Pathogenesis Of Necrosis Research Articles

Novel Mechanisms and Future Opportunities for the Management of Radiation Necrosis in Patients Treated for Brain Metastases in the Era of Immunotherapy.

Radiation necrosis, also known as treatment-induced necrosis, has emerged as an important adverse effect following stereotactic radiotherapy (SRS) for brain metastases. The improved survival of patients with brain metastases and increased use of combined systemic therapy and SRS have contributed to a growing incidence of necrosis. The cyclic GMP-AMP (cGAMP) synthase (cGAS) and stimulator of interferon genes (STING) pathway (cGAS-STING) represents a key biological mechanism linking radiation-induced DNA damage to pro-inflammatory effects and innate immunity. By recognizing cytosolic double-stranded DNA, cGAS induces a signaling cascade that results in the upregulation of type 1 interferons and dendritic cell activation. This pathway could play a key role in the pathogenesis of necrosis and provides attractive targets for therapeutic development. Immunotherapy and other novel systemic agents may potentiate activation of cGAS-STING signaling following radiotherapy and increase necrosis risk. Advancements in dosimetric strategies, novel imaging modalities, artificial intelligence, and circulating biomarkers could improve the management of necrosis. This review provides new insights into the pathophysiology of necrosis and synthesizes our current understanding regarding the diagnosis, risk factors, and management options of necrosis while highlighting novel avenues for discovery.

Warfarin Induced Necrosis of The Breast: A Case Report

Background: Warfarin induced breast necrosis is a rare complication of oral anticoagulant therapy. Although it can be related to protein C, S, and antithrombin III deficiency; the pathogenesis of necrosis is still unknown.
 Case presentation: We report a case of a 38-year-old woman with extensive left breast necrosis after receiving warfarin for treatment of deep vein thrombosis. Simple mastectomy was performed and the wound was closed secondarily with an abdominal advancement flap. Rivaroxaban was prescribed after discontinuation of warfarin.
 Conclusion: Although breast necrosis following warfarin usage is uncommon, it should be considered in women presenting with breast symptoms after initiation of warfarin. Early diagnosis and appropriate management are essential to prevent extensive loss of breast tissue.

Warfarin Induced Necrosis of The Breast: A Case Report

Background: Warfarin induced breast necrosis is a rare complication of oral anticoagulant therapy. Although it can be related to protein C, S, and antithrombin III deficiency; the pathogenesis of necrosis is still unknown.
 Case presentation: We report a case of a 38-year-old woman with extensive left breast necrosis after receiving warfarin for treatment of deep vein thrombosis. Simple mastectomy was performed and the wound was closed secondarily with an abdominal advancement flap. Rivaroxaban was prescribed after discontinuation of warfarin.
 Conclusion: Although breast necrosis following warfarin usage is uncommon, it should be considered in women presenting with breast symptoms after initiation of warfarin. Early diagnosis and appropriate management are essential to prevent extensive loss of breast tissue.

Lymph node necrosis in systemic lupus erythematosus. A histopathological and immunohistochemical study of four cases.

The lymph node lesions of lupus lymphadenitis are characterized by necrosis sometimes accompanied by hematoxylin bodies, but only a few immunohistological analyses of this unique lesion have been reported. In this study we investigated the immunopathogenesis of these lesions. Lymph node specimens from four patients were analyzed immunohistochemically by applying recently developed monoclonal antibodies to immunocompetent cells. Necrosis occupied almost the entire lymph node in two cases (extensive type), whereas small foci of necrosis were found in the paracortex in the remaining two (localized type). No hematoxylin body formation was detected in any of the samples. Necrosis of the small muscular arteries, arterioles and venules was seen in the necrotic areas in all four cases. In one case of the localized type, necrotizing angitis was seen in a few arterioles and venules in the non-necrotic area. By immunohistology, amorphous depositions of immunoglobulins and C3 were demonstrated in the walls of the arterioles and venules in two cases. Our findings indicate that vasculitis due to local deposition of immune complexes in the blood vessels may play an important role in the pathogenesis of necrosis in lupus lymphadenitis.

Expression of poly(ADP-ribose) polymerase and distribution of poly(ADP-ribosyl)ation in glioblastoma and in a glioma multicellular tumour spheroid model.

Development of necrosis is a characteristic feature of glioblastoma but its pathogenesis remains poorly understood. The process of poly(ADP-ribosyl)ation in response to DNA damage is mediated by poly(ADP-ribose) polymerase (PARP) and results in NAD+ depletion. The consequent ATP and energy depletion may result in cell necrosis. Therefore PARP activation is a potential candidate for a regulatory role in the pathogenesis of necrosis in glioblastoma. This study investigated whether there might be a relationship between both PARP expression and poly(ADP-ribosyl)ation, and necrosis in glioblastoma. The pattern of expression of PARP and of poly(ADP-ribose) groups in an archival series of glioblastoma was examined using immunohistochemistry. These parameters were also studied in multicellular tumour spheroids, derived from human glioma cell lines in which central necrosis develops with increasing spheroid diameter. Poly(ADP-ribose) groups were expressed in peri-necrotic tumour cells in glioblastoma. In the spheroid model poly(ADP-ribosyl)ation was seen centrally in pre-necrotic and necrotic cells with increasing spheroid diameter. PARP was widely expressed in viable tumour cells in the glioblastoma sections. In the spheroids, PARP expression, which was initially diffuse, became confined to the outer proliferative zone with increasing diameter. The pattern of expression of poly(ADP-ribose) groups in the spheroids and in glioblastoma raises the possibility that poly(ADP-ribosyl)ation may play a role in the development of necrosis in glioma. The high basal PARP expression in both glioblastoma and the spheroids suggests that this enzyme may have additional roles in glioma cell biology.

Genetics of Glioma Progression and the Definition of Primary and Secondary Glioblastoma

SummaryGlioblastoma multiforme, the most malignant human brain tumor, may develop de novo (primary glioblastoma) or through progression from low‐grade or anaplastic astrocytoma (secondary glioblastoma). We present evidence that these subtypes of glioblastoma constitute distinct disease entities which evolve through different genetic pathways, affect patients at different age and are likely to differ in prognosis and response to therapy. Primary glioblastomas develop in older patients (mean, 55 years) and typically show EGFR overexpres‐sion or, less frequently, MDM2 overexpression and pi6 deletion. Secondary glioblastomas develop in younger patients (mean, 40 years) and frequently contain TP53 mutations and, less consistently, loss of DCC expression. Although primary and secondary glioblastomas are considered to be histologically indistinguishable, we found that the pattern and pathogenesis of necrosis are different, large areas of ischaemic necrosis surrounded by Fas expressing tumor cells being a hallmark of primary glioblastomas. The giant cell glioblastoma occupies an intermediate position. Like the primary glioblastoma, it rapidly develops de novo but manifests in younger patients (including children) and has genetic alterations typical for secondary glioblastomas, i.e. frequent TP53 mutations and lack of EGFR overexpression.

Preferential expression of Fas/APO1 (CD95) and apoptotic cell death in perinecrotic cells of glioblastoma multiforme.

Fas/APO-1 (CD95)-mediated apoptosis is one of the major mechanisms of programmed cell death. We have previously shown by reverse transcriptase-polymerase chain reaction that Fas is frequently expressed in malignant gliomas [Tachibana et al. (1995) Cancer Res 55: 5528-5530]. In this study, we assessed Fas expression in astrocytomas using a polyclonal anti-Fas antibody. Immunoreactivity to Fas was detected in 1 out of 9 (11%) low-grade astrocytomas (WHO grade II), 2 of 11 (18%) anaplastic astrocytomas (WHO grade III) and in 13 of 15 (87%) glioblastomas (WHO grade IV). In glioblastomas, Fas expression was almost exclusively observed in glioma cells surrounding foci of necrosis. In these perinecrotic areas, there was also an accumulation of glioma cells undergoing apoptosis, as detected by in situ nick-end labeling. This suggests that Fas-mediated apoptosis may play a role in the pathogenesis of necrosis which constitutes a histological hallmark of glioblastoma multiforme.

Hypoxia of diabetic feet with abnormal arterial blood flow.

Necrotic ulcers of the feet are a dangerous complication of the diabetic foot syndrome. Besides peripheral vascular disease (PVD) peripheral neuropathy is an important factor in the pathogenesis of necroses. We examined whether the reserve of circulation during reactive hyperemia at the feet of patients with type I diabetes mellitus with abnormal blood flow (n = 17) is decreased compared with diabetic (n = 14) and nondiabetic (n = 20) controls. Further we analyzed whether there is a correlation with the oxygen supply of the foot. PVD was excluded by clinical check-up, oscillography, and Doppler ultrasound. The reserve of circulation of the foot was measured during reactive hyperemia and oxygen supply of the foot by oximetry. Abnormal blood flow of the foot was diagnosed by the pulsation index. On examination it was found that the reserve of circulation of diabetic feet with abnormal blood flow is about 52% less than in diabetic and about 50% less than in nondiabetic controls (P < or = 0.005). The decreased reserve of circulation correlates with the oxygen supply of the feet; this is about 21% less compared to diabetic feet with normal blood flow and about 16% less in comparison to nondiabetic feet. The present study shows that diabetic feet suffer from disturbed circulation although there is no evidence of PVD. This disturbed circulation is correlated with a decreased oxygen supply of the feet. Hypoxia during strain could be of great importance in the pathogenesis and treatment of necrotic ulcers of diabetic feet.

INTENSE FOCAL EXPRESSION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR MESSENGER-RNA IN HUMAN INTRACRANIAL NEOPLASMS - ASSOCIATION WITH REGIONS OF NECROSIS

To examine the potential involvement of vascular endothelial growth factor (VEGF) in vascular changes which occur in human intracranial neoplasms, we examined a series of tumor specimens for expression of VEGF mRNA by in situ hybridization. VEGF was expressed at high levels by tumor cells in discrete regions in several of the tumors examined. The highest levels were detected in glioblastomas. The presence and location of foci of intense VEGF mRNA expression were, paradoxically well correlated with the presence of necrobiosis within the tumor mass. A less consistent association was observed between VEGF expression and either the degree of vascularization or endothelial cell proliferation. Since VEGF has been shown to induce tissue factor expression, VEGF itself may be involved in the pathogenesis of necrosis. Our findings provide evidence that VEGF mRNA is highly expressed in specific intracranial malignancies and suggest that VEGF plays a complex and multifunctional role in vascular biology.

Biochemistry of alcoholic liver disease.

The biochemistry of alcohol liver disease as it relates to clinical medicine and experimental alcohol liver disease is presented. Clinical features are emphasized in the diagnosis of alcohol liver disease, particularly as it relates to staging the disease and predictors of prognosis. Currently, it is true that the biochemical diagnosis of alcohol liver disease is at best very limited in terms of the sensitivity tests and specificity of the test. It is particularly difficult to detect alcohol liver disease biochemically in the early stages when steatohepatitis is not severe. Consequently, 50% of the patients have already developed cirrhosis at the time they are diagnosed clinically. In this review indicators of malnutrition are emphasized because they have the strongest implications regarding survival during the acute hospitalization stage of the disease. They are also the best indicators of response to therapy during the recovery phase. With respect to experimental work on the pathogenesis of alcohol liver disease, it appears that necrosis is due to the inability to increase blood flow to compensate for increased oxygen utilization. The hypothesis that mitochondrial damage is the cause of liver cell damage is regarded as less important in the pathogenesis of necrosis. The shift in the redox state during alcohol metabolism accounts for the fatty change noted in the central lobular area of the liver in animals fed alcohol. Apparently, there is strong experimental evidence that highly reactive intermediates are important in the pathogenesis of liver damage due to the induction of the isozyme cytochrome P450 IIE1 by alcohol ingestion. This mechanism is enhanced by a diet high in polyunsaturated fatty acids.

Effects of Fusobacterium necrophorum on the mesenteric microcirculation of guinea pigs.

Thrombi formation was demonstrated in mesenteric microcirculation of guinea pigs inoculated with Fusobacterium necrophorum and the bacterial hemagglutinin (HA). The thrombi were initially observed in venules and later, in arterioles. Immunofluorescence study revealed that the HA bound to the thrombi in the microcirculation. These results indicate that thrombosis is an early step in the pathogenesis of necrosis.

FRACTIONAL NECROSIS OF THE FEMORAL HEAD EPIPHYSIS AFTER TRANSIENT INCREASE IN JOINT PRESSURE. AN EXPERIMENTAL STUDY IN JUVENILE RABBITS

Ischaemia resulting from increased joint pressure may play a role in the pathogenesis of necrosis of the femoral head epiphysis. We studied the effect of temporary vascular occlusion on this epiphysis in young rabbits. Occlusion for six hours resulted in necrosis of trabecular bone and of intertrabecular marrow and vascular tissue, later followed by revascularisation and repair, as has been demonstrated previously. In contrast, raised intra-articular pressure lasting for only two hours resulted in a more complex picture: trabecular osteocytes were dead, whereas the bone-forming marrow was shown by fluorochrome labelling to remain viable, and to form appositional repair bone throughout the epiphysis. We concluded that transient vascular occlusion may cause the death of trabeculae despite intact perfusion of the bone. This type of change may be important in the pathogenesis of Perthes' disease.

Aggregation of platelets in the mesenteric microcirculation of the rat induced by α- toxin (phospholipase C) of Clostridium perfringens

We have investigated the effects of purified α-toxin (phospholipase C) of Clostridium perfringens ( Yamakawa and Ohsaka, 1977) on the behavior of cellular components in the microcirculation, using cinematography on a microscopic level and electron microscopy. We demonstrated that after topical application of α-toxin to the mesentery of the rat, rolling of leucocytes along the vessel wall and sticking of leucocytes to the vessel wall occurred in venules but not in arterioles. Some of the leucocytes remained attached to the vessel wall. Thrombi were formed frequently in venules and capillaries, and at a later stage, in arterioles. With time, thrombi increased in number and size, leading eventually to stasis of the blood stream. Thrombi were also observed frequently in the mesenteric microcirculation when toxin was injected into the jugular vein of the rat. The experiments with adenosine pretreatment followed by topical application of α-toxin to the mesentery suggested that the formation of thrombi induced by this toxin does not involve the mediation of ADP. Electron-microscopic examination confirmed the formation of thrombi consisting solely of platelets. It was concluded that thrombosis must be involved as an early step in the pathogenesis of necrosis caused by α-toxin. The death of the animals injected intravenously with α-toxin may be due, at least in part, to thrombosis. It is possible that thrombosis induced by α-toxin may be one of the factors involved in the causation of toxemia often manifested in the late stage of gas gangrene.

On the Pathogenesis of Cardiac Necroses induced by Theophylline and Caffeine

Abstract In unanesthetized rats, theophylline or caffeine in a dose of 150 mg/kg intraperitoneally caused a long–lasting tachycardia, hypermetabolism and hypotension. After 48 hours myocardial necroses were found in all the animals. Propranolol diminished the cardiotoxic as well as the chronotropic, calorigenic and hypotensive effects of theophylline. The calcium antagonists verapamil and D 600 were ineffective in this respect but augmented the acute toxicity of theophylline. Furthermore, the cardiotoxic activity of theophylline was intensified by pretreatment with thyroxine. Total myocardial calcium increased within one hour after the injection of a cardiotoxic dose of isoprenaline (10 mg/kg intraperitoneally) but not after theophylline (150 mg/kg intraperitoneally). Only 24 hours after the theophylline treatment were the myocardial calcium levels elevated. In conclusion, cardiac necroses may be a consequence of hypoxia resulting from the cardiovascular and metabolic actions of theophylline or caffeine. Myocardial calcium overloading does not seem to be an essential factor in the pathogenesis of these necroses.