[Squamous cell cancer of the larynx after exposure to tar vapor--a case report].

The following case report describes the development of laryngeal cancer of a non-smoker exposed to tar-emissions due to working with asphalt. Additionally, a basal cell carcinoma in the face caused by tar-emission underlines the role of this risk factor in the development of cancer in the head and neck.


Molecular analysis of HLA-DRB1*08/12 alleles: identification of two additional alleles.

A nonradioactive oligotyping method that takes advantage of selective amplification using the polymerase chain reaction (PCR) and oligonucleotide probe hybridization was developed to distinguish all reported HLA-DRB1*08/12 alleles. Selective amplification was achieved using a primer complementary to the sequence encoding YSTGECY at positions 10-16 in the first hyperpolymorphic region (HPMR). This selective amplification of the HLA-DRB1*08/12 subset of alleles provides a refinement in HLA oligotyping that permits unambiguous oligotyping of many heterozygotes that cannot be resolved using less selective amplification alternatives. The amplified DNA was hybridized with a panel of then digoxigenin-labeled probes to resolve oligotypes that correspond to all reported HLA-DRB1*08/12 alleles. Oligotyping of HLA-DRB1*08/12 samples revealed two previously unknown HLA-DRB alleles. One allele, DRB1*0805, differs from DRB1*0801 by a leucine to alanine substitution at position 74. This allele is of particular interest because it is very similar to HLA-DRB1*08 alleles (YSTGECY and lack of an associated HLA-DRB3 gene), but it lacks leucine at position 74, which is characteristic of all previously reported DRB1*08 alleles. The second HLA-DRB1*08 allele, DRB1*0804, differs from DRB1*0802 by a glycine to valine substitution at position 86.


HIV envelope protein is recognized as an alloantigen by human DR-specific alloreactive T cells.

Recent studies from this laboratory reported the mapping of the full profile of T-cell allorecognition regions of HLA-DR2 beta subunit. The results indicated the presence of an allodeterminant within DR2 beta regions 141-156. In another study, we have shown that this allodeterminant is one of five regions of structural homology between the DR2 beta molecule and the HIV-envelope protein gp120 region 254-268. The fact that gp120 peptide 254-268 is homologous to the allodeterminant within the DR2 beta region 141-156 prompted us to investigate whether synthetic gp120 peptide 254-272 is recognized by human DR2-specific alloreactive T-cell lines. Five human alloreactive T-cell lines were prepared that were specific for the DR2 molecule and did not recognize DR1. These lines mounted in vitro proliferative responses to the allodeterminant peptide DR141-156 and also responded to the DR-similar peptide gp254-272. Removal of the residues 262-272 from the gp120 peptide (i.e., peptide 254-263) resulted in essentially complete loss of its proliferative activity. The effect of deletion of three residues of homology (Val-Val-Ser) at the N terminal (i.e., peptides DR145-156 and gp257-272) was examined. Peptide DR2 beta 145-156 exhibited very low stimulating activity, whereas peptide gp 257-272 did not cause T-cell proliferative responses in any of the alloreactive T-cell lines. The T-cell lines did not respond to unrelated peptide controls, thus further confirming the specificity of these responses. These findings indicate that the virus is recognized as an alloantigen by human alloreactive DR2-specific T cells.


HLA DQA, DQB, and DRB genotyping by oligonucleotide analysis: distribution of alleles and haplotypes in British caucasoids.

A precise method for comprehensive HLA DQA and DQB genotyping using gene amplification and hybridization with sequence-specific oligonucleotide (SSO) probes is described. Twenty-four SSO probes were used to detect all DQ allotypes defined by nucleotide sequence variation in the second exons of the DQ genes, using a standard set of conditions for all probes at each locus. Five hundred individuals were genotyped for 8 DQA1 and 16 DQB1 alleles by using this method and for 33 alleles of the DRB1, DRB3, DRB4, and DRB5 genes by using previously described SSO probes. The 4-locus DQB1-DQA1-DRB1-DRB3/4/5 haplotypes present were characterized on the basis of known linkage disequilibrium between class II alleles. Fifty-two different haplotypes that have previously been described were further characterized at the nucleotide sequence level and two novel haplotypes were identified. The distributions of these alleles and haplotypes in 177 randomly selected healthy Caucasoid controls from the United Kingdom are reported. These results identify further haplotypic diversity in the HLA class II region, even though strong linkage disequilibrium exists between the DR and DQ gene loci.


The clinical significance of a positive post-irradiation prostatic biopsy without metastases.

To define the prognostic value of a post-irradiation prostatic biopsy, the outcome of 203 previously irradiated patients who underwent post-treatment biopsy was analyzed. The majority of patients were selected for biopsy based on an abnormal digital rectal exam or elevated prostate specific antigen. Patients with distant metastases found at the time of biopsy were excluded from further analysis. One hundred thirty-nine (139) of these had a positive biopsy and 64 were negative. Those with a positive biopsy tended to present with more locally-advanced (Stage B2/C) tumors (61%) compared to those with negative biopsies (42%). The 10- and 15-year survival and cause-specific survival from the time of initial presentation were similar for both groups. However, those with a negative biopsy had a more favorable survival and cause-specific survival from the time of post-treatment biopsy and were less likely to develop distant metastases than the positive biopsy group. These data suggest that a positive prostatic biopsy is associated with a greater likelihood of subsequent distant relapse and decreased survival following biopsy relative to patients with negative biopsies. Since a positive post-treatment biopsy is more likely among patients presenting with locally-advanced disease, perhaps more aggressive initial therapy (i.e., interstitial boost or hyperthermia) would benefit this subgroup.


The significance of post-irradiation prostate biopsy with long-term follow-up.

Ninety-four patients, Stage A2-C, definitively irradiated for adenocarcinoma of the prostate from 1975 to 1981 underwent digitally directed transperineal needle biopsy of a clinically negative prostate gland at least 18 months post-therapy. Ten of 55 patients (18%) treated with Iodine-125 implantation and 7 of 39 patients (18%) externally irradiated were found to have positive biopsy specimens. Overall, clinical local failure occurred in 53% of patients with positive biopsy results but in only 18% with negative specimens, p = .006. The false negative biopsy rate in patients treated with I-125 was nearly three times that for external beam, 24% versus 9%, perhaps because of the greater possibility of inhomogeneous dose distribution with I-125, allowing for a higher degree of sampling error. Actuarial local failure at 5 years was 44% versus 8% with positive and negative biopsies, respectively, and 75% versus 24% at 10 years (p = .0001). The distant metastatic rate was twice as high in biopsy-positive as compared to biopsy-negative patients, 71% versus 35%, p = .015. Actuarially, only 19% of patients with a positive biopsy are NED at 10 years as compared to 62% of those with a negative biopsy (p = .0001). PSA values are supportive in those patients thought to be disease-free. The incidence of positive biopsy and associated local recurrence are in keeping with clinical treatment failure rates as reported in multiple studies to date.


External beam radiotherapy for incidental adenocarcinoma of the prostate discovered at transurethral resection.

This paper updates the results of 89 patients treated between 1967 and 1989 for incidental carcinoma discovered at transurethral resection of the prostate (Stanford stage T0 or AJC-UICC stage T1) with external beam irradiation. Twenty-two patients had Stanford T0 focal (less than 5% involvement of the prostatic chips) and 67 presented with Stanford T0 diffuse (5% or more involvement). Follow-up ranges from 4 months to 25.1 years, with a mean follow-up of 9.8 years. The actuarial local control for Stanford T0 focal is 100%, and 70% for Stanford T0 diffuse at 15 years. There was no difference in survival between Stanford T0 diffuse and T0 focal and the expected survival of an age-matched control population. Patients who were treated when younger than 65 had a similar local control and distant relapse when compared to those treated when 65 or older. There was no difference in local control, freedom from relapse, or disease-specific survival when the 38 patients who received irradiation to the prostate only are compared with the 29 who also received pelvic irradiation for Stanford T0 diffuse carcinoma. Patients with a Gleason score of 6 or more, when compared with those with a score of 5 or less, experienced more distant relapses and similar local control, suggesting that patients with a high grade tumor have occult metastases at presentation.


Prognostic significance of pelvic recurrence and distant metastasis in prostate carcinoma following definitive radiotherapy.

This report is a retrospective analysis of 317 patients with recurrent prostate carcinoma, following definitive radiation therapy to 738 patients with histologically confirmed, clinical Stage T1b-T4(A2-D1) adenocarcinoma of the prostate. Seventy-four patients (10%) experienced pelvic recurrence only; 100 (13%) both pelvic recurrence and distant metastasis, while 143 (20%) developed distant metastasis only. The diagnosis of prostate recurrence was histologically confirmed in 92/174 (53%), while in the others diagnosis was based on clinical and radiographic evidence. Ninety percent of all recurrences occurred within 7 years of initial treatment. The median survival from time of recurrence for all patients was 27 months, with 5-, 8-, and 10-year survival rates of 24%, 12%, and 7%, respectively. In patients who experienced pelvic recurrence only, the 5-, 8-, and 10-year survival rates were 50%, 30%, and 22%, respectively (p < 0.0001). The 5-year survival rate from time of recurrence for patients who experienced pelvic recurrence with initial Stage T1b(A2) and T2(B) disease was 71% as opposed to 39% for patients with initial Stage T3(C) disease. The time of recurrence (i.e., the disease-free interval from initial treatment) significantly affected subsequent survival: the 5-year survival rates from time of recurrence for patients with pelvic recurrence were 20%, 49%, and 94% for those who recurred within 2 years, 2 to 5 years, and more than 5 years, respectively. Two-thirds of the patients with recurrence received hormonal therapy, including bilateral orchiectomy. Salvage therapy with hormones, including bilateral orchiectomy, has a favorable impact on patient survival: The 5-year survival rate from time of pelvic recurrence salvaged with hormones was 70% compared with 21% for patients not receiving hormonal therapy. In conclusion, the prognostic factors that affect subsequent patient survival after pelvic recurrence include initial stage, disease-free interval from initial treatment, and salvage therapy with hormones. Patients with distant metastasis with or without pelvic recurrence showed statistically worse survival and were apparently not influenced by initial tumor stage, or disease-free interval from initial treatment.


Nuclear roundness factor and local failure from definitive radiation therapy for prostatic carcinoma.

Of 375 patients with prostatic carcinoma treated definitively with radiation therapy at this institution with at least a 5 year follow-up, 23 patients failed locally only, 72 failed with distant metastasis only, 60 had both local and distant failure, while 220 showed no evidence of disease. In search for a possible marker for local failure following radiation therapy, we examined several nuclear morphometric parameters which have been shown to correlate with the biologic aggressiveness of this disease. The 23 locally failed only patients were matched with 23 no evidence of disease patients for stage, grade, treatment modality, prior surgery, age at diagnosis and race. Archival hematoxylin and eosin slides were obtained for 22 of the 23 matched pairs, and morphometric features, including nuclear roundness factor and nuclear area, as well as numbers of nucleoli were assessed using computer-assisted image analysis in both tumor cells and normal prostatic epithelium. Tumor nuclei from the locally failed only patients had significantly higher nuclear roundness factor values (p = 0.0089) compared with tumor cells from no evidence of disease patients. Analysis of these data by clinical stage demonstrated no significant differences between the locally failed only and no evidence of disease patients. Likewise, there were no significant differences in nuclear roundness factor values of locally failed only and no evidence of disease patients with poorly or moderately well-differentiated tumors. However, there was a highly significant difference (p = 0.0012) in the nuclear roundness factor values of locally failed only and no evidence of disease patients with well-differentiated tumors. Thus, there appears to be a subset of patients with well-differentiated adenocarcinoma of the prostate who have significantly more irregular tumor nuclei and who fail locally only following definitive radiation therapy.


Radiotherapy for prostate cancer: should the seminal vesicles be considered target?

During radiotherapy for prostate cancer, the ability to predict occult seminal vesicle invasion is important since irradiation of the entire seminal vesicles necessitates enlarging the radiation fields beyond what is usually used to irradiate the prostate gland alone. We analyzed the records of 302 patients with clinical Stage T1 or T2 adenocarcinoma of the prostate treated with radical surgery at Duke University Medical Center between 1970 and 1983. Univariate and multivariate analyses were used to examine the relationship between the risk of occult seminal vesicle involvement (defined herein as histologic involvement of the seminal vesicles not detected by physical or radiologic examination) and the following factors: histologic grade, age, clinical stage, and preoperative acid phosphatase. Among 249 patients with complete information, increasing histologic grade (p < 0.001) and clinical stage (p < 0.04) were found to be the strongest predictors of occult seminal vesicle invasion. Conversely, seminal vesicle invasion was very unusual in well-differentiated T1-T2 tumors (6%). This low risk group represented 28% (70/249) of this patient population. There appears to be a substantial subset of patients with well differentiated T1 or T2 tumors who are at very low risk for occult seminal vesicle involvement and in whom the seminal vesicles can be excluded from the target volume. The reduction in target volume may reduce normal tissue reactions, facilitate dose escalation, and possibly increase local control rates.


The prognostic significance of race and survival from prostate cancer based on patients irradiated on Radiation Therapy Oncology Group protocols (1976-1985).

A number of studies have identified race as a prognostic factor for survival from prostate cancer. To evaluate the prognostic significance of race in a controlled setting, we evaluated 1294 patients treated on three prospective randomized trials conducted by the Radiation Therapy Oncology Group between 1976 to 1985. One-hundred and twenty (9%) of the patients were coded as black, while 1077 (83%) of the patients were coded as white. Protocol 7506 included 607 patients with clinical Stage T3-T4Nx or T1b-T2N1-2. Protocol 7706 included 484 patients with clinical Stage T1b or T2 who were node negative. Protocol 8307 included 203 Stage T2b-T4 patients with no lymph node involvement beyond the pelvis. Univariate and multivariate analyses were used to assess the possible independent significance of race and other prognostic factors, including Gleason score, serum acid phosphatase, nodal status, and hormonal status. Protocols 7706 and 8307 revealed that race was not of prognostic significance for disease-free or overall survival by either univariate or multivariate analysis. Univariate analysis of Protocol 7506 revealed that the median survival for blacks was somewhat shorter (5.4 years vs. 7.1 years, p = 0.02). This difference persisted after a multivariate analysis. A higher percentage of blacks treated on 7506 had an abnormally elevated serum acid phosphatase compared to whites (p = 0.006), and the time to distant failure tended to be shorter (p = 0.07). These findings suggest that blacks treated on 7506 may have had more extensive disease at presentation. Based on these prospective randomized trials, it is most likely that the lower survival noted for black Americans with prostate cancer reflects the tendency for blacks to present with more advanced disease. Differences in access to care, the quality of care received, and the impact of co-morbid conditions may explain the lower survival reported for black Americans elsewhere in the literature.


High grade adenocarcinoma of prostate in smokers of ethnic minority groups and Caribbean Island immigrants.

The degree of differentiation of 670 blacks and white patients treated from 1980-1990 for curative and palliative external beam radiation therapy and surgery at State University of New York Health Science Center at Brooklyn and Kings County Hospital were analyzed retrospectively, stratified according to race, age, smoking, and grade. In addition stage, birth place and median survival were also analyzed. Overall mean age was 69 years (Std. Dev. 8.97). 69% were blacks and 27.8% were whites. 65.4% were smokers and 34.6% were non-smokers. Smokers had high incidence of more invasive and high grade adenocarcinoma of prostate (p < or = 0.00005) compared to control group (non-smokers with prostate carcinoma). Statistically significant difference was found in the degree of differentiation of carcinoma of prostate in smokers compared to non-smokers. Smokers had 15.04% well, 27.07% moderate, and 57.89% poorly differentiated adenocarcinoma compared to non-smokers in which 37.1% were well, 45.16% moderate, and 17.74% poorly differentiated cancer of prostate (p < or = 0.00005). Sixty-three percent blacks and 40.16% whites had Stage D cancer (p < or = 0.00005). 68.3% smokers and 53.3% non-smokers had Stage D cancer (p = 0.01). Overall median survival for blacks was 74.04 months compared to whites of 115.73 months (p < or = 0.00005).


Combined pre- and postoperative adjuvant radiation therapy for bladder cancer--a ten year experience.

From 1978 through 1987, 78 patients with carcinoma of the bladder were treated with combined pre- and postoperative adjuvant radiation therapy. All were given a single dose of pre-operative radiation therapy, 500 cGy, either on the day of or the day before cystectomy. Histological staging on the cystectomy specimens according to the TNM classification system was performed. Forty patients with Stage P2 (high grade III and IV), P3A, P3B, P4A, or N+ underwent planned high dose postoperative radiation therapy (4000-4500 cGy) in 5 weeks. The whole pelvis was treated with conventional fractionation of 180 cGy 5 days per week. Median follow-up was 52 months, with 36 months minimum follow-up. There was a 67% overall 5-year survival, and those with P1 and P2 (Grade I and II) had an 84% 5-year survival. Survival for patients with P2 tumor (Grade III and IV), P3A, P3B, and P4/N+ stages was 57%, 56%, 39%, and 50%, respectively. Bowel obstructions developed in 8% of patients who received no postoperative radiation therapy and 37% in those who did. Genitourinary complication rates were similar in both groups, 13% in the group that received no postoperative radiation therapy and 10% in the group that did. Although the planned approach of combined pre- and postoperative radiation therapy for unfavorable stages of bladder cancer is associated with a better than 50% 5-year survival rate (except in Stage P3B cancer), the bowel toxicity was unacceptably high.


Interstitial iridium-192 for bladder cancer (a multicentric survey: 205 patients).

Interstitial irradiation is a technique currently used in the treatment of bladder cancer. We report the data on 205 patients (177 men and 28 women) treated in eight French centers. The patients had received the following treatment: a short course of pre-operative pelvic irradiation, followed by surgery consisting of partial cystectomy or tumor resection, and implantation of plastic tubes filled with inactive lead wires, which were replaced by iridium 192 wires. The tumor characteristics were: transitional cell carcinoma, 88.8%; mean size of the tumor, 29 mm; pathological stages: pTis, 1; pT1, 98; pT2, 66; pT3a, 26; pT3b, 9; pT4, 1; unknown, 4 respectively; surgical lymph node status: N+, 3; N-, 118; no node dissection, 84. The mean follow-up was 51 months. Intravesical failures were seen in 35 patients (17.0%), 25 (71.4%) of them without metastases or regional recurrences. Twenty-one patients (10.2%) presented distant metastases, 2/3 of them suffered no bladder relapse. The 5-year survival, calculated according to the Kaplan-Meier method (all causes of death taken together) was 77.4% for the T1, 62.9% for the T2, and 46.8% for the T3. Fifty-three patients had immediate side-effects and three died from surgical complications. Twenty-nine patients had delayed bladder side-effects (haematuria, fistula, chronic cystitis). Six patients presented an ureteral stenosis. Of the disease-free survivors, 96.1% retained the bladder function. Three factors were significantly predictive of delayed side-effects: partial cystectomy, pre-operative radiotherapy total dose, and linear activity of the wires (p < 0.01). Comparing our results to different authors' series interstitial irradiation is likely to provide a high local and general control of the disease and good quality of life in patients with selected tumors.


Iridium-192 interstitial therapy for squamous cell carcinoma of the penis.

From February 1971 through February 1989, 51 patients with biopsy proven epidermoid carcinoma of the penis were treated with interstitial therapy (Iridium 192). The breakdown according to the stage was T1s = 3, T1 = 14, T2 = 28, T3 = 6, N0 = 43, N1 = 7, N2 = 1. The dose ranged from 50 to 65 Gy (mean: 60 Gy). Patients without clinical nodal involvement received no treatment to the nodes. Stage N1 and N2 patients had surgery and external irradiation to the inguinal and iliac nodes. Six of fifty-one (12%) patients developed nodal and/or metastatic disease following therapy. Five of six presented initially with clinical nodal involvement. Seven of fifty-one (14%) developed local recurrence only, requiring surgery (four partial penectomies, three total penectomies). Six of these seven patients are alive and free of disease with a mean follow-up of 5.5 years. Nine of thirty eight (23%) patients with local control developed local necrosis. The treatment consisted of local excision (one patient), partial amputation (six patients) or total amputation (two patients). Partial urethral stenosis was noted in 17/38 (45%) of the patients. Foreskin sclerosis occurred in 3/38 (8%) uncircumcised patients. Interstitial irradiation for penile carcinoma provided effective local control rates, especially for T1-T2 patients (91%). Local failures could be treated successfully with surgery. Complications could be treated conservatively in most patients. Local control with penile conservation was achieved in 67% of all patients and 75% of patients with T1-T2 disease.


Conformal static field radiation therapy treatment of early prostate cancer versus non-conformal techniques: a reduction in acute morbidity.

Patients with early prostate cancer have been definitively treated using our previously described technique of CT-based 3D treatment planning and beam's eye view techniques with patients immobilized in alpha cradle casts. An average of 14% bladder (range 6-31%) and 14% rectal (range 7-25%) volume receiving a given dose was eliminated using four conformally blocked fields, with a 1.5 cm margin around the prostate contour, when compared to stage matched controls. Treatment-related acute morbidity was compared for 26 patients treated by the conformal techniques (CG) since April 1989 and 20 consecutive patients treated immediately prior to the conformal techniques with prostate only fields from May 1985-March 1989 (NCG). Acute urinary symptoms (frequency, dysuria, hematuria) or acute rectal symptoms (diarrhea, tenesmus, blood) occurred in 77% (20/26) of the CG versus 80% (16/20) of the NCG patients. Only 31% (8/26) of the CG versus 60% (12/20) of the NCG patients (p < .05) experienced symptoms to a degree which prompted physician intervention (medication and/or interruption of treatment). Two of 26 CG patients (8%) required medication for both bladder and rectal symptoms compared to 5/20 (25%) NCG patients (p = .09). Symptoms persisted for an average of 2.5 weeks versus 3.5 weeks in the CG and NCG groups, respectively. Persistent symptoms at or beyond the 1 month follow-up were present in 3/26 (11%) CG patients (average duration 1.5 months) and were present in 4/20 (20%) of the NCG patients (average duration 2.5 months). Thus, although the percentage of patients who experience acute irritation of the bladder and/or rectum is similar in the two groups, it appears that the percentage requiring medication and/or interruption of treatment is significantly less when 3D treatment planning, rigid immobilization, and conformal blocks are used. The amount of bladder and rectal tissue that is eliminated by our conformal technique is important as shown clinically by the lesser severity and shorter duration of acute symptomatology.


Phase I/II study of external radio frequency phased array hyperthermia and external beam radiotherapy in the treatment of prostate cancer: technique and results of intraprostatic temperature measurements.

As part of an ongoing Phase I/II study at Duke University Medical Center investigating the toxicity and efficacy of external beam radiotherapy plus hyperthermia for deep-seated, locally advanced or recurrent solid tumors, 12 patients with prostate malignancies (adenocarcinoma--11, leiomyosarcoma--1) were treated with radiotherapy plus hyperthermia. Hyperthermia was given after radiotherapy using a Radio Frequency Phase/Amplitude Control Sigma 60 annular phased array device. All patients had simultaneous temperature measurements made in the rectal lumen and within the prostate during at least one hyperthermia session. Intraprostate thermometers were placed via a unique method described herein using both computerized tomography scan and a rigid sigmoidoscope for guidance. We were able to achieve the desired tumor temperature of > or = 42.5 degrees C in only 1/28 (3.5%) of hyperthermia treatments. Subjective symptoms of pain and/or pressure limited power deposition in 79% of hyperthermia treatments. Higher temperatures were achieved in the distal rectum than in the prostate in all treatments, although the differences were not statistically significant. This temperature differential could not be compensated by using phase and amplitude steering. Rectal temperatures adjacent to the prostate were predictive of prostate temperatures. We conclude that using this regional heating technique we were unable to demonstrate an ability to get an advantageous temperature differential between the prostate and normal tissue. This technique is not useful as an adjuvant to radiation therapy for prostate cancer. The usefulness of other regional heating techniques and devices should be explored.


Accelerated fractionation radiotherapy for laryngeal cancer, acute, and late toxicity.

The acute toxicity of an accelerated radiotherapy scheme was compared with a conventional schedule. Eighteen patients with squamous cell carcinoma of the larynx were treated with accelerated fractionation radiotherapy. An average reduction of overall treatment time of 11 days was accomplished by giving 2 fractions a day during the last part of the treatment. Total dose and fraction dose were left unchanged. Acute reactions of skin and mucosa in these patients were compared with those in 40 patients treated with a conventional fractionation scheme, that is, 2 Gy per fraction, 5 fractions per week, to a total dose of 64-70 Gy. Acute reactions were maximal between 5 and 7 weeks after the start of treatment. Complete healing occurred within 3 months in all patients. Mucosal reactions and, as a consequence, dysphagia were clearly increased in those patients treated with accelerated fractionation. For confluent mucositis an ED50 of 66 Gy was calculated compared to 69 Gy for conventional fractionation. To a lesser degree, skin toxicity was also enhanced in the patients treated with the accelerated schedule. Severe edema of the laryngeal mucosa occurred only in patients treated to a total dose of 68 or 70 Gy and was somewhat more frequent with accelerated fractionation (4/10) than with conventional fractionation (4/24). One patient in the accelerated fractionation group underwent laryngectomy for persistent edema and laryngeal necrosis. No severe late skin reactions were observed. It can be concluded that the fractionation schedule tested in this study is feasible. Further shortening of overall treatment time without reduction of total dose will likely lead to unacceptable acute and, possibly, also late toxicity.


Radiation tolerance and fractionation sensitivity of the developing rat cervical spinal cord.

To investigate the influence of age at irradiation on single dose radiation tolerance and fractionation sensitivity, the cervical spinal cord of rats was irradiated at the age of 1 week and at 15-18 weeks (adult). While the main histological lesions seem to be comparable after irradiation at the two ages, differences were found in single dose tolerance, latency to paresis due to white matter lesions, and fractionation sensitivity. The 50% effect dose (ED50) for single dose irradiation at one week was 19.5 Gy, which is only 10%, but significantly (p < 0.05), lower than the ED50 of about 21.5 Gy at 3 weeks and above. The latency to paresis was clearly influenced by the age at irradiation. The latency in the rats irradiated at 1 week was about 2 weeks, while for adult rats a latency of about 8 months was observed. The fractionation sensitivity for irradiation at 1 week was lower than the fractionation sensitivity of the adult rats; the alpha/beta value at 1 week was estimated to be 4.5 Gy, while for the adult rats an alpha/beta value of 1.8 Gy was found. As a consequence, the observed small difference in tolerance to single doses between 1 week-old and adult rats is further enhanced after fractionated irradiation. During prolonged irradiation treatments this decreased tolerance may be compensated by a higher proliferation rate in the immature central nervous system. The results of the present experiments indicate that, for a single tissue and endpoint, paresis due to white matter lesions in the rat cervical spinal cord, the latency to expression of damage and the fractionation sensitivity clearly change with age at irradiation.


The hybrid spheroid clonogenic assay for the intrinsic radio- and chemo-sensitivities of human tumors.

The Hybrid Spheroid assay is based on packaging tumor cells into agglomerates of non-proliferating, but metabolically active, HeLa cells. These agglomerates provide an in vivo-like environment for entrapped test cells. Clonogenicity is determined by varying the number of test cells per hybrid spheroid so that some, but not all, spheroids give rise to macrocolonies. From the fraction of noncolony forming spheroids and the Poisson distribution, the average number of clonogens per spheroid can be calculated. The clonogenicity and radiation survival curves of cells derived from human tumors (of the maxilla, tongue, larynx, mouth floor, lung, breast, ovary, and colon) were so determined. Plating efficiency was increased in these normally poorly plating tumor cells, thus enabling survival measurements which are not practical using conventional methods. The Hybrid Spheroid assay has also been applied to determine the chemosensitivity of colon cancer cells.


Heterogeneity of 5-fluorouracil radiosensitivity modulation in cultured mammalian cell lines.

There is ample evidence that 5-fluorouracil (5-FU) improves both local control and survival of a variety of gastrointestinal tumors when added to radiotherapy. However, the modulation of radiosensitivity by 5-FU is incompletely understood and some reports are apparently contradictory. Therefore, we have reevaluated the modulation of radiosensitivity by 5-FU in a variety of mammalian cells. HT-29 and WiDr (human colon adenocarcinoma), DU-145 (human prostate adenocarcinoma), V-79 (Chinese hamster lung fibroblast), and HeLa cell lines were maintained in exponential growth as monolayer cultures. Cell survival following treatment with drug and/or radiation was determined by colony formation assay. Radiation was delivered either alone; midway through a 1 hr exposure to 7-25 micrograms/ml 5-FU (pulse); or following initiation of 0.1-1.5 micrograms/ml 5-FU present throughout the entire incubation for assay of colony forming ability (continuous exposure). These 5-FU levels were selected to approximate those achieved in vivo in humans. The results indicate that mammalian cell lines may vary substantially insofar as modulation of their radiosensitivity by 5-FU is concerned. Radiosensitization, defined by reduction in D0, was observed for continuous exposure only in V-79, WiDr, and HT-29 cell lines, was observed for both pulse exposure and continuous exposure in DU-145, and was not present in HeLa cells. Radioenhancement, defined by reduction in n, was observed in V-79, WiDr, and HT-29 but not in the other cell lines. This effect, characterized by reduction in the shoulder portion of the curve, is naturally accompanied by a decrease of Dq. This indicates that mammalian cell lines may have different responses to radiosensitivity modulation by 5-FU. Though the cell lines may exhibit radiosensitivity by either alterations in the slope or shoulder of the cell survival curve, the mechanisms responsible for both the heterogeneity as well as the radiosensitization itself are completely unknown at this time. Insight into the mechanisms for both the heterogeneity and the radiosensitization will be important areas for further investigation.


Cellular glutathione (GSH) and glutathione S-transferase (GST) activity in human ovarian tumor biopsies following exposure to alkylating agents.

In vitro studies have suggested that elevated levels of the thiol glutathione (GSH) may be associated with acquired alkylating agent resistance, but there is currently little data on the relationship between elevated GSH and glutathione S-transferase levels and clinical alkylating agent resistance. In this study, GSH and glutathione S-transferase levels have been determined in 23 human ovarian tumor samples obtained prior to the onset of combination chemotherapy, and in 23 samples obtained after the development of acquired chemoresistance. GSH levels were 10-fold greater in human ovarian tumor cells obtained after alkylating agent resistance developed, than in biopsy samples obtained prior to treatment. No significant changes in the expression of total glutathione S-transferases were seen in relation to prior drug exposure.


Radiosensitivity of mouse skin epithelial cell line established in serum-free culture: an alternative to animal use.

A cultured line of murine skin epithelial cells was established to investigate the potential use of cultured cells as an alternative to animal use in radiation research. C3Hf/Sed newborn mouse skin cells have been successfully cultured in serum- and Ca(2+)-free medium with no terminal differentiation to keratinized cells. Presently, more than 25 passages have passed with no loss of stem cell capability. The radiosensitivity and repair of sublethal and potentially lethal radiation damages were investigated in this epithelial cell line. The population cell doubling time was 25 +/- 2.9 hr at 37 degrees C. The clonal growth of epithelial cells after irradiation was performed in the serum-free medium in the presence of lethally irradiated skin fibroblasts. Single dose survival curves of exponentially growing epithelial cells were investigated from the seventh to the twenty-third passages, and no significant changes in radiosensitivity and doubling time were found. The confluent epithelial cells also showed an identical sensitivity to radiation. The alpha/beta ratios of survival curves fitted by the linear quadratic model were 6.1 +/- 1.0 and 5.9 +/- 1.3 Gy for cells in exponential and confluent phases, respectively. The survival curve of epithelial cells left in confluence for 8 hr after irradiation showed a smaller beta value than that of cells plated immediately after irradiation with a resultant alpha/beta ratio of 9.5 +/- 3.8 Gy. This alpha/beta ratio was identical to those found in many animal experiments, suggesting a potential use of this cell line as an alternative to animal use. The magnitude of repair of sublethal damage following 6 Gy was greater than that following 3.9 Gy. Survival curves were also obtained following twice-a-day irradiations with no sign of rapid repopulation. These results are discussed by comparing with published in vivo and in vitro data.


Changes in heat and radiation sensitivity during long duration, moderate hyperthermia in HeLa S3 cells.

Step-up heating and thermal radiosensitization were studied at 41.5 degrees C in HeLa S3 cells under conditions where chronic thermotolerance was not expressed. In spite of this lack of thermotolerance expression, it was possible that thermotolerance to higher temperature treatment had developed. Accordingly, cells were incubated for various times at 41.5 degrees C, then immediately shifted up to 45 degrees C, whereupon heating continued for up to 75 min. Thermotolerance to 45 degrees C heating was observed after 8 hr incubation at 41.5 degrees C and decayed by 32 hr of continuous incubation at 41.5 degrees C. When the time of 45 degrees C treatment was extended to 150 min, the biphasic survival response indicated that chronic thermotolerance was expressed at 45 degrees C, even though it was not expressed during the 41.5 degrees C treatment. Thus, chronic thermotolerance can develop under conditions (e.g., at 41.5 degrees C) where it is not expressed, yet be expressed under other conditions (e.g., during 45 degrees C exposure). When cultures were x-irradiated after various periods of 41.5 degrees C treatment, maximum thermal radiosensitization was observed after 4 hr of incubation at 41.5 degrees C, for which no cell killing was observed due to heat alone. The radiosensitization observed decreased the Do and Dq values from about 1.3 Gy to 0.7 Gy and from about 2.0 Gy to 1.0 Gy, respectively. As the duration of the 41.5 degrees C pre-treatment was extended up to 32 hr, no additional thermal-radiosensitization was observed; all killing due to the heat exposure at 41.5 degrees C was additive to the radiation killing after the initial induction of thermal radiosensitization. These results demonstrate differences in the thermal and radiation responses of HeLa cells when compared to earlier studies using CHO cells and may be more relevant to the clinical setting.


Ultrasonically guided transperineal seed implantation of the prostate: modification of the technique and qualitative assessment of implants.

During the period 1988-1991, 23 patients with prostatic carcinoma were treated by transperineal iodine seed implantation guided by transrectal ultrasound. We introduce a refinement of the implantation technique using a rigid column of seeds and spacers. The uniformity parameter based on the peak width of the natural volume-dose histogram demonstrated quantitatively that this refinement resulted in a more accurate seed arrangement.


Quality assurance for intraoperative electron radiotherapy clinical trials: ionization chamber and mailable thermoluminescent dosimeter results.

Ionization chamber and thermoluminescent dosimeter measurements were made to verify the dosimetry data provided to the Radiation Therapy Chart Review office of interinstitutional electron intraoperative radiotherapy clinical trials. The ionization measurements included intraoperative radiotherapy applicator output and depth dose measurements made at the stated 80% and 50% depths at 14 different radiotherapy facilities. Mailable thermoluminescent dosimeter measurements, including output and depth dose measurements were made at 16 institutions. The mailable thermoluminescent dosimeter results show similar inter-institutional agreement, both for output and depth dose comparison, with the corresponding ion chamber results for intraoperative radiotherapy applicators. These results are compared to similar measurements made for conventional electron applicators.


Gene therapy targeted by ionizing radiation.

Gene therapy used for the treatment of neoplastic diseases is not well localized. Ionizing radiation can be used to activate the transcription of exogenous genes that encode cytotoxic proteins. This may be accomplished through the use of radiation responsive elements distal to the transcription start site of such genes. We discuss this concept and describe a technique which can be used to amplify the signal initiated by localized radiation therapy. These techniques may be used to target gene therapy during the treatment of human neoplasms.


Social interaction, cardiovascular activation and the Type A behavior pattern.

The purpose of the study was to explore the relationship between social interaction and cardiovascular activity during a conflict-inducing communication task in Type A and B subjects. One of the subjects, the leader, was instructed to lead the other subject, the follower, through defined routes on a city map merely by help of instructions. The subjects were facing each other on each side of a screen which allowed eye contact but shielded the maps from view. 40 male students (mean age 24 years) exhibiting Type A or Type B behavior according to the Videotaped Structured Interview participated in the study. The results demonstrated large cardiovascular increases during task performance, particularly for leaders, in systolic blood pressure and heart rate. There were no main effects of Type A vs. Type B, but dyads composed of two Type As showed larger increase in diastolic blood pressure during the conflict phase of the task compared to dyads composed of Type Bs.


Effect of task difficulty and interstimulus interval on blink parameters.

The effects of task difficulty and interstimulus interval (ISI) on blink rate, blink latency and blink duration, were studied in a modified Sternberg memory task in which either two or six characters were to be memorized. Stimuli were presented in ISI blocks at either 5.3 or 9.3 s (SOAs of 6 or 10 s). While blink rate and blink duration declined prior to each stimulus, the difficulty of the expected task (the length of the memory set) did not affect the rate of decline or the final prestimulus level. Concerning ISI, blink rate declined more rapidly during shorter ISIs but the final prestimulus level, as was the case with task difficulty, was unaffected by the ISI duration. Presentation of the 6-character memory set produced a marked immediate inhibition of blinking. The data suggest that the encoding of visual stimuli is more akin to processes invoked in preparation for input than to ensuing processing stages since both encoding as well as preparation are accompanied by inhibition of blinking.


Directed coherence as a measure of interhemispheric correlation of EEG.

Based on a bidirectional model and the temporal relation of the signals, directed coherence is defined to describe the EEG correlation according to the direction of information transmission in the frequency domain. The interhemispheric directed coherences of EEG pairs in the prefrontal, frontal, central, parietal and occipital cortices were investigated. Statistically, significantly greater right-left directed coherences were found in the parietal and occipital regions than that of the left-right direction for alpha activity. The results indicate different information processing for different frequency bands between the left and right hemispheres, and this can not be derived from the examination of original coherence. This may suggest that the measure of directed coherence can provide more information than that of original coherence.


Electrodermal differentiation of deception: potentially confounding and influencing factors.

The demonstration of deception as a psychological process requires a comparison of physiological responding to questions answered honestly or deceptively, under conditions which differ only with respect to deception. Such electrodermal (skin conductance response (SCR) differentiation was recently reported in the Differentiation-of-Deception Paradigm. The present study had two empirical goals: (a) to assess the possible confounding role of retrieval-difficulty and novelty in producing the differentiation effect; (b) to ascertain any influencing effects of a memorial ('cumulative' mental load) and two motivational (Monetary-Incentive and Ego-Involvement) factors on the electrodermal differentiation phenomenon and on overall responding. In addition to the basic Deceptive vs. Honest manipulation of the Differentiation-of-Deception Paradigm, the present study varied, within 60 subjects, Question Type (easily retrieved Autobiographical vs. more difficult-to-retrieve Biographical). The two two-level motivational factors were varied between subjects. Finally, to assess the confounding issue, voice latency (VL), known to be sensitive to retrieval-difficulty, was measured in addition to SCR. SCRs to deceptive answers exceeded those to the honestly-answered questions, demonstrating the differentiation phenomenon. Results showed that although VL and SCR was significantly greater to Biographical than to Autobiographical questions, the differentiation effect emerged only in the SCR and not in VL, which suggests that memorial difficulty does not confound the electrodermal differentiation effect.


Anxiety, emotion and cerebral blood flow.

Regional cerebral blood flow was measured by the xenon inhalation technique using a DSPECT system, during neutral and emotional auditory stimulations. Subjects were 10 high and 10 low trait anxiety, right-handed females. State anxiety was retrospectively assessed. Results indicated a lower rCBF in the high trait or state anxiety subjects who presented also a global rCBF asymmetry in the right > left direction. Additionally, the emotional content of the stimuli interacted significantly with the side of the brain in the thalamic area.


Theta rhythmicities following expected visual and auditory targets.

Evoked (EPs) as well as event-related potentials (ERPs) were recorded from two groups of 10 healthy, voluntary subjects in auditory and visual modalities. For ERP recordings 'the omitted stimulus paradigm' was employed, in which the subjects were expected to mark mentally the onset time (time prediction task) of the omitted stimulus (target). The standard auditory (AEP) and visual (VEP) evoked potentials and auditory and visual ERPs to the preceding stimuli of the omitted ones were analyzed in time and frequency domains. In the time domain the time prediction task induced increases of the amplitudes of waves existing in standard EPs; however, an additional wave or component could not be detected. Analysis of amplitude frequency characteristics (AFCs) revealed, however, selective, significant increases of the theta (3-6 Hz) frequency components of the responses concerned. These theta increases were especially evident in the frontal and parietal recording sites. Our findings suggest an association between the theta frequency components of transient evoked responses, the association areas of the brain and cognitive performance. The neurophysiological basis of scalp recorded ERPs are discussed in relation to the findings of animal studies with EEG and single unit recordings from cortical and subcortical structures.


P300-response: possible psychophysiological correlates in delta and theta frequency channels. A review.

The present paper combines a review of event-related potentials (ERPs) with empirical data concerning the question: what are the differences between auditory evoked potentials (EPs) and two types of ERPs with respect to their frequency components? In this study auditory EPs were elicited by 1500 Hz tones. The first type of ERPs was responses to 3rd attended tones in an omitted stimulus paradigm where every 4th stimulus was omitted. The second type of ERPs was responses to rare 1600 Hz tones in an oddball paradigm. The amplitudes of delta and theta components of EPs and ERPs showed significant differences: in responses to 3rd attended tones there was a significant increase in the theta frequency band (frontal and parietal locations; 0-250 ms). In the delta frequency band there was no significant change. In contrast a diffuse delta increase occurred in oddball responses and an additional prolongation of theta oscillations was observed (late theta response: 250-500 ms). These results are discussed in the context of ERPs as induced rhythmicities. The intracranial sources of ERPs, their psychological correlates and the role of theta rhythms in the cortico-hippocampal interaction are reviewed. From these results and from the literature a working hypothesis is derived assuming that delta responses are mainly involved in signal matching, decision making and surprise, whereas theta responses are more related to focused attention and signal detection.


How to select epochs of cognitive event-related potentials for brain mapping?

Event-related potentials were recorded in healthy volunteers while they were performing cognitive tasks. The new parameter developed for evaluation of how ERPs from different electrodes are not like each other allowed to study the mental chronometry as well as the localization of specific cortical areas. Occipital lobes were most active in passive visual word perception, the left anterior frontal lobe was activated in semantic association. The developed approach allows the combination of imaging and chronometric studies.


Contingent negative variation as an indicator of sexual object preference: revisited.

This study attempted to replicate the finding of Costell et al. (1972) that contingent negative variation (CNV) in anticipation of opposite sex nudes is of greater amplitude than CNV in anticipation of same sex nudes. In order to control for variation in level of attention, which may have accounted for the result of Costell et al., a 'match/mismatch' CNV paradigm was used in which S2 was either identical to S1 or differed from it. Subjects (n = 6 males) were required to indicate a same/different judgement by button pressing at S2 offset. CNV in anticipation of opposite sex nudes was of significantly greater amplitude than CNV in anticipation of same sex nudes, confirming the finding of Costell et al. This offers encouragement for the application of CNV to the assessment of sexual object preference in sex offenders.


Spicy meal disturbs sleep: an effect of thermoregulation?

Tabasco sauce and mustard taken with the evening meal markedly disturbed sleep of six, young, healthy male subjects; reducing slow wave and stage 2 sleep, increasing total time awake and tending to increase sleep onset latency. Whilst post meal effects on temperature and oxygen consumption were not significantly different from control meals the spicy food condition elevated body temperature during the first sleep cycle. The possibility that the spice principle capsaicin affects sleep via changes in body temperature is discussed.


Effects of countercurrent scalding and postscald spray on the bacteriologic profile of raw chicken carcasses.

In June and September 1988, the USDA Food Safety and Inspection Service sampled raw chicken carcasses at a federally inspected slaughter establishment in Puerto Rico to determine the effects of changing the scalding equipment on bacterial contents of raw poultry products. The scalding equipment was changed to a countercurrent configuration, with a postscald hot-water rinse cabinet that sprayed carcasses as they exited the scalder. Analysis of 250 carcass-rinse samples collected at preevisceration, prechill, and postchill sites over 7 days indicated that carcasses had mean aerobe plate counts of log(10)3.73 before evisceration, 3.18 before chilling, and 2.87 after chilling; Enterobacteriaceae counts of log(10)2.70 before evisceration, 2.25 before chilling, and 1.56 after chilling; and Escherichia coli counts of log(10)2.09 before evisceration, 1.61 before chilling, and 0.89 after chilling. Salmonellae were found on 24% of the carcasses before evisceration, on 28% before chilling, and on 49% after chilling. Although bacterial count reductions were significant at all 3 sites, the proportion of carcasses contaminated with salmonellae in this study was higher at the postchill than prechill site (49 vs 28%). This no doubt was caused by cross-contamination in the chiller. These percentages indicated that although simple scalder changes contributed substantially to the improvement of the bacterial quality of chicken carcasses, additional interventions in the chilling process (such as chlorination of chill water) are important to control cross-contamination and to preserve the positive effects obtained by the scalder changes.


Induced transplacental transmission of Neospora caninum in cattle.

Three Jersey cows were inoculated SC and IM with 26 million Neospora caninum tachyzoites at 129 (cow 1), 126 (cow 2), and 81 (cow 3) days after mating. Cows remained clinically normal for at least 1 month after inoculation of N caninum. Cow 1 was euthanatized 32 days after inoculation because of gangrenous mastitis. Cow 1 had a live fetus with no gross lesions; however, microscopic lesions were seen in the fetus and consisted of severe nonsuppurative necrotizing encephalitis of the cerebral white matter. Neospora caninum was identified in lesions by staining with anti-N caninum serum in an immunohistochemical test, by bioassays in mice, and by inoculation of bovine monocyte cultures with fetal tissue homogenate. Neither N caninum nor lesions were associated with infection with the protozoon identified in tissues of cow 1. Cows 2 and 3 aborted small autolysed fetuses 101 and 74 days, respectively, after inoculation with N caninum; the fetuses and attached placenta were unsuitable for laboratory investigations. Cows 2 and 3 remained clinically normal 4 months after abortion. Results of this study indicated that N caninum can be transmitted transplacentally in cattle.


Characterizing biological variability in livestock blood cholinesterase activity for biomonitoring organophosphate nerve agent exposure.

A biomonitoring protocol, using blood cholinesterase (ChE) activity in livestock as a monitor of potential organophosphate nerve agent exposure during the planned destruction of US unitary chemical warfare agent stockpiles, is described. The experimental design included analysis of blood ChE activity in individual healthy sheep, horses, and dairy and beef cattle during a 10- to 12-month period. Castrated and sexually intact males, pregnant and lactating females, and adult and immature animals were examined through at least one reproductive cycle. The same animals were used throughout the period of observation and were not exposed to ChE-inhibiting organophosphate or carbamate compounds. A framework for an effective biomonitoring protocol within a monitoring area includes establishing individual baseline blood ChE activity for a sentinel group of 6 animals on the bases of blood samples collected over a 6-month period, monthly collection of blood samples for ChE-activity determination during monitoring, and selection of adult animals as sentinels. Exposure to ChE-inhibiting compounds would be suspected when all blood ChE activity of all animals within the sentinel group are decreased greater than 20% from their own baseline value. Sentinel species selection is primarily a logistical and operational concern; however, sheep appear to be the species of choice because within-individual baseline ChE activity and among age and gender group ChE activity in sheep had the least variability, compared with data from other species. This protocol provides an effective and efficient means for detecting abnormal depressions in blood ChE activity in livestock and can serve as a valuable indicator of the extent of actual plume movement and/or deposition in the event of organophosphate nerve agent release.


Ivermectin treatment of naturally acquired and experimentally induced Strongyloides stercoralis infections in dogs.

Treatment of Strongyloides stercoralis infection was investigated in 2 dogs with naturally acquired, chronic-active infections, and in 3 dogs with corticosteroid-enhanced, experimentally induced hyperinfections. A single oral dose of ivermectin was given to naturally infected (200 micrograms/kg of body weight) and experimentally infected (800 micrograms/kg) dogs. Five dogs with experimental hyperinfections served as controls. Dogs with naturally acquired infections ceased to shed first-stage larvae in the feces 1 week after treatment, but 1 dog had recrudescence and required a second dose. Ivermectin was 100% effective in removing adult S stercoralis from the intestinal tract of the experimentally infected dogs, but it was not effective in removing third-stage larvae from parenteral sites. Ivermectin-treated dogs had few intestinal parasites of any stage, whereas at necropsy, 4 of 5 experimentally infected dogs not treated had massive infections (greater than 100,000 adults, greater than 92,000 larvae) in the intestinal tract, and 3 of 5 had larvae (greater than 2,500) in parenteral sites.


Episodic weakness associated with exertional lactic acidosis and myopathy in Old English sheepdog littermates.

Two Old English Sheepdog littermates were evaluated for weakness that developed during periods of minimally intense exercise. Lactic acidosis accompanied by increased muscle enzyme activity, an increased lactate/pyruvate ratio, and increased venous PO2 supported the possibility of defective mitochondrial oxygen use. Electromyographic abnormalities included increased insertional activity and complex repetitive discharges. Muscle alterations included scattered myofiber necrosis, abundant endomysial connective tissue, excessive glycogen accumulation, and greater than normal numbers and vacuolation of mitochondria. A distinctive pattern of subsarcolemmal mitochondrial aggregates, referred to as "ragged red fibers" in human mitochondrial myopathies, was observed in muscle biopsy samples from 1 dog. Several features of the disease in these dogs, including onset of weakness during early life, simultaneous disease in littermates, subtle nonprogressive weakness of at least 3 years' duration, and partial reversibility of lactic acidosis following rest were suggestive of an inborn error of metabolism, consistent with mitochondrial myopathy.


Paraneoplastic leukocytosis associated with a rectal adenomatous polyp in a dog.

A dog with a rectal adenomatous polyp had extreme neutrophilic leukocytosis, monocytosis, and eosinophilia consistent with a paraneoplastic syndrome. Resolution of the leukogram abnormalities after tumor excision supported this belief. Except for a lack of circulating myeloblasts, the dog had leukogram findings consistent with a neutrophilic leukemoid reaction.


Belt loop gastropexy in the management of gastroesophageal intussusception in a pup.

Gastroesophageal intussusception and megaesophagus were diagnosed in a 5-week-old German Shepherd Dog. Exploratory surgery was performed, and belt loop gastropexy was used to maintain proper gastric position after manual reduction of the intussusception. The pup survived surgery and was clinically normal when it was 6 months old. Follow-up contrast radiography revealed resolution of the megaesophagus and apparent permanent gastropexy. Previous reports have indicated extremely high mortality for gastroesophageal intussusception, and resolution of megaesophagus in the dog is unusual.


Ultrasonographic characteristics of splenic and hepatic lymphosarcoma in three horses.

Splenic and hepatic ultrasonography were beneficial for diagnosis of lymphosarcoma in 3 horses with anorexia, weight loss, and lethargy. Ultrasonographic abnormalities of the spleen included a large, complex, hypoechoic mass in 1 horse, multiple well-marginated, hypoechoic nodules in 1 horse, and diffuse hyperechogenicity in another horse. Ultrasonographic abnormalities of the liver included a spherical, hypoechoic nodule in 1 horse and diffuse hyperechogenicity in another. Histologic examination of ultrasound-guided biopsy specimens or aspirates revealed lymphosarcoma. Necropsy findings confirmed diagnosis of lymphosarcoma in all horses. Necropsy findings of the liver and spleen correlated well with antemortem ultrasonographic images.


Tubular duplication of the cervical portion of the esophagus in a foal.

Tubular duplication of the cervical portion of the esophagus was diagnosed in a 10-day-old female Quarter Horse. The foal was examined because of the development of a 12- to 15-cm diameter mass at the caudal aspect of the mandible after suckling. The foal was dyspneic when in lateral recumbency. Radiography and ultrasonography revealed a fluid- and gas-filled mass. Endoscopy revealed a normal-appearing upper airway and esophagus. Complete surgical resection of the mass was successful. The mass had a 3-mm diameter communication with the esophageal lumen at the pharyngoesophageal oriface. Histologic examination revealed stratified squamous epithelium lining the cyst-like cavity. The wall of the mass had circumferential and longitudinal layers of smooth muscle with few submucosal glands. The clinical, gross pathologic, and histopathologic findings were consistent with tubular duplication of the cervical portion of the esophagus.


Cholelith causing duodenal obstruction in a horse.

A 10-year-old Appaloosa stallion was referred for evaluation of colic. At admission, the heart rate, capillary refill time, respiratory rate, and rectal temperature were high. Fifteen liters of reflux was obtained by nasogastric intubation. Palpation of an abdominal mass per rectum elicited signs of pain. At exploratory laparotomy, a mass was palpated in the ascending portion of the duodenum. The small intestine ruptured at the site of obstruction during manipulation. The horse was euthanatized. A large cholelith was the cause of the duodenal obstruction. At necropsy, multiple choleliths of various sizes were found in the pancreatic and common bile ducts and in the stomach.


Use of the neodymium:yttrium-aluminum-garnet laser for treatment of squamous cell carcinoma of the nasal planum in a cat.

A mature castrated male domestic shorthair cat was referred for treatment of an excoriated, ulcerated area on the nasal planum. Undifferentiated squamous cell carcinoma was diagnosed. Surgical resection of the nasal planum was not an option, so the lesion was treated 4 times with neodymium:yttrium-aluminum-garnet laser. Laser surgery results in uniform photovaporization of large volumes of tissue. Although treatment with laser does not yield tissue specimens suitable for histologic evaluation, it can result in a cosmetically suitable appearance and can extend the predicted life span. A diagnosis of undifferentiated squamous cell carcinoma has a guarded prognosis: however, the cat of this report survived more than 18 months.


Treatment by digital amputation of subungual squamous cell carcinoma in dogs: 21 cases (1987-1988)

Malignant digital tumors were diagnosed in 62 dogs during a 1-year period. Twenty-one (33.9%) of the dogs had subungual squamous cell carcinoma. Each of these dogs had involvement of single digits. Sixteen (76.2%) of the dogs with squamous cell carcinoma were large-breed dogs, and 15 (71.4%) had predominantly black coats. Labrador Retrievers (n = 5, 23.8%) and Standard Poodles (n = 3, 14.3%) were the most commonly represented purebreeds. None of the dogs had evidence of metastases prior to treatment. All 21 tumors were treated by amputation of the involved digit. Histologic evidence of neoplastic bone invasion was found in 15 of the 21 amputated digits (71.4%). Local tumor recurrences were not observed. Only 1 dog developed documented metastatic disease; this dog was euthanatized because of pulmonary metastases 5 months after surgery. At the time of this report, 9 dogs (42.9%) were alive with no evidence of disease (median, 26 months after surgery), and 11 dogs (52.4%) had died or were euthanatized (median, 20 months after surgery). The cause of death in 7 dogs was known to be unrelated to squamous cell carcinoma, and the cause of death in 4 dogs was unknown. The 1-year and 2-year survival rates were 76.2% and 42.9%, respectively.


Hypoplasia of the trachea in dogs: 103 cases (1974-1990).

A multi-institutional retrospective study of 103 dogs in which hypoplasia of the trachea was diagnosed was conducted. Bulldogs (55%) and Boston Terriers (15%) were most commonly affected. Age at diagnosis ranged from 2 days to 12 years, with a median of 5 months. Hypoplasia of the trachea was diagnosed more frequently in males (66%) than females (34%). Congenital anomalies in dogs with hypoplasia of the trachea included elongated soft palate (n = 44), stenotic nares (n = 23), cardiac defects (n = 12), and megaesophagus (n = 10). Ratios between tracheal lumen diameter and depth of the thoracic inlet or width of the third rib did not correlate with dyspnea. Of 42 dogs reexamined greater than 6 months after diagnosis, 25 (60%) were clinically normal. The remaining 17 were dyspneic and 15 (88%) had concurrent respiratory or cardiovascular disease that could account for their clinical signs. Hypoplasia of the trachea appears to be tolerated well in the absence of concurrent respiratory or cardiovascular disease.


Prevalence and type of splenic diseases in cats: 455 cases (1985-1991).

Retrospective data on the type and prevalence of splenic disease in cats were evaluated in a large number of feline splenic tissues (n = 455) submitted as surgical and necropsy specimens from private veterinary hospitals in California during a period of approximately 5.5 years. Primary and metastatic neoplasia accounted for 37% of all feline splenic lesions. Mastocytoma, lymphosarcoma, myeloproliferative disease, and hemangiosarcoma, in that order, accounted for the bulk of neoplasia. Submission of accessory splenic tissue from either the omentum or pancreas accounted for 4% (17/455), whereas hyperplastic nodules, hematomas, and the combination of these changes in the spleen accounted for 4% (19/455). Splenitis was found in 2% (8/455) of submissions. Thromboembolism with regional splenic infarction accounted for 1% (4/455) of splenic lesions in cats. The remaining splenic lesions each accounted for less than 1% of total splenic submissions, and as such, were considered incidental and of questionable clinical importance.


Treatment of mandibular squamous cell carcinoma in cats by use of mandibulectomy and radiotherapy: seven cases (1987-1989).

Seven cats with squamous cell carcinoma involving the mandible were treated by surgery and radiotherapy. Surgery consisted of hemimandibulectomy or combined rostral and hemimandibulectomy, gastrostomy tube placement, and submandibular lymph node excisional biopsy. Radiotherapy (orthovoltage or 60Co) commenced 2 weeks after surgery. Histologically, the tumor invaded surgical margins in 6 of 7 cats. Nerve infiltration was histologically identified in 2 cats. All cats had stage-3 disease with radiographic evidence of mandibular bone involvement. Age ranged between 8 and 16 years (median, 10 years). Hypercalcemia (2), feline immunodeficiency virus (2), and hyperthyroidism (1), were detected in cats prior to treatment. Survival after surgery was a median of 14 months (range = 3 to 36 months, mean = 15 months). Six cats were euthanatized because of recurrence of disease at 3, 7, 9, 16, 21, and 36 months. One cat was euthanatized at 14 months because of an unrelated disease. Complications of tongue lagging, drooling after meals, mandibular drift, maxillary ulceration, and alopecia of the jaw developed in a few cats. Radiation at the primary site and regional lymph nodes after surgery of curative intent extended survival in cats with mandibular squamous cell carcinoma.


Colopexy in broodmares: 44 cases (1986-1990).

Colopexies were performed in 44 broodmares requiring abdominal surgery for large colon volvulus or right dorsal displacement of the large colon. Colopexies were performed by suturing the lateral bands of the left and right ventral colon to the ventral abdominal wall. Forty-seven percent of the mares in which a colopexy was performed had previous surgery for a large colon volvulus or right dorsal displacement of the large colon. Postoperative complications considered directly associated with the colopexy procedure were intermittent abdominal pain in 7, reoperation in 5, subcutaneous fistulous tracts in 1, and catastrophic rupture of the left ventral colon in 2 horses. Thirty-six horses survived greater than 6 months after colopexy, 34 of which had complete follow-up examinations. Twenty-seven mares have foaled at least once subsequent to the colopexy procedure, totalling 40 foals. Colopexy was considered a viable technique to prevent recurrence of large colon displacement or volvulus in selected predisposed populations.


Effects of limited food consumption on the incidence of hip dysplasia in growing dogs.

Forty-eight 8-week-old Labrador Retrievers were allotted to 2 groups of 24 dogs each; 1 group was fed ad libitum and the other group was given 25% less of the same feed until the dogs were 2 years old. Radiography of the hip joints was done when the dogs were 30, 42, 54, 78, and 104 weeks old. Subluxation was measured by the Norberg angle on radiographs made with the dog in the standard (extended limb) position. Independent of age at which the radiography was done, there was less subluxation of the femoral heads in the limit-fed dogs. Using the Swedish method of hip joint evaluation on the same radiographs, it was found that fewer dogs on limited food intake had signs of hip dysplasia. Radiographs done when dogs were 2 years old, for all the methods used (Norberg angle in standard and frog-limb position, the Orthopedic Foundation for Animals [OFA] score, and the Swedish score), revealed less hip dysplasia (less joint subluxation and less degenerative joint disease) in the limit-fed dogs. Using the OFA method, 7 of the 24 limit-fed dogs and 16 of the 24 ad libitum-fed dogs were diagnosed as having hip dysplasia. Similarly, using the Swedish method, 5 of the 24 limit-fed dogs and 18 of the 24 ad libitum-fed dogs were diagnosed as having hip dysplasia. The food-intake-related differences were significant both for the OFA score and for the Swedish score.(ABSTRACT TRUNCATED AT 250 WORDS)


Salmonella infections in neonatal dairy calves.

To estimate herd prevalence of Salmonella spp, fecal specimens were obtained for culture from neonatal calves of 47 Ohio dairy herds. Of the 452 calves tested, 10 calves from 7 farms were culture-positive. Salmonella serotypes isolated were S dublin, S typhimurium, S enteritidis, S agona, S mbandaka, and S montevideo. Bulk tank milk filters from these dairies were also submitted for culture. Salmonella sp was isolated from 1 of the 50 filters, and 2 calves from this herd were found to be shedding Salmonella sp of the same serotype.


Effects of selenium supplementation in cattle on aquatic ecosystems in northern California.

The potential impact on aquatic ecosystems of supplementing the diets of beef cattle with selenium (Se) was studied on 4 northern California ranches. All study sites included an area of concentrated use by cattle that had diets supplemented with Se. In each case, a stream flowed through the site and provided a control sampling area upstream and a treated sampling area downstream. Specimens of water, sediment, algae, aquatic plants, aquatic invertebrates, and fish were analyzed fluorometrically for total Se content. Significant differences in Se concentration were not found between specimens from upstream control areas and those from downstream areas subjected to use by Se-treated cattle. Evidence was not found that Se supplementation in cattle at maximal permitted concentrations caused Se accumulation in associated aquatic ecosystems.


Factors associated with and prevalence of high Malassezia pachydermatis numbers on dog skin.

The prevalence of cutaneous Malassezia spp was evaluated in a semiquantitative fashion at 3 sites on 98 dogs examined because of various dermatoses. Thirty (10.2%) of the sites and 19 (19.4%) of the dogs had Malassezia spp amounts higher than that found on grossly normal skin. The prevalence of higher than normal amounts did not correlate significantly with sample site, sex, or age. The factors associated with an increased prevalence of increased Malassezia spp counts were seborrheic dermatitis, recent antibiotic treatment, and breed.


Acute thallium toxicosis in a dog.

A Doberman Pinscher was evaluated for acute onset of gastroenteritis, characterized by anorexia, hematemesis, and hematochezia. The dog had ingested mole bait containing thallium 2 days prior to admission. Thallium toxicosis was confirmed by detection of thallium in the urine, using colorimetric analysis. The dog responded well to administration of antibiotics, fluids administered IV, warm-water enemas, and oral administration of activated charcoal slurries.


Anaerobic bacterial infections causing osteomyelitis/arthritis in a dog.

A 3-year-old German Shepherd Dog was examined for lameness, signs of pain, swelling, a draining fistulous tract, and osteolysis after a dog bite on the left carpus. After failure of the lesion to respond to several antibiotics, Peptostreptococcus sp and Propionibacterium sp were isolated from swab specimens and then from surgically collected bone and soft tissue specimens. The bone fragments had mild purulent osteomyelitis associated with numerous gram-positive rods and cocci. The dog was successfully treated by surgical debridement of the lesion and clindamycin administration.


Reversible megaesophagus associated with atypical primary hypoadrenocorticism in a dog.

Megaesophagus, hypercalcemia, and eosinophilia associated with glucocorticoid deficiency were detected in a 5-year-old neutered female Standard Poodle with concurrent hypothyroidism. Clinical and biochemical abnormalities resolved with glucocorticoid replacement treatment, and the dog was normal 29 months after diagnosis. The dog's breed and sex and the existence of a second endocrinopathy supported an underlying immunologic disorder.


Treatment of a mandibular bone cyst by use of a corticocancellous bone graft in a horse.

A 1-year-old Appaloosa stallion had a mass on the right rostral hemimandible. The mass was firm, did not cause signs of pain, and was identified as a bone cyst by radiography and biopsy. Surgical correction included curettage of the cystic cavity and grafting the defect with both cortical and cancellous bone. By 5 months, the cystic cavity was ossifying; continued remodeling with an increase in bone density was apparent 22 months after surgery.


Stabilization of a proximal femoral physeal fracture in a filly by use of cancellous bone screws.

A Salter-Harris type-II fracture of the proximal portion of the right femur in a 2-month-old filly was reduced and stabilized with three 6.5-mm-diameter, 100-mm-long cancellous bone screws through a dorsal approach to the right coxofemoral joint. The screws were removed after 11 months because the filly became lame in the affected limb. The surgical wounds dehisced despite preventive measures, most likely because of tightness of skin in the coxal region. Seven years after the original injury, the horse could perform vigorous paddock exercise without any disability. Early internal fixation of proximal femoral physeal fractures in foals can provide a good long-term prognosis.


Antemortem diagnosis of cholangiocellular carcinoma in a horse.

A 10-year-old Tennessee Walking Horse gelding was admitted to the veterinary teaching hospital for evaluation of intermittent fever, lethargy, and anorexia. Initial laboratory analyses revealed anemia and hyperfibrinogenemia. Abdominocentesis and thoracentesis yielded fluid samples with high nucleated cell counts and total protein concentrations. The tentative diagnosis was nonseptic peritonitis. The horse did not improve after 4 days of antimicrobial treatment, and pitting edema of the ventral midline developed. Thoracic radiography and ultrasonography revealed consolidation of the ventral aspect of the lung fields and pleural effusion. Pleuroscopy of the right hemithorax revealed pleural effusion and a soft-tissue mass in the caudal portion of the mediastinum. Findings on biopsy of the liver and mediastinal mass led to a presumptive diagnosis of metastatic cholangiocellular carcinoma. The horse was euthanatized, and the diagnosis was confirmed at necropsy.


Focal premature physeal closure (hyena disease) in calves.

Focal premature closure of long-bone physes was the cause of conformational abnormalities that affected about 1% of a herd of dairy replacement calves. Affected calves were noticed to "bunny hop" by 3 months of age, and by 6 months of age, they developed abnormal conformation characterized by short pelvic limbs. This condition resembled "hyena disease," which has been described in dairy calves in Europe and Japan. With the exception of the aforementioned abnormalities and femoropatellar joint distention, a group of 5 affected calves examined were clinically normal. At necropsy, focal to almost complete closure of physes was found in the humeri, tibias, and femurs. Cause was not established for the condition; however, it was discovered that the calves had been given supplemental vitamin A/D3 in amounts greater than 10 times those recommended.


Polycystic kidney disease and renal lymphoma in a cat.

A 2-year-old castrated domestic shorthair cat was determined to have polycystic kidney disease (PKD) and renal lymphoma. History and examination findings consisted of progressive lethargy, asymmetric renomegaly, thick segments of small intestine, and anisocoria. Initial diagnostic tests revealed nonregenerative anemia, mild azotemia, and multiple, round anechoic cysts in both kidneys. Renal cystic fluid contained many mature lymphocytes, and results of biochemical analysis indicated that the fluid was consistent with proximal tubular fluid. Stage-3 lymphoma was diagnosed on the basis of histologic evidence of unresectable lymphoma in multiple abdominal organs. Chemotherapy with vincristine sulfate, cytarabine, cyclophosphamide, and prednisone was unsuccessful. Morphologic association between PKD and lymphoma could not be identified after histologic evaluation of the kidneys.


Coccidioidomycosis in horses: 15 cases (1975-1984).

Fifteen confirmed cases of equine coccidioidomycosis that originated in California and Arizona were studied retrospectively. Age, breed, and sex varied among affected horses. The most common historical problems were chronic weight loss (53% of cases) and persistent cough (33% of cases). The most frequent physical examination abnormalities were related to the respiratory tract (60% of cases). In 27% of cases, horses had signs of musculoskeletal pain. Horses consistently had hyperproteinemia, hyperfibrinogenemia, leukocytosis, and neutrophilia. An antemortem etiologic diagnosis was made for 11 (73%) horses, all of which had positive serologic tests for coccidioidomycosis. Of the seropositive horses, 5 (46%) also had positive cultures for Coccidioides immitis. One horse died naturally. The other 14 were euthanatized. Prolonged treatment with specific antifungal agents was attempted in 4 horses without apparent benefit. Postmortem abnormalities included pulmonary parenchymal lesions (64% of cases), thoracic lymphadenopathy (57% of cases), hepatic parenchymal involvement (43% of cases), and osteomyelitis (29% of cases). The lesions were granulomatous or pyogranulomatous and C immitis was observed microscopically in 83% of cases.


Cutaneous actinomycosis and nocardiosis in dogs: 48 cases (1980-1990).

Medical records of 48 dogs with cutaneous actinomycosis or nocardiosis were reviewed. Male, large-breed dogs kept outdoors were overrepresented. The mean age at admission was 3.6 years. Cutaneous swelling (68%), abscesses (65%), draining tracts (48%), fever (36%), and signs of pain (13%) were the most common clinical findings. The cervicofacial area was affected in 48% of the dogs. Abdominal and thoracic wall involvement was less common. Leukocytosis, neutrophilia with left shift, monocytosis, and hyperglobulinemia were common. The diagnosis was confirmed by cytologic examination, bacteriologic culture, or histologic examination. Gram-positive filamentous bacteria were seen in 69% of the fine needle aspirates and in 50% of the biopsy specimens. Actinomyces spp were isolated from cutaneous lesions in 27 (60%) dogs. Nocardia asteroides was isolated from 1 dog. Treatment consisted of surgical debridement, drainage, and administration of antibiotics in 29 dogs (group A) and antibiotics alone in 13 dogs (group B). The infection redeveloped in 10 (42%) group-A dogs and 6 (60%) group-B dogs. Of the 10 group-A dogs with recurrent infection, 6 had resolution after a second surgery and 4 were euthanatized. Of the 6 group-B dogs, 1 had resolution after surgery, 4 were euthanatized or died because of persistent disease, and 1 had an unresolved infection. The combination of surgery and antibiotic treatment appeared to be superior to antibiotic treatment alone in resolving cutaneous Actinomyces and Nocardia infections.


Lens-induced uveitis in dogs: 151 cases (1985-1990).

During a 5-year period, phacolytic uveitis was diagnosed in 202 eyes of 151 dogs admitted to the veterinary teaching hospital. The diagnosis of phacolytic uveitis was based on the finding of a cataractous lens and anterior uveitis, unassociated with other identifiable causes of uveal inflammation. The most commonly affected breeds were the Toy and Miniature Poodle (35%) and the American Cocker Spaniel (19%). The mean age was 7.0 years for all breeds, 5.1 years for the Cocker Spaniel, and 9.0 years for the Poodle breeds. Evidence of cataract resorption was visible in 72% of the eyes. Fifty-one dogs were affected bilaterally and 100 dogs unilaterally. The mean interval between recognition of the cataract and the onset of lens-induced uveitis (LIU) was 17 months; mean times of 25 and 11 months were seen in the Poodle breeds and American Cocker Spaniel, respectively. The mean age of dogs requiring greater than 1 revisit before the inflammation had subsided was 5.5 years. Complications, referable to the uveitis, were seen in 14% of eyes, the most important of which were glaucoma (16 eyes) and phthisis bulbi (9 eyes). Lens extraction surgery was done on 50 LIU-affected eyes, and on 35 normal eyes in LIU-affected animals. The 2- and 6-month success rates for LIU-affected eyes were 78 and 39%, respectively, and for normal eyes in LIU-affected animals were 85 and 71%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


Perceived differences in the importance and frequency of practice of clinical teaching behaviors.

The purpose of this study was to identify whether or not discrepancies existed between the importance of clinical teaching behaviors and the frequency with which those behaviors were practiced in the clinical setting. Surveys listing clinical teaching behaviors were distributed to preceptors and their students. Both groups completed the survey twice, ranking their perception of the importance of each behavior, as well as the frequency with which it was practiced in the clinical setting. Four different allied health disciplines from four, four-year undergraduate institutions in Ohio participated in the study. Means and standard deviations were calculated for each item. Two-tailed t-tests were applied to each set of responses, with p < 0.05 considered statistically significant. Results revealed that while both students and preceptors agreed on the importance of the items, they differed significantly (p < 0.05) with regard to the frequency with which effective clinical teaching behaviors were practiced.


Job orientation and motivation of cytotechnologists.

Little is known about what motivates cytotechnologists as a distinct group. The Job Attitude Survey (JAS), developed by Shoukry Saleh, was applied to a cohort of 261 cytotechnologists. The group was divided between nondegreed cytotechnologists (CTs) (n = 97) and bachelor's degreed cytotechnologists (BSCTs) (n = 164) to see if there were noticeable motivational differences between the two. No statistical difference was found between the two groups. Compared to other groups of professionals who had previously taken the JAS, cytotechnologists ranked responsibility as a very low factor, demonstrating that it does not function as a motivator. In contrast, salary was ranked very high by cytotechnologists, suggesting it functions as a large dissatisfier. Based upon these findings, educational attainment changes the cytotechnologists' attitude very little. The findings are also consistent with the views that JAS-type surveys are important and that both motivators and dissatisfiers should be addressed in order to improve retention of cytotechnologists.


Differences in innovation-related characteristics between singleskilled and multiskilled health practitioner educational programs.

A survey of educational programs preparing single- and multiskilled health practitioners was conducted to determine the predictive power of organizational formalization and centralization and individual program director cosmopolitanism (ie, orientation to their larger profession as opposed to local environment) upon readiness to innovate for the educational units. Questionnaires were sent to 45 directors of programs preparing multiskilled health practitioners and 49 directors of programs preparing singleskilled health practitioners. Results indicated no significant differences between program directors of single- and multiskilled programs in their perceptions of the readiness to innovate for their educational units. Regression analysis indicated that a decentralized organization was a predictor of an educational unit's readiness to innovate. This finding held for both single- and multiskilled programs. Although cosmopolitanism was not a significant predictor of readiness to innovate, program directors at four-year institutions had a significantly higher level of that characteristic than directors at two-year institutions. The results of this study, although limited by individual and not multiple responses from each institution, do not indicate any differences in the ability of organizational formalization and centralization to predict the innovative characteristics of single- and multiskilled allied health programs. Additionally, the cosmopolitanism of program directors also does not predict these same characteristics.


Environmental and physiological influences on human natural killer cell activity in relation to good health practices.

We examined the association of natural killer (NK) cell activity with a number of life style factors by a cross-sectional analysis on 2892 Japanese individuals. The following habits were found to be associated with increased NK activity: 1) alcohol drinking (males, P less than 0.05), 2) not smoking cigarettes (males and females, P less than 0.001), 3) increased intake of green vegetables (females, P less than 0.001), 4) increased intakes of meat, milk, dairy products, and soybean products (males, P less than 0.01), 5) daily workload of less than 3 hours per day (females, P less than 0.05), 6) regular meals (females, P less than 0.05), 7) regular sleep of more than 7 hours (females, P less than 0.05), 8) proper body weight. In addition, systolic blood pressure showed a positive correlation with NK activity (P less than 0.001), while proportion of helper/inducer (OKT4+) T cells and fraction of beta-globulin showed negative correlations (P less than 0.001). We thus found that the living habits associated with increased NK activity were consistent with generally accepted good health practices, except alcohol drinking.


Cigarette smoking, alcohol use and adenomatous polyps of the sigmoid colon.

The relationship of adenomatous polyps of the sigmoid colon with cigarette smoking and alcohol use was investigated in male self-defense officials in Japan. In the comparison between 116 cases and 930 controls, total ethanol intake was not at all associated with the risk of adenomatous polyps, but cigarette smoking was strongly related to adenomatous polyps. After adjustment for total ethanol intake, body mass index and rank, odds ratios (and 95% confidence interval) for the categories of 0, 1-399, 400-799, and 800 or more cigarette-years were 1.0 (referent), 2.3 (1.1-4.6), 2.9 (1.5-5.4) and 3.2 (1.6-6.5), respectively. Among five alcoholic beverages (sake, shochu, beer, whiskey including brandy, and wine), only whiskey consumption was weakly related to the risk of adenomatous polyps. Because the present findings disagree with an earlier observation on self-defense officials, we examined the association with smoking and alcohol use separately for small (less than 5 mm) and large (greater than or equal to 5 mm) adenomas, combining data from these two studies. Cigarette smoking was more strongly associated with small adenomas while the positive association with certain alcoholic beverages were largely confined to large adenomas. These findings suggest that cigarette smoking and alcohol use may be linked with the development of adenoma at different stages of colon tumorigenesis.


Modifying effects of various chemicals on tumor development in a rat wide-spectrum organ carcinogenesis model.

The efficacy of a wide-spectrum organ carcinogenesis model for detection of modification potential of exogenous agents was investigated in F344 male rats. Groups of animals were sequentially injected with N-bis(2-hydroxypropyl)nitrosamine (1000 mg/kg body weight, i.p., in saline, twice in week 1), N-ethyl-N-hydroxyethylnitrosamine (1500 mg/kg body weight, i.g., in distilled water, twice in week 2) and 3,2'-dimethyl-4-aminobiphenyl (75 mg/kg body weight, s.c., in corn oil, twice in week 3) for wide-spectrum initiation of target organs and then given one of 10 test chemicals, comprising 6 hepatocarcinogens and 4 non-hepatocarcinogens, for 12 weeks. All 10 chemicals exerted modifying effects in their respective target organs. Enhancing influence could be detected in the liver and urinary bladder with 2-acetylaminofluorene, ethionine, and 3'-methyl-4-dimethylaminoazobenzene; in the liver and thyroid with 4,4'-diaminodiphenylmethane and phenobarbital; in the esophagus and urinary bladder with N-butyl-N-(4-hydroxybutyl)nitrosamine; in the forestomach and urinary bladder with butylated hydroxyanisole; in the liver with 7,12-dimethylbenz[a]anthracene and in the liver and lung with 3-methylcholanthrene. Inhibitory effects on development of glutathione S-transferase placental form-positive liver cell foci were observed with clofibrate. The results indicate that the present model can be reliably utilized as a whole body medium-term bioassay system for assessment of environmental cancer modifiers.


Inorganic alkalizers and acidifiers under conditions of high urinary Na+ or K+ on cell proliferation and two-stage carcinogenesis in the rat bladder.

Effects of alkalizers and acidifiers on bladder cell proliferation and two-stage carcinogenesis were investigated under conditions of high urinary Na+ or K+. Animals were given 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine in their drinking water for 4 weeks and then received Na3PO4, NaH2PO4, NaCl, NaH2PO4 + NaCl, K3PO4, KH2PO4, KCl, KH2PO4 + KCl or no chemical supplement in the diet from weeks 5 to 8 and from weeks 12 to 20. During weeks 9 to 11, the rats were fed 3% uracil in their diet for acceleration of promotion. Na3PO4 or K3PO4 induced marked natriuresis or kaluresis and alkalinuria associated with strong promoting potential for bladder carcinogenesis. NaH2PO4 induced moderate natriuresis and aciduria and exhibited weak promoting activity. NaH2PO4 + NaCl or KH2PO4 + KCl caused marked increase in the respective cation levels and aciduria with elevation of promotion as compared to NaH2PO4 or KH2PO4 alone. NaCl or KCl induced moderate natriuresis or kaluresis and did not alter urinary pH. NaCl but not KCl also exerted weak promoting activity for bladder carcinogenesis. Increased DNA synthesis after test chemical exposure for 8 weeks and morphological alterations observed by scanning electron microscopy in the bladder epithelium were only quantitatively linked with promoting activity in the Na3PO4 case. With the other treatments no clear correlation between early cell proliferation and promotion potential was apparent. The present results suggest that although elevation in urinary Na+ or K+ level may be an essential factor for promotion of rat bladder carcinogenesis, the action of these cations may depend strongly on urinary alkalinity.


Inhibitory effect of cryptoporic acid E, a product from fungus Cryptoporus volvatus, on colon carcinogenesis induced with N-methyl-N-nitrosourea in rats and with 1,2-dimethylhydrazine in mice.

The antitumorigenic effect of cryptoporic acid E (CPA-E), a dimeric drimane sesquiterpenoid isolated from the fungus Cryptoporus volvatus, on colon carcinogenesis was investigated. Female F344 rats given an intrarectal instillation of 2 mg of N-methyl-N-nitrosourea 3 times weekly in weeks 1 and 2 were fed diet containing 0.2% CPA-E from week 3. Female ICR mice given 15 weekly intraperitoneal injections of 10 mg of 1,2-dimethylhydrazine/kg body weight during weeks 1 to 15 were fed diet containing 0.06% CPA-E from week 1. The experiment was terminated at week 35 for rats and at week 25 for mice. The incidence and the number of tumors per animal were reduced in CPA-E-fed animals compared to the controls: 31% vs. 75% (P less than 0.05) and 0.4 +/- 0.2 (SEM) vs. 0.9 +/- 0.2 (0.1 greater than P greater than 0.05) in rats, and 31% vs. 63% (0.1 greater than P greater than 0.05) and 0.4 +/- 0.2 vs. 2.4 +/- 0.8 (P less than 0.05) in mice (16 animals in each group). Intrarectal deoxycholic acid-induced colonic mucosal ornithine decarboxylase activity was significantly lowered in CPA-E-fed animals compared to controls. This shows an antipromoting activity of CPA-E against colon carcinogenesis. Thus, it was concluded that CPA-E inhibits colon cancer development in both rats and mice treated with 2 different colon carcinogens.


Inhibitory effects of the natural products indole-3-carbinol and sinigrin during initiation and promotion phases of 4-nitroquinoline 1-oxide-induced rat tongue carcinogenesis.

The modifying effects of indole-3-carbinol (I3C) and sinigrin (SIN) on the initiation and post-initiation phases of tongue carcinogenesis induced by 4-nitroquinoline 1-oxide (4-NQO) were investigated in male ACI/N rats. Rats were divided into eight groups: group 1 was given 4-NQO (10 ppm) in the drinking water for 12 weeks, starting at 7 weeks of age; groups 2 and 3 were given 4-NQO and fed the diets containing I3C (1,000 ppm) and SIN (1,200 ppm) for 14 weeks, respectively, starting at 6 weeks of age; groups 4 and 5 were given 4-NQO and then they were fed I3C and SIN containing diets for 23 weeks, respectively, starting one week after 4-NQO exposure; groups 6 and 7 were given I3C and SIN alone, respectively, during the experiment; group 8 served as an untreated control. At the termination of the experiment (week 37), the incidence of tongue neoplasms (squamous cell papilloma and carcinoma) in group 2 (1/15, 7%), group 3 (1/15, 7%), group 4 (3/15, 20%) or group 5 (2/15, 13%) was significantly smaller than that in group 1 (12/17, 71%) (P = 0.0003, P = 0.005 or P = 0.002). No tongue carcinomas developed in rats of groups 2, 3, and 5. Similarly, the incidence of preneoplastic lesions (hyperplasia and dysplasia) of the tongue in group 2 (11/15, 73%), group 3 (10/15, 67%), group 4 (11/15, 73%) or group 5 (10/15, 67%) was significantly lower than that in group 1 (17/17, 100%) (P = 0.04 or P = 0.02). There were no tongue neoplasms in rats of groups 6, 7, and 8. Administration of I3C and SIN also caused significant decreases in the number and area of silver-stained nucleolar organizer regions protein (AgNORs), a new cell proliferation index, of tongue squamous epithelium. Thus, I3C and SIN inhibited rat tongue carcinogenesis in both the initiation and post-initiation phases, when administered in these respective phases together with, or following treatment with, 4-NQO.