NIHSS score (median 10 in patients with no anticoagulation, 13 in undertreated VKA, 7 in sufficient VKA and 6 in DOAC, P = 0.018) was different among the groups. Multivariate analysis showed that DOAC was independently and negatively associated with severe (initial NIHSS score ≥ 10) stroke (odds ratio, 0.39; P = 0.041), compared with no anticoagulant therapy. CONCLUSIONS: Direct oral anticoagulant treatment prior to the event should reduce initial stroke severity in patients with AIS and non-valvular AF.

FOLFIRI plus bevacizumab as second-line therapy in patients with metastatic colorectal cancer after first-line bevacizumab plus oxaliplatin-based therapy: the randomized phase III EAGLE study.

BACKGROUND: A targeted agent combined with chemotherapy is the standard treatment in patients with metastatic colorectal cancer (mCRC). The present phase III study was conducted to compare two doses of bevacizumab combined with irinotecan, 5-fluorouracil/leucovorin (FOLFIRI) in the second-line setting after first-line therapy with bevacizumab plus oxaliplatin-based therapy. PATIENTS AND METHODS: Patients were randomly assigned to receive FOLFIRI plus bevacizumab 5 or 10 mg/kg in 2-week cycles until disease progression. The primary end point was progression-free survival (PFS), and secondary end points included overall survival (OS), time to treatment failure (TTF), and safety. RESULTS: Three hundred and eighty-seven patients were randomized between September 2009 and January 2012 from 100 institutions in Japan. Baseline patient characteristics were well balanced between the two groups. Efficacy was evaluated in 369 patients (5 mg/kg, n = 181 and 10 mg/kg, n = 188). Safety was evaluated in 365 patients (5 mg/kg, n = 180 and 10 mg/kg, n = 185). The median PFS was 6.1 versus 6.4 months (hazard ratio, 0.95; 95% confidence interval [CI] 0.75-1.21; P = 0.676), and median TTF was 5.2 versus 5.2 months (hazard ratio, 1.01; 95% CI 0.81-1.25; P = 0.967), respectively, for the bevacizumab 5 and 10 mg/kg groups. Follow-up of OS is currently ongoing. Adverse events, including hypertension and hemorrhage, occurred at similar rates in both groups. CONCLUSION: Bevacizumab 10 mg/kg plus FOLFIRI as the second-line treatment did not prolong PFS compared with bevacizumab 5 mg/kg plus FOLFIRI in patients with mCRC. If bevacizumab is continued after first-line therapy in mCRC, a dose of 5 mg/kg is appropriate for use as second-line treatment. CLINICAL TRIAL IDENTIFIER: UMIN000002557.

Elevated glucose level adversely affects infarct volume growth and neurological deterioration in non-diabetic stroke patients, but not diabetic stroke patients.

BACKGROUND AND PURPOSE: Hyperglycemia is recognized as a common occurrence associated with a high risk of poor outcome in ischaemic stroke patients. However, little is known about the association between elevated glucose level, growth of infarct volume and neurological deterioration in ischaemic stroke patients without diabetes. The present study aimed to clarify this issue in acute ischaemic stroke patients with arterial occlusion. METHODS: We studied 375 acute ischaemic stroke patients with arterial occlusion within 24 h of onset. Diabetes was diagnosed in patients with a known history of diabetes or HbA1c value ≥ 6.5%. Infarct volume was measured on admission and at follow-up within 48 h using diffusion-weighted imaging. Neurological deterioration was defined as an increase of ≥ 4 points in National Institutes of Health Stroke Scale score within 7 days of stroke onset. We examined the relationship between glucose level on admission, infarct volume growth and neurological deterioration in three categories (all patients, non-diabetes and diabetes) using multivariate modeling. RESULTS: Diabetes was present in 104 patients (27.7%). Multivariate regression analysis showed that elevated glucose level was independently associated with infarct volume growth in all patients (P = 0.034) and non-diabetes (P = 0.002), but not in diabetes (P = 0.871). Moreover, elevated glucose level was independently associated with neurological deterioration in all patients [odds ratio (OR), 1.010; 95% confidence interval (CI), 1.004-1.017; P = 0.002] and non-diabetes (OR, 1.014; 95% CI, 1.002-1.026; P = 0.022), but not diabetes (OR, 1.006; 95% CI, 0.998-1.014; P = 0.151). CONCLUSIONS: Glucose level appears to influence infarct volume growth and neurological deterioration, particularly in non-diabetic patients with ischaemic stroke.

Admission hyperglycemia causes infarct volume expansion in patients with ICA or MCA occlusion: association of collateral grade on conventional angiography.

BACKGROUND AND PURPOSE: Hyperglycemia (HG) is associated with infarct volume expansion in acute ischaemic stroke patients. However, collateral circulation can sustain the ischaemic penumbra and limit the growth of infarct volume. The aim of this study was to determine whether the association between HG and infarct volume expansion is dependent on collateral circulation. METHODS: We performed a retrospective analysis of 93 acute ischaemic stroke patients with internal carotid artery or middle cerebral artery occlusion within 24 h of onset were retrospectively studied. HG was diagnosed in patients with an admitting blood glucose value ≥140 mg/dl. Angiographic collateral grade 0-1 was designated as poor collateral circulation and grade 2-4 as good collateral circulation. Infarct volume was measured at admission and at again within 7 days using diffusion-weighted magnetic resonance images. RESULTS: Among 34 patients with poor collateral grade, the change in infarct volume was significantly greater in the HG group than in the non-HG group (106.0 ml vs. 22.7 ml, P = 0.002). Among the 59 patients with good collateral circulation, the change in infarct volume was greater in the HG group than in the non-HG group (53.3 ml vs. 10.9 ml, P = 0.047). Multiple regression analysis indicated that admission HG (P = 0.004), baseline National Institutes of Health Stroke Scale score (P = 0.018), and poor collateral circulation (P = 0.040) were independently associated with infarct volume expansion. CONCLUSIONS: Infarct volume expansion was greater in individuals with HG on admission regardless of collateral circulation status.

[Peripheral intrapulmonary lipoma: report of a case].

A 62-year-old woman who had undergone a left mastectomy for a breast cancer consulted us for an abnormal chest shadow. Chest computed tomography showed a well-defined nodule of 1 cm diameter periphery in lower lobe of the right lung. The differential diagnosis included benign lung tumors, such as intrapulmonary lymph nodes, granuloma etc. However, because of her past history we needed to consider metastasis. To make diagnosis, a wedge resection of the pulmonary nodule was performed. The tumor was diagnosed as a lipoma. No malignant cells were seen. Although peripheral intrapulmonary lipoma is very rare, it should be kept in mind in the differential diagnosis of an intrapulmonary nodule.

Akt-dependent nuclear localization of Y-box-binding protein 1 in acquisition of malignant characteristics by human ovarian cancer cells.

Y-box-binding protein 1 (YB-1), which is a member of the DNA-binding protein family containing a cold-shock domain, has pleiotropic functions in response to various environmental stimuli. As we previously showed that YB-1 is a global marker of multidrug resistance in ovarian cancer and other tumor types. To identify YB-1-regulated genes in ovarian cancers, we investigated the expression profile of YB-1 small-interfering RNA (siRNA)-transfected ovarian cancer cells using a high-density oligonucleotide array. YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C. Exogenous serum addition stimulated YB-1 translocation from the cytoplasm to the nucleus, and treatment with Akt inhibitors as well as Akt siRNA and integrin-linked kinase (ILK) siRNA specifically blocked YB-1 nuclear localization. Inhibition of Akt activation downregulated CXCR4 and upregulated MDR1 (ABCB1) gene expression. Administration of Akt inhibitor resulted in decrease in nuclear YB-1-positive cancer cells in a xenograft animal model. Akt activation thus regulates the nuclear translocation of YB-1, affecting the expression of drug-resistance genes and other genes associated with the malignant characteristics in ovarian cancer cells. Therefore, the Akt pathway could be a novel target of disrupting the nuclear translocation of YB-1 that has important implications for further development of therapeutic strategy against ovarian cancers.

Unsuspected small ameloblastoma in the alveolar bone: a collaborative study of 14 cases with discussion of their cellular sources.

BACKGROUND: Intraosseous ameloblastoma (IA) is the quintessence of epithelial odontogenic tumor and histologically and behaviorally defined as an undoubted neoplastic process. Current information must lead to the consensus that IA arises from the embryologic inclusions of odontogenic epithelium within the jawbone. Nevertheless, clinically oriented evidence is limited to this day. METHODS: The clinical and radiographic features, behavior, and pathology of 14 cases of small IA confined to the alveolar region were systematically examined. RESULTS: Six cases were a chance finding. There was no gender predilection and half of the lesions clustered in middle age (>40 years). The posterior region of the mandible (n = 7) and the anterior segment of the maxilla (n = 4) were favored. Five radiographic characteristics were recognized: interradicular (n = 5) and periradicular (n = 3), and periapical, residual and pericoronal (n = 2 each). They showed solid (n = 12) or unicystic (n = 2) growth pattern and 12 lesions were divided into seven follicular, three desmoplastic, and two plexiform subtypes. The main location of tumor was microscopically traceable in six cases; three interradicular type outside the periodontal ligament space and two periradicular and one periapical variants inside. CONCLUSION: By in-depth evaluation of the spatial relationship between tumor and its surrounding structure, the alveolar process, periodontal ligament space, and pericoronal area are all the likely starting points of IA. This report re-awakens the oral pathologist to the histogenetic significance of incipient IA as the only available human specimen for reappraisal of their origin.

Perivascular myoid tumors of the oral region: a clinicopathologic re-evaluation of 35 cases.

BACKGROUND: Myopericytoma (MPC) is a generic denomination to describe tumors showing differentiation toward perivascular myoid cells /myopericytes. It has been suggested that MPC forms a morphologic continuum with glomus tumor (GT), solitary myofibroma (SMF), and angioleiomyoma (ALM). This proposed relationship has not yet been assessed in the oral region. METHODS: We reviewed our 28-year experience with 35 oral tumors, originally diagnosed as ALM (n = 28), SMF (n = 4), GT (n = 2), and MPC (n = 1) to analyze their overlapping microscopic features, with the assistance of immunohistochemistry. RESULTS: Myopericytoma showed a wide range of growth patterns; concentric perivascular whorls, hemangiopericytomatous areas, glomangiopericytoma (GPC)-type vessels and leiomyomatous foci. Intravascular growth was also seen. Among 28 cases studied, three ALM were reclassified as MPC (n = 2) and SMF (n = 1), based on the present diagnostic criteria. Additional MPC-type components, at varying degrees, were similarly found in four ALM and three SMF, at least focally. One GT featured intravascular whorls of spindle cells. These four interrelated groups of tumors had in common GPC-type vasculature and intraluminal cellular proliferation was nearly ubiquitously present. Diffuse immunoreactivity for alpha-smooth muscle actin and less staining intensity of muscle-specific actin were observed in all tumors. Only ALM displayed desmin positivity of variable extent. Neither case tested expressed CD34. CONCLUSIONS: Our data matches with the recent results in extraoral sites that MPC, GT, SMF, and ALM exhibit histologic and immunohistochemical overlap with each other. A common perivascular myoid differentiation between these tumor types is further reinforced by the present oral series.

Characterisation of kilo electron volt neutron fluence standard with the 45Sc(p,n)45Ti reaction at NMIJ.

We are developing a national standard of a monoenergetic kilo electron volt neutron field with the (45)Sc(p,n)(45)Ti resonance reaction. A wide resonance yields 27.4 keV neutrons at 0 degrees with respect to the proton beam. The proton energy was precisely determined in the measurement of the relative neutron yield as a function of the proton energy from the threshold energy to 2.942 MeV. Absolute measurement of the monoenergetic neutron fluence was performed using a (3)He proportional counter. Relative measurement was also carried out using a Bonner sphere calibrated at our 144 keV standard neutron field. Calibration factors were obtained between the count of a neutron monitor and the neutron fluence. A silicon-surface barrier detector with a (6)LiF foil converter was also being developed for the neutron fluence measurement. Successful results were obtained in the tests in the 144 keV standard neutron field.

Development of the fast neutron standard using a Be({alpha},n) reaction at the National Metrology Institute of Japan.

This paper describes the 8-MeV neutron field where the neutrons are generated in the (9)Be(alpha,n)(12)C reaction by bombardment of a beryllium target with a 2.4-MeV (4)He(+) beam from a Van de Graaff accelerator. The neutron field is being prepared for a new national standard on neutron fluence in Japan. Absolute measurement of the neutron fluence was taken using a proton recoil neutron detector, consisting of a silicon surface barrier detector with a polyethylene radiator. Neutron spectra were measured using a newly developed recoil proton spectrometer and a liquid organic scintillation detector. The gamma rays existing in the field were also characterised using a liquid organic scintillation detector. The ambient dose equivalents of the gamma rays were estimated to be <100 microSv at the neutron fluence of 10(7) neutrons cm(-2).

Abnormal pontine activation in pathological laughing as shown by functional magnetic resonance imaging.

To explore the aetiology of pathological laughing, a 65-year-old woman with pathological laughing was examined by 3-T functional magnetic resonance imaging (fMRI) before and after treatment with drugs. Here, we report that the patient consistently showed exaggerated pontine activation during the performance of three tasks before treatment, whereas abnormal pontine activation was no longer found after successful treatment with the selective serotonin reuptake inhibitor, paroxetine. Our findings in this first fMRI study of pathological laughing suggest that serotonergic replacement decreases the aberrant activity in a circuit that involves the pons.

Pacinian neuroma in adipose herniation of the buccal mucosa.

An interesting case of a trauma-induced tender mass of the buccal mucosa in a 45-year-old man was presented. Following surgery, the patient was relieved from pain. Microscopically, the mature adipose tissue is unique in that it contained a single enlarged Pacinian corpuscle near the deep margin. This is the hitherto undescribed intraoral lesion of Pacinian neuroma in the herniated buccal fat pad.

DL-Serine: promoting activity on renal tumorigenesis by N-ethyl-N-hydroxyethylnitrosamine in rats.

Subcutaneous injection of DL-serine increased the number and size of renal tubular cell tumors in male W rats treated with 500 or 1,000 ppm N-ethyl-N-hydroxyethylnitrosamine [(EHEN) CAS: 13147-25-6, 2-(ethylnitrosamino)ethanol]. At the end of the 32-week experiment, the incidences of renal tumors were 95% in rats treated with 1,000 ppm EHEN for 2 weeks and then given three sc injections of DL-serine every 2 weeks, 33% in rats treated with 1,000 ppm EHEN for 2 weeks, and 28% in rats treated with 500 ppm EHEN for 2 weeks and then given three sc injections of DL-serine every 2 weeks. No renal tumors were found in rats treated with 500 ppm EHEN alone or given three sc injections of DL-serine alone every 2 weeks.

4,4'-Diaminodiphenylmethane: promoting effect on the development of thyroid tumors in rats treated with N-bis(2-hydroxypropyl)nitrosamine.

4,4'-Diaminodiphenylmethane (4,4'-methylenedianiline) (DDPM) promoted the development of thyroid tumors in rats treated with a subeffective dose of N-bis(2-hydroxypropyl)nitrosamine (2,2'-dihydroxy-N-nitrosodipropylamine) (DHPN) for thyroid tumorigenesis. Male inbred W rats were given a single ip injection of 280 mg DHPN/100 g body weight and fed diets with or without 1,000 ppm DDPM. Thyroid tumor incidences at the end of week 20 of the experiment were 90% (19/21) in rats given DHPN and then DDPM and 28% (6/21) in rats given DHPN alone. The incidence of thyroid cancers was 9.5% (2/21) in rats first given DHPN and then DDPM. Untreated rats and rats given DDPM alone had no thyroid tumors after 20 weeks. Incidences of kidney tumors were 38% (8/21) in rats given DHPN and then DDPM and 28% (6/21) in rats given DHPN alone. No tumors were found in the kidneys and lungs of rats given DDPM alone and in those of control rats. Treatment with DDPM alone slightly but not significantly decreased the serum concentrations of thyroxine and triiodothyronine; treatment with DHPN plus DDPM had no such effect.

Trisodium nitrilotriacetate monohydrate: promoting effects on the development of renal tubular cell tumors in rats treated with N-ethyl-N-hydroxyethylnitrosamine.

The effect of trisodium nitrilotriacetate monohydrate [N,N-bis(carboxymethyl)glycine trisodium salt] (Na3NTA X H2O) on development of renal tubular cell tumors induced with N-ethyl-N-hydroxyethylnitrosamine [CAS:13147-25-6; 2-(ethylnitrosamino)-ethanol] (EHEN) was studied. Six-week-old male inbred W rats were given a diet containing 1,000 ppm of EHEN for 2 weeks and then a diet containing a high (10,000 ppm) or low (500 ppm) concentration of Na3NTA X H2O for 30 weeks. The rats were killed during week 32. The higher concentration of Na3NTA X H2O enhanced the development of renal tubular cell tumors and increased the number and size of tumors in rats treated with EHEN, but the lower concentration of Na3NTA X H2O did not. The incidence of renal tubular cell tumors in week 32 was 33% in rats treated with 1,000 ppm EHEN for 2 weeks, 100% in rats treated with 1,000 ppm EHEN for 2 weeks plus high Na3NTA X H2O diet for 30 weeks, and 39% in rats treated with 1,000 ppm EHEN for 2 weeks and then given low Na3NTA X H2O diet for 30 weeks. Numbers of atypical cell foci per kidney area (No./cm2) were 17.0 +/- 7.6 in rats treated with EHEN and high Na3NTA X H2O, 7.3 +/- 2.2 in rats treated with EHEN and low Na3NTA X H2O, 3.7 +/- 1.4 in rats treated with EHEN alone, and 1.0 +/- 2.4 in rats treated with high Na3NTA X H2O diet alone. Atypical cell foci retained a tubular pattern and consisted of basophilic cells with a large nucleus or clear cells with a small nucleus.

Trisodium nitriloacetate monohydrate: promoting effect in urinary bladder carcinogenesis in rats treated with N-butyl-N-(4-hydroxybutyl)nitrosamine.

The effect of trisodium nitrilotriacetate monohydrate [(Na3NTA X H2O) CAS: 18662-53-8] on development of urinary bladder tumors in rats initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine [(BBN) CAS: 3817-11-6] was studied. Twenty-one male inbred W rats 6 weeks of age were given drinking water containing 500 ppm of BBN for 4 weeks and then put on diet containing 10,000 ppm of Na3NTA X H2O for 28 weeks. Na3NTA X H2O promoted the development of urinary bladder tumors in rats treated with BBN. The incidences of papilloma and transitional cell carcinomas in the urinary bladder were 90% (18/20) and 25% (4/20), respectively, in rats treated with BBN and then Na3NTA X H2O and 0 in those treated with BBN or Na3NTA X H2O alone. The incidence of papillary or nodular hyperplasia in week 32 was 100% (20/20) in rats treated with BBN and then Na3NTA X H2O and 61% (13/21) in rats treated with BBN only.

Sex differential and dose dependence of phenobarbital-promoting activity in N-bis(2-hydroxypropyl)nitrosamine-initiated thyroid tumorigenesis in rats.

Studies were made on the dose and sex dependence of thyroid tumor development in rats pretreated with N-bis(2-hydroxypropyl)nitrosamine (DHPN) followed by exposure to various doses of phenobarbital (PB). A direct dose-response relationship in induction of thyroid tumors was found in both male and female rats. Upon feeding the DHPN-treated rats with basal diet containing 20, 100, 500, and 2500 ppm of PB, the incidences of follicular adenoma were, respectively, 8, 45, 70, and 66% in male rats and 12, 17, 50, and 58% in female rats. Development of papillary adenomas in male rats was observed only at the higher doses of PB, at incidences of 12 and 20% for doses of 500 and 2500 ppm. Follicular carcinoma was also seen at higher doses of PB, at 16 and 12%, respectively, for the 500- and 2500-ppm groups. Neither follicular nor papillary carcinomas were induced in female rats; only a low incidence of papillary adenoma (4%) was observed with a PB concentration as high as 2500 ppm. A single injection of DHPN resulted in production of approximately 1 tumor/female rat and 2.5 tumors/male rat. DHPN combined with posttreatment with PB at doses up to 500 ppm did not increase tumor yield in female rats, whereas a 3-fold increase was observed in male rats for the 500-ppm-treated groups. When PB was increased to 2500 ppm a marked increase (8-fold) in tumor yield in male rats was observed, in contrast to a less than 3-fold increase in similarly treated female rats.