Prognostic factors and outcome in cats with thymic epithelial tumours: 64 cases (1999-2021).

OBJECTIVES: To describe the clinical presentation, treatment and outcomes of cats diagnosed with thymic epithelial tumours and to determine prognostic factors for survival and recurrence. MATERIALS AND METHODS: Clinical records of cats diagnosed with a thymic epithelial tumour between 1999 and 2021 at three referral institutions were retrospectively reviewed. RESULTS: Sixty-four cats were included. Paraneoplastic syndromes were present in nine cats and metastatic disease was seen in two cats, one at diagnosis and one at the time of recurrence. Median tumour diameter was 6 cm (range, 2 to 15) and a cystic appearance was described on imaging in 25 cats. Surgical excision was attempted in 54 cats with a perioperative mortality rate of 11%. Median survival time for cats surviving to hospital discharge was 897 days (range, 21 to 3322). The 1-, 2- and 5-year survival rates for surgically treated thymic epithelial tumour were 86%, 70% and 66%, respectively. Survival was longer for cats with Masaoka-Koga stage I and II tumours compared to stages III and IV (1366 days versus 454 days; P=0.002). Masaoka-Koga stage was the only significant prognostic factor detected on multi-variable analysis, with stage III and IV tumours associated with increased risk of death (hazard ratio: 5.67, 95% confidence interval: 1.29 to 24.91, P=.021). Tumour recurrence occurred in 11 cats at a median of 564 days (range, 93 to 1095); no significant prognostic factors for recurrence were identified. CLINICAL SIGNIFICANCE: Cats with thymic epithelial tumours had a good long-term prognosis following surgery. Tumour recurrence can occur late in the disease course and ongoing monitoring should therefore be considered. Masaoka-Koga stage may influence survival time and could be used to predict outcome.

Inhibition of mammalian mitochondrial protein synthesis by oxazolidinones.

The effects of a variety of oxazolidinones, with different antibacterial potencies, including linezolid, on mitochondrial protein synthesis were determined in intact mitochondria isolated from rat heart and liver and rabbit heart and bone marrow. The results demonstrate that a general feature of the oxazolidinone class of antibiotics is the inhibition of mammalian mitochondrial protein synthesis. Inhibition was similar in mitochondria from all tissues studied. Further, oxazolidinones that were very potent as antibiotics were uniformly potent in inhibiting mitochondrial protein synthesis. These results were compared to the inhibitory profiles of other antibiotics that function by inhibiting bacterial protein synthesis. Of these, chloramphenicol and tetracycline were significant inhibitors of mammalian mitochondrial protein synthesis while the macrolides, lincosamides, and aminoglycosides were not. Development of future antibiotics from the oxazolidinone class will have to evaluate potential mitochondrial toxicity.

Prevention of human recombinant interleukin-1 beta (rhIL-1 beta) embryolethality with progesterone or indomethacin.

PROBLEM: Bropirimine and tilorone were found in earlier studies to be embryolethal when administered to Crl:TUC(SD)spf (TUC) rats on gestation day 10. Progesterone or indomethacin could, at least partially, prevent this effect. The immunomodulators appeared to mimic the luteolytic effects of PGF2 alpha, resulting in a shutdown in progesterone release by the corpora lutea, followed by a disruption in maternal support to the pregnant uterus and embryolethality. Since bropirimine has been shown to induce interleukin-1, and since this cytokine has been found to increase PGF2 alpha levels in human decidual cells, the decision was made to investigate whether human interleukin-1 beta might act in an analogous manner to bropirimine and tilorone. METHOD: Bropirimine (400 mg/kg, p.o.) or rhIL-1 beta (20, 30, or 40 micrograms/kg, s.c.) was administered on gestation day 10 to Crl:CD[BR] (CD) or TUC rats, alone and in combination with progesterone (2 mg/kg/day, s.c.) or indomethacin (0.6 mg/day, s.c., days 9-11). On gestation day 14 the dams were killed and their uterine contents examined. RESULTS: rhIL-1 beta (30-40 micrograms/kg) was embryolethal when administered to CD or TUC rats on gestation day 10. Progesterone or indomethacin coadministration prevented, at least partially, the embryolethality seen when rhIL-1 beta was administered (30 micrograms/kg) to TUC rats. CONCLUSION: Evidence was obtained in support of the hypothesis that interleukin-1 is involved in the embryolethal actions of the immunomodulators bropirimine and tilorone.

A clinical, histologic, and DNA study of vulvodynia and its association with human papillomavirus.

OBJECTIVE: To compare the clinical and histologic characteristics of vulvodynia with or without associated human papillomavirus (HPV) DNA, as determined by polymerase chain reaction (PCR). METHODS: We conducted a standardized chart review of patients referred for vulvodynia lasting for more than 3 months and systematically reviewed all vulvar biopsy specimens histologically. In addition, specimens were amplified by PCR followed by Southern blot hybridization to detect HPV DNA, and positive cases were typed using the Hybrid Capture system. RESULTS: Of 55 cases, 48 were evaluable by PCR. Human papillomavirus DNA was detected in 35% (17 of 48), including 44% (four of nine) of normal cases, 25% (eight of 32) with reactive squamous atypia, 67% (four of six) with condyloma/mild dysplasia, and 100% (one of one) with moderate/severe dysplasia. Patients who were positive for HPV DNA (n = 17) were not significantly different from HPV-negative patients (n = 31) for any of 82 clinical or epidemiologic variables. When patients with normal biopsies (n = 9) were compared to those with reactive squamous atypia (n = 39), there were significant differences in only two of 82 variables (duration of symptoms and current sexual activity). Of the 17 HPV-positive cases, 13 were typeable by the Hybrid Capture system. Five (38%) were positive for low-risk HPV types, three (23%) were positive for high-risk HPV types, and five (38%) were positive for both low- and high-risk types. CONCLUSIONS: Vulvodynia associated with HPV DNA is clinically identical to vulvodynia without HPV DNA, and vulvodynia associated with normal biopsy findings is very similar to that with reactive squamous atypia. These data suggest that HPV does not cause vulvodynia.

Birth defects, cancer, chemicals, and public hysteria.

The "media" consistently inform us of all the "things" that are dangerous to us. However, time/space constraints, along with lack of knowledge and understanding of the area, often lead to inaccurate and/or insufficient dissemination of information. The areas of cancer and birth defects are particularly misrepresented. Such dissemination of inaccurate/incomplete/misleading information has resulted in almost a state of hysteria. As a result, the public's perception of the role of chemicals in the incidences of cancer and birth defects is inconsistent with what has actually been documented in these areas. Although no one wants to be exposed to risks, people generally do not wish to be encumbered with unnecessary safety precautions. Thus, accurate information in the areas of carcinogenicity and teratogenicity should be documented in an effort to show how one can better assess the risks involved in work/home exposures to specific chemicals. A better understanding of how society perceives risk should enable one to better appraise the situation when confronted with information that could lead to "chemophobia." The consequences of misinformation about drugs and other synthetic chemicals have been particularly unfortunate with pregnant women: negligence in necessary drug use, unnecessary anxiety, and termination of planned pregnancies without reasonable cause.

Prevention of tilorone developmental toxicity with progesterone.

The immunomodulator tilorone hydrochloride was administered (gastric intubation) once to time-pregnant Upj:TUC(SD)spf (Sprague-Dawley) rats in four experiments. In experiment 1, tilorone (250 or 500 mg/kg) was administered on day 10 of gestation. The dams were killed 4 or 72 hr after dosing. Interferon-like activity and drug levels were determined in maternal blood, spleen, and thymus, as well as in the embryos. In experiment 2, the test groups received progesterone (2 mg/kg), or tilorone (200 or 400 mg/kg), or progesterone and tilorone. The dams from each group were killed 24 or 48 hr after receiving tilorone. Experiment 3 was similar to experiment 2, except that the dams were killed on gestation day 20. In experiment 4, tilorone (400 mg/kg) was administered on gestation day 17, 18, or 19, and the dams were killed 24 hr after dosing or on gestation day 20. In all four experiments, tilorone-related maternal toxicity (regardless of whether progesterone also was administered) was observed, as characterized by marked decreases in weight gain, the occurrence of clinical signs, and in experiment 1 by decreased thymus weights, 72 hr post-dosing. Dose-related increases in the mean number of dead embryos and in serum interferon titers occurred 72 hr postdosing. In experiment 2, there was an increase in the number of dams in the 400-mg/kg (tilorone only) group with dead embryos only, 24 hr postdosing; similar results occurred in both the 200- and 400-mg/kg groups, 48 hr postdosing. However, in the groups that also received progesterone, a partial prevention of such embryolethality was evident. In experiment 3, embryotoxicity again was observed in both tilorone-treated groups, whereas several of the dams that were also given progesterone through day 19 of gestation experienced at least a partial prevention of the embryolethal effects of tilorone. In experiment 4, no fetotoxicity was observed despite the severe maternal toxicity evident.

Reversal of bropirimine developmental toxicity with progesterone.

Bropirimine is an immunomodulator with experimental antiviral and antitumor activities. This pyrimidinone has been found to be embryolethal at doses (200 and 400 mg/kg) that produce only transient maternal toxicity, when administered to pregnant Upj:TUC(SD)spf rats on specific days of gestation. Serum analyses carried out in previous studies have shown marked decreases in progesterone levels in the 24 hr following bropirimine administration. In the present study, each of four groups of 5 bred rats and four groups of 10 bred rats was given bropirimine (gastric intubation) on Day 10 of gestation. Also, on Day 10 of gestation, progesterone (0.25, 0.50, or 1.00 mg/rat) was administered (im) twice (12-hr interval) a day to three of the groups of 5 dams each that had received bropirimine. In addition, three of the groups of 10 dams each received progesterone (0.25, 0.50, or 1.00 mg/rat) twice a day on Days 10-19 of gestation. Another group of 5 dams received progesterone only (0.50 mg/rat, b.i.d.) on Day 10 while a group of 10 dams received this same dose of progesterone on Days 10-19 of gestation. The groups containing 5 dams each were killed 24 hr postdosing while the groups containing 10 dams each were killed on Day 20 of gestation. The uteri were removed from the dams and examined. Administration of bropirimine alone resulted in the death of 100% of the embryos, at both the 24-hr and the Gestation Day 20 terminations. Exogenous administration of progesterone protected against bropirimine-mediated embryolethality; however, maternal effects were not alleviated. Thus, it appears likely that the embryolethality of bropirimine is the result of interruption of progesterone release from, or synthesis by, the corpora lutea, rather than direct toxicity toward the embryo, or lethal defects during organogenesis (terata).

Variability in the developmental toxicity of bropirimine with the day of administration.

The aim of this study was to determine the mechanism by which bropirimine exerts its developmental toxicity. This drug is an immunomodulator and interferon inducer with antiviral and antitumor activities in experimental models. Timed-pregnant Upj:TUC(SD)spf (Sprague-Dawley) rats were given a single oral (gastric intubation) dose of bropirimine at 200 or 400 mg/kg (doses as high as 100 mg/kg/day have been employed in human cancer trials) on days 5, 6, 7, 8, 9, 10, 11, or 12 of gestation and in a second experiment on day 12, 13, 14, 15, 16, 17, 18, or 19 of gestation. The dams were killed 24 hours after dosing and their uterine contents examined. In a third experiment, bropirimine (400 mg/kg) was administered on day 4 of gestation and the uteri of different groups were examined on day 8, 9, 10, 11, or 12 of gestation. Serum progesterone levels were measured at sacrifice. In the first two experiments a battery of hematologic/clinical chemistry assays also were performed. In all three experiments, bropirimine-related maternal toxicity was observed; such toxicity was characterized by significant decreases in weight gain, relative to the concurrent vehicle controls, as well as significant differences in several blood parameters including platelets, white blood cells, alanine aminotransferase, and aspartate transaminase. In the first experiment, bropirimine treatment on day 11, but not day 12, resulted in significant decreases in the mean number of live embryos per litter. In the second experiment, significant decreases in the number of live fetuses per litter occurred 24 hours after dosing on day 18 (200 and 400 mg/kg groups) or day 19 (400 mg/kg group). Decreases in serum progesterone appeared to correlate well with the embryolethal effects seen after treatment between days 6 and 11 of gestation, but not with the fetal lethality seen when treatment was given on day 17 or 18. The decreases in serum progesterone levels found most likely were the result of a luteolytic effect, although it is unknown if bropirimine has a direct or indirect effect on the corpora lutea. In the third experiment, bropirimine treatment on day 4 of gestation resulted in only slight preimplantational losses, but significant decreases were found in mean number of live embryos per litter after day 9. Uterine decidual necrosis has been observed in the first experiment where bropirimine was given on day 11; however, treatment on day 4 resulted in an apparent decrease in decidual development but not necrosis.

Developmental toxicity of bropirimine in rats after oral administration.

Timed-pregnant Upj:TUC(SD)spf (Sprague-Dawley) rats were orally (gastric intubation) dosed with bropirimine (an immunomodulator and inducer of interferon with antiviral and antitumor activities against experimental models) at 100, 200 or 400 mg/kg/day (first experiment), or at 25, 50, or 100 mg/kg/day (second experiment), on days 7-15 of gestation. In the first experiment, maternal toxicity occurred in all bropirimine-treated groups as evidenced primarily by significant decreases in weight gain, as compared to the vehicle control group. Embryotoxicity also occurred as evidenced by a dose-related increase in the number of dams with early implantation sites only. This pronounced effect on early embryonic development led to an insufficient number of offspring to access the developmental toxicity of bropirimine. This effect and the fact that all three doses were toxic to the dams dictated that a second experiment be carried out at lower doses. Significant effects on maternal weight gain also were observed in the second experiment, at least in the first 4 days of dosing, although only one dam in the 100 mg/kg/day group had early implantation sites only, in contrast to 11 such dams at this dosage in the first experiment. However, the fact that there were significant dose-related increases in the incidence of several variations in fetuses in this group indicated that there also was embryotoxicity at 100 mg/kg/day in the second experiment. Thus, although no biologically significant increases in the incidence of any malformation or major variation were found in this study, the results did indicate that bropirimine was embryotoxic at dosages which also produced significant maternal toxicity.

Teratologic and postnatal evaluation of aniline hydrochloride in the Fischer 344 rat.

Timed-pregnant Fischer 344 rats were dosed by gavage with aniline hydrochloride (10, 30, or 100 mg/kg/day), a positive control agent (hydroxyurea, 200 mg/kg/day), or vehicle (distilled water) on gestational days (gd) 7 through 20 or gd 7 through parturition. At termination on gd 20 confirmed-pregnant dams exhibited characteristic signs of aniline HCl toxicity, i.e., methemoglobinemia, increased relative spleen weight, decreased red blood cell (RBC) count, and hematological changes indicative of increased hematopoietic activity. High-dose dams exhibited mild methemoglobinemia, increased relative spleen weight, and increased RBC size at termination on postnatal day (pnd) 30. At termination on gd 20, fetuses from aniline-treated dams exhibited increased relative liver weight and enhanced hematopoietic activity, but no evidence of an embryolethal or teratogenic effect was observed. Postnatal signs of toxicity in litters from aniline-treated dams (i.e., decreased body weight, elevated relative liver weight, and elevated relative spleen weight) were transient, and no evidence of toxicity was observed in pups surviving to pnd 60. Hydroxyurea (200 mg/kg/day) administered by gavage proved to be an excellent positive control for embryotoxicity, maternal toxicity, teratogenicity, and postnatal maturational deficits in the Fischer 344 rat. In conclusion, aniline hydrochloride was not teratogenic to Fischer 344 rats, even at maternally toxic doses; transient signs of toxicity were observed postnatally in the offspring in conjunction with mild, but persistent signs of maternal toxicity through pnd 30.

Effect of the preestrogen 4-androstene-3,17-dion-19-al on the Dunning R3327 prostatic adenocarcinoma.

The purpose of this pilot study was to determine if biogenetic precursors of estrone such as 4-androstene-3,17-dion-19-al, which is virtually devoid of thrombotic potential as well as androgenic and uterotrophic activity, could replace estrogen in the treatment of the hormone-sensitive Dunning R3327 prostatic adenocarcinoma in the male Copenhagen rat. If such were the case, the way would be open to an improved form of palliative therapy of prostatic cancer with the potential for decreased estrogenic side effects and cardiovascular complications. To this end, the R3327 tumor was transplanted (Day 0) into the flank of 10-week-old male Copenhagen rats, and treatment was begun 20 weeks later at which time the tumors reached a mean volume of 2160 cu cm. In addition to 4-androstene-3,17-dion-19-al (1 and 10 mg/day), diethylstilbestrol (33 micrograms/day) and 17 beta-estradiol (3.3 and 33 micrograms/day) were studied (daily for 60 days). At 1 mg/day, 4-androstene-3,17-dion-19-al produced a 43% inhibition of tumor growth (Day 203) while, in the 10 mg/day group, a 72% inhibition of tumor growth was measured on Day 196 (roughly equivalent to that produced by estradiol at 3.3 micrograms/day), with a 50% inhibition on Day 231. It is concluded that the tumor-inhibiting activity of 4-androstene-3,17-dion-19-al, coupled with its very low thrombotic potential, indicated that orally active analogues of this steroid may offer advantages over estrogens in the palliative treatment of prostatic cancer.

Influence of formaldehyde and Sonacide (potentiated acid glutaraldehyde) on embryo and fetal development in mice.

Pregnant outbred albino mice were given formaldehyde or Sonacide (potentiated acid glutaraldehyde) by gavage on days 6--15 of gestation. The mice were killed on day 18, the general health and reproductive status of the dam evaluated, and the fetuses examined and processed in order to characterize external, visceral, and skeletal malformations. Although formaldehyde (stock solution containing 12--15% methanol as a preservative) was lethal to 22 of 34 dams treated with 185 mg/kg/day, and one of 35 dams treated with 148 mg/kg/day, these doses did not produce statistically significant (two-sided p < 0.05 versus controls) teratogenic effects in the fetuses of the surviving dams. Sonacide was also judged not to be teratogenic to the mice employed in this study, in spite of the fact that relatively high doses were employed. The highest doses of Sonacide studied (5.0 ml/kg/day, which is equivalent to 100 mg/kg/day of glutaraldehyde) killed 19 of 35 dams and caused a significant reduction in the mean weight gain of the surviving mothers. In addition, this dose produced a significant increase in the number of stunted fetuses.

Characterization and responsiveness of the Madison 109 lung carcinoma to various antitumor agents.

The Madison 109 (M109) tumor was discovered in 1964 in the lung of a BALB/c mouse. This experimental carcinoma is maintained in vivo by sc passage in the right axillary region. When implanted im (5 X 10(5) cells) into the right hind leg of BALB/c mice for testing, the primary progresses with metastases to the lung, spleen, and liver. The metastases to the lung are visible within 3 weeks and result in the death of the host in about 35 days after tumor implant. Implantation of a lung nodule is tumorigenic and lethal. Pyran polymer therapy delayed the appearance of lung metastases, inhibited the growth of the primary tumor, and significantly increased the lifespan of BALB/c mice inoculated with the M109 tumor. No spontaneous regression has been observed and very few "no takes" have occurred in untreated BALB/c mice inoculated with at least 500 M109 cells. Of the 82 agents tested so far, the M109 model has selected active agents such as actinomycin D, adriamycin, daunorubicin, DNA, procarbazine, and pyran polymer. It has not shown sensitivity as tested to several standard therapeutic agents including cytosine arabinoside, BCNU, hydroxyurea, mechlorethamine, melphalan, triethylenemelamine, and vincristine.

Potentiation of actinomycin D or adriamycin antitumor activity with DNA.

Several antitumor agents known to bind DNA were complexed with this macromolecule and tested for activity against experimental animal tumor systems. Combination studies with these agents and DNA were carried out at the same time. Actinomycin D activity against the P388 lymphocytic leukemia in BALB/c X DBA/2 F1 mice was significantly potentiated by calf thymus DNA, both when complexed and when injected in combination. The DNA could be given as much as 4 hr before or after the antibiotic and still give potentiation. Synergism was also obtained when the DNA was autoclaved prior to complexing and/or injecting. Similarly, adriamycin activity against the L1210 lymphoid leukemia in DBA/2 mice was significantly potentiated by autoclaved herring sperm DNA, both as a complex and when injected in combination. When above-optimal levels of adriamycin were complexed with autoclaved herring sperm DNA and injected into BALB/c mice inoculated with the Madison 109 alveogenic carcinoma, the early lethality was delayed and antitumor activity was sometimes observed. Herring sperm DNA injected alone also had antitumor activity against the Madison 109 tumor. Similarly, activity was obtained against this tumor system with calf thymus DNA and actinomycin D when injected alone. In addition, DNA, in combination and when complexed with actinomycin, prevented the toxicity observed with BALB/c mice, inoculated with the Madison 109 tumor, were given injections of an above-optimal dose of this antibiotic.