Biphasic sarcomatoid basal cell carcinoma (carcinosarcoma): four cases with immunohistochemistry and review of the literature.

BACKGROUND: Biphasic sarcomatoid carcinoma (BSC), or carcinosarcoma, is an uncommon biphasic neoplasm that has been reported in diverse anatomical sites. The tumor is composed of a malignant epithelial component intimately associated with a malignant mesenchymal component, which may be homologous or heterologous. Twenty-three cases of primary cutaneous BSC have been reported in the English literature. In only eight of these cases was basal cell carcinoma the epithelial component. METHODS: We report a further four cases of primary cutaneous biphasic basal cell carcinoma, and include the clinical, histological and immunohistochemical features. RESULTS: The four cases showed basal cell carcinoma associated with a pleomorphic sarcomatous stroma. In addition, myofibroblastic differentiation and foci of osteoid were present in one case, and leiomyosarcomatous areas in another. The epithelial components were positive for several epithelial markers. The mesenchymal components were positive for vimentin and CD99, and negative for epithelial markers. p53 was positive with equal intensity in both epithelial and mesenchymal components. A significantly worse outcome was observed in patients with tumors measuring 40 mm or more at excision. CONCLUSIONS: The sarcomatous component of the tumor is best regarded as a metaplastic transformation of the carcinomatous component. These tumors are potentially aggressive if incompletely excised, and complete resection is recommended.

The impact of intestinal ischaemia-reperfusion on caerulein-induced oedematous experimental pancreatitis.

BACKGROUND: Intestinal ischaemia is a feature of severe acute pancreatitis. It is not known whether intestinal ischaemia and reperfusion contributes to the progression from mild to severe pancreatitis. AIM: The aim of this study was to examine the impact of intestinal ischaemia-reperfusion on caerulein-induced oedematous experimental pancreatitis. METHOD: Male Wistar rats (n = 48) were randomised to 6 experimental groups: controls (CO), saline infusion (S), saline infusion and intestinal ischaemia-reperfusion (SIR), caerulein infusion (C), caerulein and sham operation (CS), and caerulein infusion with intestinal ischaemia reperfusion (CIR). Caerulein was infused over 6 h to induce mild oedematous pancreatitis. Clamping the superior mesenteric artery for 10 min induced mild intestinal ischaemia. The reperfusion time was 24 h. The primary end point was histology of the pancreas at 24 h. RESULTS: There was no significant difference in histologic severity of pancreatitis at 24 h (Kruskal-Wallis, p = 0.37). CONCLUSION: The severity of acute oedematous pancreatitis was not increased by 10 min of intestinal ischaemia followed by 24 h of reperfusion.

Caerulein-induced pancreatitis in Wistar rats.

We describe a refined model of intravenous caerulein-induced pancreatitis by using osmotic infusion pumps in the conscious unrestrained Wistar rat. The volume of caerulein required for the 6-h infusion is loaded into PE-55 catheter tubing attached to an Alzet (Alza Corporation, Palo Alto, CA) implantable osmotic pump that has been primed with saline. The technique has reliably induced mild edematous pancreatitis, which we verified histologically. Our refined model has the advantages of unrestrained animals, reduced animal handling and acclimation, and decreased cost.

Plasma von Willebrand factor and intestinal ischaemia-reperfusion injury in rats.

The purpose of this study was to determine whether plasma von Willebrand factor concentrations are correlated with the degree of intestinal ischaemia-reperfusion injury. Forty-six anaesthetised adult Wistar rats were divided into five groups. The sham-operated group (S, n=10) had laparotomy and isolation of the superior mesenteric artery without clamping. Three ischaemia-reperfusion groups (n=10 in each) had clamping of the superior mesenteric artery for 15, 30, and 45 minutes, respectively, and reperfusion for 15 minutes. A control group (C, n=6) had direct puncture of the heart to sample blood. Mean arterial pressure was measured continuously. Blood was collected at the end of the study to measure von Willebrand factor. The small bowel injury was graded histologically. There was a significant systemic hypotension after declamping in all ischaemia-reperfusion groups, which had a high negative correlation with the histological score (R=-0.46, F=10.1, p<0.003, simple linear regression). Plasma von Willebrand factor was significantly elevated in the three ischaemia-reperfusion groups compared with the control group but not significantly different from the sham-operated group (mean von Willebrand factor concentration (SEM): 156 (29), 283 (29), 295 (25), 381 (44), and 366 (40)% in C, S, ischaemia-reperfusion 15, ischaemia-reperfusion 30, and ischaemia-reperfusion 45 groups, respectively). The concentration of von Willebrand factor was not correlated to the histological score (R=0.22, F=1.83, p<0.2) or the degree of hypotension after the removal of the clamp (R=-0.22, F=1.8, p<0.2, simple linear regression). This study shows that von Willebrand factor concentration does not correlate with the degree of intestinal ischaemia-reperfusion injury. It is unlikely that von Willebrand factor can be used as a predictor of disease severity.

Enhancement of the anti-tumour effects of the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by combination with 5-hydroxytryptamine and bioreductive drugs.

The tumour blood flow inhibitor 5,6-dimethylxanthenone-4-acetic acid (DMXAA) causes dramatic haemorrhagic necrosis in murine tumours, but activity is seen only at doses close to the toxic limit. This study investigates two approaches for increasing the therapeutic ratio of DMXAA. The first approach combines DMXAA with a second tumour blood flow inhibitor, 5-hydroxytryptamine (5-HT). Co-administration of 5-HT (700 micromol kg(-1)) to C3H mice caused marked enhancement of DMXAA effects against MDAH-MCa-4 tumours, with dose-modifying factors (DMFs) of >3 for blood flow inhibition (at 4 h), 2.3 for necrosis (at 12 h) and 2.0 for growth delay, without compromising the maximum tolerated dose of DMXAA (90 micromol kg(-1)). The data are consistent with ischaemic injury to the tumour being the major mechanism of anti-tumour activity. The second approach combines DMXAA (+/- 5-HT) with hypoxia-selective bioreductive drugs. Anti-tumour activity of all three bioreductive drugs tested (tirapazamine, CI-1010, SN 23816) was strongly potentiated by DMXAA, suggesting that there is a population of reversibly hypoxic tumour cells after DMXAA treatment. Co-administration of 5-HT further potentiated anti-tumour activity, but also increased host toxicity of tirapazamine and CI-1010 so that little therapeutic benefit was achieved. In contrast, the host toxicity of the dinitrobenzamide mustard SN 23816 was only slightly increased by DMXAA/5-HT, whereas the tumour growth delay at the maximum tolerated dose of SN 23816 was increased from 3.5 to 26.5 days. This study demonstrates that 5-HT and/or bioreductive drugs can improve the therapeutic activity of DMXAA in mice, and that with SN 23816 both approaches can be used together to provide considerably enhanced anti-tumour activity.

Evaluation of potential health effects of 10 kHz magnetic fields: a rodent reproductive study.

New technology involving the use of high-frequency inductive power distribution (HID) has recently been developed for use in materials handling and personnel transfer. Sinusoidal magnetic fields at a frequency of 10 kHz with field intensities of approximately 0.2 mT are generated directly between the current-carrying coils of this equipment. Effects of 10 kHz magnetic fields on cell division, migration, and differentiation have never been previously investigated. To evaluate potential effects on these parameters, a rodent reproductive study was undertaken using Wistar rats. Exposures were at 0.095, 0.24, and 0.95 mT with a background exposure of 5-10 microT. Three sets of parental rats were exposed continuously for 20-23.5 h/day to the fields: maternal rats during gestation, paternal rats for at least 45 days prior to mating and maternal rats 1 month prior to mating. Exposure phases thus covered spermatogenesis, maturation of the ovum and ovulation, fertilization, implantation, embryogenesis, organogenesis, and maturation of the fetus immediately prior to parturition. In all experiments pregnancy outcome was assessed. These studies failed to demonstrate any reproductive toxicity resulting from maternal or fetal exposure during gestation or following paternal or maternal exposure for several weeks prior to mating. No quantitative or qualitative effects on spermatogenesis occurred after exposure, and no effects on the estrous cycle or ovulation could be demonstrably linked to the 10 kHz magnetic field exposure at 0.095, 0.25, or 0.95 mT. Where possible, parental clinical chemistry and hematology were also examined. As in mouse toxicology studies previously reported, minor differences were observed between control and treated groups. These were regarded as statistically, but not biologically, significant and could not categorically be attributed to magnetic field exposure.

Assessment of invasive growth pattern and lymphocytic infiltration in colorectal cancer.

A total of 122 specimens of colorectal cancer were re-assessed in relation to the reporting of invasive growth pattern (expanding vs. infiltrating) and presence or absence of peritumoral lymphocytic infiltrate as used in the Jass prognostic classification. Jass agreed with 69% of cases reported as infiltrating and 90% of reported as expanding. This parameter was distributed similarly amongst Dukes B and C cases in the original assessment (P = 0.27), whereas in the reviewed data infiltrating cases were more likely to be staged as Dukes C (P = 0.04). Jass agreed with 44% of lymphocyte present and 94% of lymphocyte absent assessments. The original lymphocyte assessments showed no significant differences in distribution between Dukes A and B cases (P = 0.12) or B and C cases (P = 0.75), whereas the reviewed data showed significant differences for A vs. B (P = 0.015) and B vs. C cases (P = 0.0025). Criteria for assessment were circulated to eight observers who revisited 20 of the cases in which there was disagreement. Consensus agreement with Jass was achieved in nine of 10 cases for invasive growth pattern and seven of 10 cases for lymphocyte infiltration (with two being evenly split). Most observers showed at least fair levels of agreement with Jass and some achieved excellent levels of agreement. This study indicates that assessment of criteria used in the Jass prognostic system for colorectal cancer is less than optimal in routine practice, but is improved through the provision of simple guidelines.

Evaluation of potential health effects of 10 kHz magnetic fields: a short-term mouse toxicology study.

A high-frequency inductive power distribution (HID) technology has been developed that generates sinusoidal magnetic fields at a frequency of 10 kHz. In typical industrial applications, field intensities in the order of 0.2 mT can be expected between the current-carrying coils. Because the possible health effects of 10 kHz sinusoidal magnetic fields of this type had never been investigated, a broad evaluation of possible effects on animal health was made in a preliminary 14 day acute study and in a 90 day subchronic study using male and female B6C3F1 mice. Exposures were at 0.08, 0.28, and 1.0 mT vs. a background exposure of 3.7 microT and were essentially continuous. These studies failed to demonstrate any health effects that can be clearly related to the magnetic field exposure. No changes in animal behaviour or indications of morbidity were detected during the initial exposure to the fields. There were no significant differences in body weight between exposed and unexposed (control) mice at any time in the study, and the clinical chemistry and hematology parameters were essentially unchanged. Although minor differences in some clinical chemistry and hematology parameters were seen between control and exposure groups, the lack of exposure dependence, the lack of consistency between sexes, and the lack of correspondence with the results of the two studies all suggest that these were chance associations. Even if the changes were real, the magnitude of the changes was very small and does not indicate serious biological effects. Finally, all organs were macroscopically and microscopically normal except for isolated, generally mild, histological lesions and lesions that were ascribed to fighting among males. There was no obvious association with field intensity.

Validation of the Banff criteria for acute rejection in renal transplant biopsies.

BACKGROUND: The histological criteria for the diagnosis of mild acute rejection in renal transplant biopsies have not been well defined. AIM: To ascertain the value of the Banff criteria for transplant biopsy reporting, particularly for the diagnosis of acute rejection, and the 'borderline' category. METHODS: We compared two systems of histological assessment in 23 transplant biopsy specimens and compared histological diagnoses to separately defined clinical diagnoses. The histological criteria applied were those of the recently described Banff criteria which were compared with our traditional diagnostic method for each specimen. RESULTS: We found the Banff diagnoses more closely related to the clinical outcome than the system of histological diagnosis that we had previously been using. CONCLUSIONS: We conclude that the Banff criteria more accurately reflect the clinical situation.

Late seminomatous relapse of a mixed germ cell tumor of the testis on intensive surveillance.

We report a case of a pure seminomatous relapse in the retroperitoneum 6 years after orchiectomy for an apparent stage I mixed germ cell tumor of the testis. The 4 cm. metastatic mass was not imaged on computerized tomography, tumor markers were negative and confounding symptoms made diagnosis difficult. The propensity for seminomatous tumors to relapse later than nonseminomatous tumors has profound implications for intensive surveillance programs for apparent stage I disease in mixed germ cell tumors. These programs often involve routine computerized tomography only for the first 2 years and rely on physical examination, simple radiology and serum tumor markers thereafter. Such programs may fail to detect pure seminomatous relapse and delay the onset of curative treatment.

Is phenytoin contraindicated in patients receiving cranial irradiation?

Three recent publications have reported the development of erythema multiforme and Stevens-Johnson syndrome in patients receiving cranial irradiation and sodium phenytoin. Some authors have recommended that patients receiving whole brain radiation therapy and who have had seizures should not be prescribed phenytoin but an alternative anti-convulsant. This article reviews the current literature pertaining to the development of this potentially lethal complication in patients receiving whole brain radiation and phenytoin, with reference to the single recorded case of Stevens-Johnson syndrome in a patient receiving cranial irradiation and phenytoin in Auckland, New Zealand. While the clinical picture in the 16 patients reported in the literature and the current case report differed from the classical form of erythema multiforme, a similar pattern of presentation and outcome appeared in all patients reviewed, suggesting that the combination of phenytoin, cranial irradiation and the gradual reduction of concomitant steroids seem to lead to the development of erythema multiforme and/or Stevens-Johnson syndrome. The data presented, although sparse, suggest that phenytoin should not be prescribed in patients receiving cranial irradiation.

The morphological effects of the anti-tumor agents flavone acetic acid and 5,6-dimethyl xanthenone acetic acid on the colon 38 mouse tumor.

Flavone acetic acid and 5,6-dimethyl xanthenone acetic acid have a broad spectrum of anti-tumor activity in mice, and act by stimulating immune cells and inhibiting tumor blood flow, resulting in hemorrhagic necrosis within 24 hrs. To study the evolution of hemorrhagic necrosis, subcutaneous Colon 38 tumors were examined by light and electron microscopy from 30 min to 24 hrs after treatment with these agents, and measurements of tumor energy metabolites made. The results show that both agents cause apoptosis beginning at 30 min, and that by 4 hrs necrosis supervenes, accompanied by rupture of tumor blood vessels. The absence of early endothelial cell damage or thrombosis suggests that vessel rupture, and consequent loss of blood flow and energy metabolite depletion, is caused by loss of extravascular mechanical support by the tumor parenchyma.

Correlation between immune and vascular activities of xanthenone acetic acid antitumor agents.

To determine whether xanthenone acetic acid (XAA) analogues of flavone acetic acid (FAA) have similar ischemic and nonischemic mechanisms of antitumor action to FAA, a series of such compounds was evaluated in vivo and in vitro. Necrotising activity and changes in tumor blood flow were measured in Colon 38 tumors, and morphological changes assessed in immune cell-infiltrated EMT6 tumor cell spheroids, after treatment with FAA, XAA and its derivatives (5-methyl XAA, 5,6-dimethyl XAA, 3-O-methyl XAA, 8-methyl XAA and xanthenone-4,5-diacetic acid). FAA, XAA and the 5-methyl and 5,6-dimethyl analogues of XAA were active in inducing tumor necrosis, falls in tumor perfusion and characteristic morphological changes in multicellular spheroids. The other XAA analogues lacked these activities. 5-methyl XAA and 5,6-dimethyl XAA were more potent than FAA or XAA. The results suggest that XAA and its analogues have the same mechanisms of action as FAA, and that both the vascular and the immune effects of these compounds are mediated via a common biochemical receptor.

Fulminant hepatic failure in a young mother.

We report the case of a mother who developed fulminant hepatic failure with hypoglycaemia, coagulopathy, Grade III hepatic encephalopathy, two days after the delivery of her fourth child. She had complained of pruritus for the final two weeks of pregnancy. She received supportive medical management within a critical care unit, and the hepatic failure resolved completely within 48 hours. Liver biopsy confirmed the diagnosis of acute fatty liver of pregnancy. This case is unusual in that this patient deteriorated markedly following delivery, at a time when spontaneous recovery is normally expected.

The role of immune effector cells in flavone acetic acid-induced injury to tumor cells in EMT6 spheroids.

Inhibition of tumor blood flow appears to a major antitumor mechanism of flavone acetic acid (FAA), although non-ischemic processes may also be a significant role. To distinguish between direct and immune effector cell-mediated cytotoxicity as the basis for non-ischemic killing, effects of FAA were compared in EMT6 spheroids grown entirely in vitro and spheroids recovered from the peritoneal cavities of mice after six days of in vivo growth (ex vivo spheroids). Approximately 50% of the cells in the latter case were of host origin (macrophages and lymphocytes). Ex vivo spheroids showed specific histological changes when exposed to FAA, including tumor cell rounding, apoptosis, depression of mitotic activity and dissolution of necrotic debris in the spheroid core. Quantitation of histological changes indicated these effects to be significantly greater in ex vivo than in vitro spheroids. The histological changes in FAA treated ex vivo spheroids were partially inhibited by dexamethasone. Oxygen tension did not influence the response of spheroids to FAA. The results suggest that immune effector cells, probably macrophages, mediate blood flow-independent antitumor effects of FAA.

Haematological effects in mice of the antitumour agents xanthenone-4-acetic acid, 5,6-dimethyl-xanthenone-4-acetic acid [correction of 5,6-methyl-] and flavone acetic acid.

Treatment of C57Bl/6 x DBA/2 mice with the maximal tolerated dose of flavone-8-acetic acid (FAA, 1300 mumol/kg), xanthenone-4-acetic acid (XAA, 1090 mumol/kg), or its dose-potent derivative 5,6-dimethyl-xanthenone-4-acetic acid (5,6-MeXAA, 100 mumol/kg) resulted within 24 h in a dramatic reduction in the number of circulating lymphocytes, an elevation in haemoglobin concentrations and a reduction in platelet numbers. Neutrophil counts either remained unchanged or were slightly elevated. All three compounds caused a marked loss of cells in the thymus. Examination of histological sections of thymus at 48 h following treatment with XAA revealed a selective depletion of cortical thymocytes and no effects on the epithelium or other thymic structures. A transient decrease in cell numbers was seen in the spleen and femoral bone marrow, with recovery to normal levels occurring within 3 days. The number of haemopoietic stem cells, colony-forming units in culture (CFU-c), in the femoral bone marrow increased after drug administration despite the occurrence of a decrease in the overall number of cells in the femur. In contrast to the increase in CFU-c numbers seen in vivo, 2 h exposure of bone-marrow cells to FAA, XAA or 5,6-MeXAA in vitro resulted in a decrease in the surviving fraction of CFU-c. The results are consistent with the hypothesis that the in vivo haematological effects of these compounds are indirect, perhaps being mediated through the induction of cytokines, and contrast with the haematological effects of conventional antitumour agents. The biochemical and haematological effects are unlikely to be the cause of the acute toxicity observed for these compounds.

Inhibition of growth of colon 38 adenocarcinoma by vinblastine and colchicine: evidence for a vascular mechanism.

Vinblastine or colchicine, administered intraperitoneally to B6D2F1 mice with advanced subcutaneous colon 38 tumours, induced substantial tumour growth delays with progressive development of haemorrhagic necrosis beginning within 8 hours of treatment. Two multidrug-resistant P388 leukaemia sublines, refractory to vinblastine and vincristine when grown as intraperitoneal ascites, were sensitive to necrosis induction when grown as subcutaneous tumours. Vascular labelling with two fluorescent markers indicated that vincristine substantially reduced tumour blood flow within 4 hours after treatment. The effects of vinblastine, vincristine and colchicine were similar to those of tumour necrosis factor alpha in that: (a) similar tumour necrosis and blood flow changes were induced, (b) coadministration of the serotonin antagonist cyproheptidine prevented tumour necrosis and (c) plasma nitrate levels were elevated, indicative of the stimulation of oxidation of L-arginine to nitric oxide. The results suggest that vinca alkaloids and colchicine act on solid tumours by host cell-mediated vascular effects as well as by direct tubulin-mediated cytotoxicity.