Clinicopathologic characterization of squamous-cell carcinoma arising from pilonidal disease in association with condylomata acuminatum in HIV-infected patients: report of two cases.

Pilonidal disease is a common acquired condition believed to arise from penetration of short hairs into the subcutaneous tissue that induces a cyst or sinus formation. Malignant degeneration is rare and is typically seen only after decades of antecedent disease presence. Condylomata acuminatum in association with pilonidal disease have been described in two prior case reports, however, the coexistence of condyloma with pilonidal disease complicated by malignant degeneration has not been previously reported. Condylomata have known potential for malignant degeneration and are correlated with human papilloma virus infection, with certain serotypes of higher oncogenic potential. Coinfection with human immunodeficiency virus and human papilloma virus is associated with higher rates of anal neoplasia. We report two cases of human immunodeficiency virus-infected patients with the constellation of pilonidal disease, condylomata acuminatum, and subsequent malignant degeneration into squamous-cell carcinoma. In contrast to other case reports in the literature, these two patients had considerably shorter antecedent periods of pilonidal disease before malignant degeneration was detected. Both cases also had intractable courses. We conclude that the existence of condylomata acuminatum and pilonidal disease in an immunocompromised patient may represent a more ominous condition than solitary pilonidal disease. Therefore, careful inspection of the pilonidal area in human immunodeficiency virus-infected patients presenting with condylomata is important and earlier intervention should be considered. Moreover, further evaluation of the prevalence of squamous-cell carcinoma arising from pilonidal disease complicated by condylomata, particularly in the immunosuppressed, is warranted.

Cadmium hepatotoxicity and alterations of the mitochondrial function.

OBJECTIVE: To examine the effect of low concentrations of cadmium on isolated liver mitochondrial function as related to hepatotoxicity. METHODS: Tetraphenyl phosphonium ion uptake and retention, estimated with a tetraphenyl phosphonium-sensitive electrode, was used to monitor changes in liver inner mitochondrial membrane potential. Ca2+ efflux was measured spectrophotometrically with the Ca2+ indicator Arsenazo III. Mitochondrial swelling was measured spectrophotometrically at 540 nm. Oxygen consumption was measured with a Clark-type oxygen microelectrode. RESULTS: Incubation of isolated liver mitochondria with cadmium (5-30 microM) altered mitochondrial function as indicated by swelling, inhibition of respiration, loss of inner mitochondrial membrane potential, and loss of preaccumulated Ca2+. The presence of dithiothreitol (2 mM) in the incubation medium restored mitochondrial function to almost the control level. Cyclosporin A (1 microM), however, did not provide any protection against cadmium toxicity. CONCLUSIONS: The findings point to a direct effect of cadmium on liver mitochondrial function. Cadmium toxicity may be due to loss of reduced glutathione rather than to increased mitochondrial inner membrane permeability. The effect of cadmium on liver mitochondria seems to be an early event in cadmium-induced hepatotoxicity.

Ibuprofen-induced liver mitochondrial permeability transition.

This study examined the effect of the nonsteroidal anti-inflammatory drug ibuprofen on liver inner mitochondrial membrane permeability transition in the presence of Ca2+ and phosphate. Incubation of isolated liver mitochondria with ibuprofen (0.1-0.4 mM) induced inner mitochondrial membrane permeability as indicated by loss of inner mitochondrial membrane potential, swelling of matrix and loss of pre-accumulated Ca2+. The presence of cyclosporin A (1 microM) in the incubation medium preventing ibuprofen from causing loss of inner mitochondrial membrane potential, swelling and loss of pre-accumulated Ca2+. It is concluded that ibuprofen acted as an activator of Ca2+ and phosphate in promoting the opening of inner mitochondrial membrane pore.

Salicylate-induced kidney mitochondrial permeability transition is prevented by cyclosporin A.

The effect of salicylate, the active metabolite of aspirin (acetyl salicylic acid) in the presence of Ca2+ and phosphate on mitochondrial permeability transition (MPT) was studied. MPT is often associated with opening of a Ca2+ -induced pore. The opening of this pore leads to swelling, loss of mitochondrial membrane potential and release of accumulated Ca2+. In freshly isolated rat kidney mitochondria, salicylate (400 microM) in the presence of 20 nmol Ca2+/mg protein and 0.1 mM phosphate induced swelling, loss of mitochondrial membrane potential and release of accumulated Ca2+. All these changes were eliminated when cyclosporin A (1 microM), (a pore inhibitory agent) was included in the incubation medium. Unlike salicylate, unhydrolyzed aspirin (400 microM) induced these changes slightly. We concluded that salicylate acts as an activator of Ca2+ and phosphate in promoting the opening of kidney inner mitochondrial membrane pore. As a result a great consideration should be given to its toxicological effect.

In vivo prevention of adriamycin cardiotoxicity by cyclosporin A or FK506.

The use of adriamycin, an antitumour agent, is restricted by its cardiotoxicity. The objective of this study was to investigate the role of mitochondrial Ca2+ in adriamycin-induced cardiotoxicity and the effect of either cyclosporin A (CsA) or tacrolimus (FK506) on that cardiotoxicity. A single dose of adriamycin (10 mg/kg body weight) caused myocardial damage that was manifested by elevation of serum enzymes, glutamate-oxaloacetate transaminase (GOT), glutamate-pyruvate transaminase (GPT), lactate dehydrogenase isoenzyme (LDH-iso) and creatine phosphokinase isoenzyme (CPK2-MB). The permeability of heart inner mitochondrial membrane of adriamycin-treated rats was examined. Tetraphenyl phosphonium ion (TPP+) uptake, estimated with a TPP+-sensitive electrode was used to monitor changes in heart inner mitochondrial membrane potential. Ca2+ efflux was measured spectrophotometrically with the Ca2+ indicator arsenazo III. The ability of heart mitochondria isolated from adriamycin treated rats to retain accumulated Ca2+ or TPP+ was sharply reduced. The increase of diagnostic serum enzymes and isoenzymes and the reduced ability to retain Ca2+ or TPP+ by heart mitochondria were restored to almost the normal levels when (500 microg/kg body weight) of CsA or FK506 were injected with adriamycin. The data suggested that adriamycin cardiotoxicity might be due to the increase of inner membrane permeability in heart mitochondria as a result of increasing the sensitivity of a Ca2+ dependent-pore of the inner mitochondrial membrane to calcium, leading to dissipation of membrane potential and release of pre-accumulated Ca2+. Suitable antagonists of Ca2+-dependent pore formation such as CsA or FK506 may improve heart tolerance to adriamycin.

In vivo prevention of cyclophosphamide-induced Ca2+ dependent damage of rat heart and liver mitochondria by cyclosporin A.

The use of Cyclophosphamide, an anti-cancer and immunosuppressant drug, is accompanied by a number of side effects. Rats injected with a single dose of cyclophosphamide (200 mg kg-1 body weight) showed an increase in the levels of serum glutamate-oxaloacetate transaminase, serum glutamate-pyruvate transaminase, glucose-6-phosphate dehydrogenase and creatine phosphokinase isoenzyme by 53, 24, 55 and 135%, respectively. Also the ability of heart or liver mitochondria to retain accumulated Ca2+ and tetraphenylphosphonium ion was sharply affected in treated rats. Rats injected with the same dose of cyclophosphamide plus cyclosporin A (500 micrograms kg-1 body weight) showed reduction in the levels of those enzymes by about 44, 21, 43 and 57%, respectively compared to cyclophosphamide-treated rats. Cyclosporin A treatment also restored mitochondrial ability to retain accumulated Ca2+ and tetraphenyl phosphonium ions nearly to the level of untreated rats. We suggest that cyclophosphamide induced cardio and hepatotoxicity by increasing heart and liver inner mitochondrial membrane permeability to Ca2+. The protective effect of cyclosporin A against cyclophosphamide-induced damage also support this suggestion.

Renal insufficiency induced by cisplatin in rats is ameliorated by cyclosporin A.

Cyclosporin A (CsA) is a potent inhibitor of the Ca(2+)-dependent "pore" in isolated mitochondrial from diverse sources. Cisplatin-induced acute renal failure has been associated with morphological and functional alterations in renal cortex mitochondrial (RCM). This study was undertaken to examine the probable involvement of Ca(2+)-dependent permeabilization of RCM in cisplatin nephrotoxicity. RCM from rats injected with cisplatin (5 mg/kg body wt) 4 days earlier showed a significantly reduced capacity of retaining matrix Ca2+ and membrane potential in the presence of 15 nmol Ca2+/mg protein and 0.1 mM Pi (inorganic phosphate), compared to controls (those of rats that received carrier alone). These indices of mitochondrial dysfunction were restored to control levels when 1 microM CsA was added to assay media of RCM obtained from cisplatin-treated rats. Renal insufficiency induced by cisplatin assessed by serum creatinine and urea levels was significantly alleviated in rats 4 days after i.p. injections of cisplatin (5 mg/kg body wt) and CsA (50 micrograms/kg body wt), compared to those injected with cisplatin alone. Our findings support an involvement of Ca(2+)-mediated RCM damage in the mechanism of cisplatin nephrotoxicity, and suggest that suitable antagonists of Ca(2+)-dependent "pore" formation may improve renal tolerance to cisplatin.

Dexamethasone inhibits inorganic phosphate stimulated Ca(2+)-dependent damage of isolated rat liver and renal cortex mitochondria.

The prevention of Ca(2+)-induced permeabilization of rat liver and kidney cortex mitochondria by dexamethasone, a common anti-inflammatory glucocorticoid, was the subject of this study. A non-specific release of matrix Ca2+ and membrane depolarization was observed in respiring mitochondrial suspensions subjected to a 30 nmol Ca2+/mg protein load in the presence of 2 mM inorganic phosphate (Pi), or 20 nmol Ca2+/mg protein with 1 mM Pi, for liver and renal cortex mitochondria (RCM), respectively. Additions of dexamethasone prior to Ca2+ in mitochondrial suspensions from liver or kidney cortex (80 and 200 microM final concentrations, respectively) led to 75-80% protection from these permeabilization-associated alterations of functional integrity. In conclusion, dexamethasone appears to show great promise in blocking the opening of a Ca(2+)-dependent 'non-specific pore' in the inner membranes of mitochondria from various sources.

Chemoembolization for hepatocellular carcinoma: epinephrine followed by a doxorubicin-ethiodized oil emulsion and gelatin sponge powder.

PURPOSE: This study evaluates chemoembolization (CE) of the liver with minimal vasoconstriction followed by selective intraarterial delivery of an emulsion of iopamidol, doxorubicin, and ethiodized oil and temporary occlusion of hepatic artery with gelatin sponge powder in patients with hepatocellular carcinoma. PATIENTS AND METHODS: Since 1988, 30 patients with nonresectable hepatocellular carcinoma underwent CE with the above protocol. Intraarterial epinephrine (0.5-1 microgram diluted in 10 mL of saline) was rapidly injected directly into the proper hepatic artery or selectively into the right or left hepatic arteries and was followed by 40-60 mg of doxorubicin dissolved in 10 mL of iopamidol and emulsified in 20 mL of ethiodized oil. The chemoembolic mixture was injected at the rate of arterial flow. Liver function and clotting parameters were monitored three times a day until there was a downward trend toward preembolic levels. Computed tomography (CT) was performed immediately after embolization and at 1-3-month intervals. Embolization was repeated when CT demonstrated recurrent or progressive disease. RESULTS: Disease recurred or progressed in 11 patients at 2-17 months after embolization. CE was repeated in four patients; one individual underwent three embolizations. Re-embolization was performed up to 14 months after initial embolization (median, 10 months). Five patients (16.7%) died within 1 month of embolization. Ten patients died at 3-33 months after CE. Two of these patients died of cirrhosis at 6 and 14 months, without evidence of recurrent tumor. Fifteen patients remain alive 5-28 months after CE. Kaplan-Meier estimation of probability of survival curves demonstrates a median survival of 14 months. Sixty-one percent of patients were alive at 1 year and 36% at 2 years after the procedure. CONCLUSION: CE with use of the above technique is effective for palliating inoperable hepatocellular carcinoma. It causes a significant prolongation of survival over the expected 18-24 weeks in untreated patients; this may occur because high doses of chemotherapeutic agents are delivered and come in contact with the tumor for a longer period, followed by ischemia brought about by temporary arterial occlusion.

Occult axillary lymph node metastases in "node-negative" breast carcinoma.

The presence of occult axillary nodal metastases was evaluated in 159 patients with "node-negative" invasive breast carcinoma. Multiple additional levels of the lymph nodes were examined with hematoxylin-eosin staining and keratin immunostaining. Occult nodal metastases were detected in 50 (31%) patients; of these, 28 (17%) were detectable by hematoxylin-eosin stain alone, while the other 22 (14%) consisted of mostly single cells or very small clusters and required immunostaining for detection. The size of the metastatic deposit was < or = 0.2 mn in 31 (19%) patients and greater than 0.2 mm in 19 (12%) patients. Occult nodal metastasis correlated with the presence of peritumoral lymphatic invasion (P = .02) and was seen more frequently with larger tumor size, increased microvasculature, and aneuploidy. As a group occult metastases had no significant prognostic impact. However, patients with metastases measuring greater than 0.2 mm had significantly worse recurrence (P = .02), disease-free survival (P = .04), and overall survival (P = .07) rates; those with metastases detectable by hematoxylin-eosin stain alone also had a less favorable, although not significant, outcome. In contrast, patients with occult metastases that were < or = 0.2 mm or that were detected only by immunostaining had a survival rate comparable to and in fact slightly higher than that of the group without occult metastasis; 23 of these patients were without recurrence after a median follow-up of 11 years. Extension into perinodal soft tissue was an unfavorable feature. In a multivariate analysis peritumoral lymphovascular invasion and increased microvasculature were the most important prognostic parameters, and the presence of occult metastases greater than 0.2 mm was no longer significant. Our data suggest that occult metastases < or = 0.2 mm, especially those consisting of single cells, do not add useful prognostic information, and immunohistochemical studies to detect them are probably unnecessary. Larger metastases and extranodal involvement may have important prognostic value, but in this study they accounted for only 20% of patients who had recurrences or 6% of the total population. This underscores the importance of using more than one prognostic parameter in evaluating breast carcinoma.