Experimental study on the pathogenesis of pulmonary insufficiency in acute pancreatitis and changes in the pulmonary surfactant

Serious pulmonary complications are often associated with acute pancreatitis. The destruction of pulmonary surfactant by the action of pancreatic phospholipase A2 (PLA2), together with pulmonary edema, is considered an important etiopathogenic factor of acute respiratory insufficiency. This experimental study was undertaken to elucidate the destruction of pulmonary surfactant in acute pancreatitis using the lung pressure volume curve (P-V curve). Acute hemorrhagic pancreatitis was induced in mongrel dogs by a retrograde injection of Na-taurocholate into the main pancreatic duct. Pulmonary surface tension was measured by P-V curve and the effect of PLA2 on pulmonary surfactant was assessed by the ratio of lysolecithin and lecithin, which are essential components of pulmonary surfactant (Ly/Le) in lung wash. Extravascular lung water volume (Ww/Dw) and blood gases were also measured. The value of Ly/Le and serum PLA2 rose significantly from the 3rd hour. On the contrary, no significant differences were seen on P-V curve until the 12th hour but after 20 hours surface tension increased significantly. Ww/Dw and A-aDO2 increased after 3 and 12 hours, respectively. These findings, the degradation of lecithin and the elevation of surface tension accompanied with an increase of serum PLA2, suggest that pulmonary surfactant is destroyed in severe acute pancreatitis, and that the increased capillary permeability of the lung precedes the deterioration of surface tension as the cause of pulmonary insufficiency.     

Changes of alveolar stability and phospholipids in pulmonary surfactant in acute pancreatitis

We investigated changes of alveolar stability and phospholipids in the pulmonary surfactant in case of acute pancreatitis induced in rats. Alveolar stability was examined by recording the pressure-volume relationship. The lung volumes during deflation decreased significantly at equivalent transpulmonary pressures, particularly when the pressure was lower than 6 cm H₂O. Bubble stability ratio and surface tension indicated that the surface activity of the pulmonary surfactant did decrease in the rats with acute pancreatitis. The alveolar phospholipid content decreased, and the lecithin fraction also decreased significantly, as compared to the control groups. The metabolism of alveolar lecithin was examined following intravenous administration of¹⁴C-labeled palmitate. The biological half-life of the radioactivity of alveolar lecithin was approximately 6 hours in the pancreatitis group, 12 hours in the hepatic ducts ligated group and 14 hours in the simple laparotomy group. The degradation of alveolar lecithin, as well as its synthesis, was accelerated in the rats with acute pancreatitis. However, a decrease in alveolar phospholipid, mainly in lecithin fraction, indicated that the synthesis was inadequate, to maintain normal levels and the impairment in pulmonary surfactant may result in a respiratory insufficiency. Presented at the 82nd Annual Meeting of the Japan Surgical Society, 1982, Chiba, Japan.     

肺灌洗及外源性肺表面活性物质治疗烟雾吸入性损伤的实验研究

为探讨肺灌洗与外源性肺表面活性物质（ＰＳ）治疗对严重烟雾吸入伤后内源性ＰＳ功能障碍和急性呼吸衰竭的防治效果,作者将重度烟雾吸入伤后Ｗｉｓｔａｒ大鼠经气管插管注入含ＰＳ的等渗盐水或等量盐水行肺灌洗,机械通气４小时,观察２４小时,检测动脉血气、肺水量、静态肺顺应性（Ｃｓｔ）、支气管肺泡灌洗液（ＢＡＬＦ）蛋白含量、ＢＡＬＦ表面张力特性和２４小时病死率等。结果显示：动物伤后立即出现严重缺氧和一氧化碳中毒。烟雾吸入组发生急性呼吸衰竭、高通透性肺水肿和ＰＳ功能障碍。烟雾吸入加灌洗加ＰＳ加机械通气组Ｃｓｔ和ＢＡＬＦ表面张力特性明显改善,氧合能力显著增强,肺水量和ＢＡＬＦ蛋白含量降低,２４小时病死率明显下降。烟雾吸入加灌洗加机械通气组也有一定疗效。作者认为,早期肺灌洗和外源性ＰＳ治疗能有效恢复烟雾吸入所致内源性ＰＳ功能抑制,改善肺功能,防止高通透性肺水肿和呼吸衰竭,降低早期病死率。     

Experimental study of respiratory failure with acute pancreatitis in dogs

In this experimental study, we investigated pathophysiology of respiratory failure with acute pancreatitis. Pancreatitis was induced by injection of 15% Na-taurocholate 1 ml/kg into the main pancreatic duct of the dogs. Experimental dogs were divided into two groups based on the value of Respiratory Index (R-Index). Group A included 9 dogs in whom respiratory failure was not recognized (R-Index less than 0.5) and Group B included 9 dogs with respiratory failure (R-Index less than 0.5). All the dogs were sacrificed 12 hours after induction of pancreatitis, and histological findings were examined. Quantity of water in the lung (Qwl) was also measured by gravimetric method. Group B showed severe hypoxia with hypocapnia, and increase of A-aDO2, R-Index, and decrease of a/A PO2. Qwl in Group B increased significantly comparing with Group A. In biochemical study, increase of serum lipase, triglyceride, free fatty acid, and angiotensin converting enzyme were observed in Group B. These results indicate that respiratory failure with acute pancreatitis is due to lung edema following injury of the capillary of the lung. The role of free fatty acid liberated by lipolysis was suggested in the mechanism of pulmonary damage with acute pancreatitis.     

Bacteriology of the closed duodenal loop model of acute pancreatitis and ultrastructural changes induced in the lungs

Injection of infected human bile into a closed duodenal loop in the rat consistently produces lethal pancreatitis with severe pulmonary damage. Lung abnormalities, resembling the human adult respiratory distress syndrome (ARDS) are frequently seen in this model and are usually ascribed to the pancreatitis. Similar pulmonary problems are seen in the human form of acute pancreatitis. Recently, it has been suggested, that the lung changes in the experimental animal are more likely to be due to bacteremia than to the pancreatitis. The aim of this study was to determine whether bacteremia occurred in this model, and if so, to determine whether bacteremia alone, in the absence of pancreatitis could produce this lung damage. A group of rats underwent induction of acute pancreatitis by a closed duodenal loop method and were compared to two groups comprising a closed small bowel loop bile infusion preparation, isolated from the pancreas, and a control group of rats undergoing a "sham" gastrotomy. Both pancreatitis and closed small bowel groups of animals were found to be bacteremic when sacrificed at 6 hr. The lungs from the animals with pancreatitis were significantly heavier than those in the other groups and scanning electron micrographs of the lungs in pancreatitis showed gross abnormalities, with marked increases in the alveolar wall thickness. The lungs in the closed small bowel loop preparation were indistinguishable from a control sham gastrotomy group of non-bacteremic rats. These results indicate that although the closed duodenal loop model of pancreatitis produces bacteremia, pancreatitis is necessary for development of pulmonary abnormalities.     

Surfactant analysis and replacement therapy: a future tool of the lung transplant surgeon?

From 1965 to 1974 extensive research was carried out concerning the effects of experimental lung reimplantation and allografting on the surface tension properties of pulmonary surfactant. Since then, surfactant has been more rigorously examined in terms of its composition and function, and the potential roles of three surfactant-associated proteins have been established. Furthermore, surfactant replacement therapy for neonatal respiratory distress syndrome has come of age. The efficacy of surfactant treatment for adult respiratory distress syndrome is currently under clinical scrutiny, and experimental work on alterations in surfactant after lung transplantation has resumed after a 15-year hiatus. This article reviews current knowledge of the pulmonary surfactant system, as well as previous studies of the changes in surfactant after experimental lung transplantation. The experience in surfactant replacement therapy for the neonatal and adult respiratory distress syndromes is briefly described. Suggestions are made concerning the potential experimental and clinical applications of surfactant analysis and replacement therapy in lung transplantation.     

Evidence of a central role for p38 map kinase induction of tumor necrosis factor alpha in pancreatitis-associated pulmonary injury.

BACKGROUND: Tumor necrosis factor alpha (TNF alpha) has been implicated as an important mediator in acute pancreatitis-associated adult respiratory distress syndrome, but the precise pathogenesis remains unclear. The purpose of this work was to clarify the role of TNF alpha that is produced within the lung parenchyma in the inducement of pancreatitis-related pulmonary injury and to examine 1 of the potential pathways leading to the production of pulmonary TNF alpha. METHODS: Bile salt pancreatitis was induced in rats (n = 40) that were randomized to receive a p38 mitogen-activated protein (MAP) kinase inhibitor or vehicle. A separate group (n = 16) underwent sham operation. Pulmonary capillary permeability was determined with fluorescein isothiocyanate-labeled albumin and Evans blue dye, and lung histologic analysis was performed. TNF alpha protein was measured in bronchoalveolar lavage fluid, and p38 MAP kinase was activity determined by Western blot analysis. RESULTS: The induction of pancreatitis resulted in increased pulmonary capillary leakage and worsened histologic condition (P < .01 vs sham). Effective inhibition of p38 MAP kinase-induced TNF alpha production completely prevented pancreatitis-associated pulmonary injury (P < .01 vs vehicle). CONCLUSIONS: p38 MAP kinase-induced TNF alpha production plays a central role in the development of pulmonary dysfunction, which accompanies severe acute pancreatitis in this rodent model.     

Lung lavage and artificial surfactant replacement therapy--animal experimentation and clinical application

Lung lavage may cause a surfactant deficient condition. We examined the effect of artificial surfactant replacement on the post-lavage condition in rabbits and in a patient with alveolar pulmonary proteinosis. Adult rabbits (n = 21) were subjected to whole-lung lavage, and the PaO2 was made to decrease to less than 70 mmHg (FIO2 = 1.0). In the replaced group (n = 11), an artificial surfactant which was a saline suspension of lipids (mixture of dipalmitoylphosphatidylcholine, phosphatidylglycerol and tripalmitin) was administered into the airway. The PaO2 was elevated to a level higher than 400 mmHg at 30 min after the surfactant replacement. On the other hand, the PaO2 in the non-replaced group (n = 10) remained below 100 mmHg. In the patient with alveolar pulmonary proteinosis, we performed the artificial surfactant replacement after the therapeutic lung lavage. By the replacement, the PaO2 increased from 89 mmHg (FIO2 = 1.0) to 128 mmHg. These results demonstrate the therapeutic effects of surfactant replacement on the acute respiratory failure induced by lung lavage.     

Murine pancreatic duct ligation induces stress kinase activation, acute pancreatitis, and acute lung injury

Background

Acute lung injury is a major determinant of outcomes in acute pancreatitis. We evaluated acute lung injury and stress kinase activation in ligation-induced acute pancreatitis in mice.

Methods

Mice with duct ligation or sham operation were killed after 24 or 48 hours.

Results

In addition to acute pancreatitis, duct ligation was associated with pulmonary morphologic changes indicative of acute lung injury (alveolar septal thickening, congestion, and neutrophil infiltration). Furthermore, immunoblotting showed stress kinase activation in the pancreas and lung after ligation. Although mortality was observed in the ligated group, that is consistent with severe lung injury, it requires further evaluation.

Conclusions

Bile and pancreatic duct ligation in the mouse is associated with pancreatic and pulmonary stress kinase activation and acute inflammatory changes consistent with early acute pancreatitis and acute lung injury. Our findings are important as acute lung injury increases mortality in clinical acute pancreatitis and stress kinases are established proinflammatory signal transducers.     

肺表面活性物质对盐酸吸入性肺损伤肺渗出的影响

目的：探讨外源性ＰＳ盐权吸入性损伤家兔肺组织渗出的影响。方法：健康家兔２０只复制盐酸吸入肺损伤模型后随机分为二组,Ａ组（ｎ＝１０）为ＰＳ治疗组,Ｂ组（ｎ＝１０）为对照组,气管内分别注入３７℃ＰＳ１００ｍｇ／ｋｇ和生理盐水（ＮＳ）,对比观察ＰＳ治疗对肺水、ＢＡＬＦ蛋白浓度及肺组织形态学改变。另设Ｃ（ｎ＝８）组,未行盐酸吸入,而在相应时间注入同等体积的ＮＳ作为ＰＳ疗效的对照。结果：Ａ、Ｂ组各尿参数明显     

Diminished lung injury with vascular adhesion molecule-1 blockade in choline-deficient ethionine diet-induced pancreatitis

BACKGROUND: Lung injury in severe acute pancreatitis is mediated by infiltrating leukocytes. Our laboratory has previously demonstrated that acute lung injury in acute pancreatitis results in an up-regulation of vascular adhesion molecule-1 (VCAM-1) cell surface receptor expression on pulmonary vascular endothelium and neutrophil sequestration. The objective of this study was to determine whether blocking expression of VCAM-1 in acute pancreatitis would modify acute pulmonary injury. METHODS: Young female mice were fed a choline-deficient ethionine (CDE) supplemented diet to induce acute pancreatitis. After initiation of the diet, one group (acute pancreatitis treated [n = 18]) was treated with blocking doses (2.35 mg/kg) of monoclonal anti-VCAM-1 receptor antibody (Ab) at 48, 96, and 120 hours. A second group (acute pancreatitis treated control [n = 5]) was treated with a similar dose of an isotypic control for VCAM-1 (nonbinding Ab) at the same time points. A third group (acute pancreatitis untreated [n = 12]) received a CDE diet, and a fourth group (control [n = 11]) received standard food with no Ab treatment. All animals were killed at 144 hours. The dual radiolabeled monoclonal Ab method was used to quantitate VCAM-1 cell surface expression in lung tissue. Lung injury was assessed histologically, and apoptosis was detected by transferase-mediated deoxyuridine triphosphate nick end labeling assay. Pulmonary leukocyte sequestration was determined by myeloperoxidase (MPO) assay and CD18 staining. RESULTS: Pulmonary VCAM-1 cell surface expression was significantly increased in animals with acute pancreatitis when compared to controls (P <.001) and was reduced to near control levels in acute pancreatitis treated animals. On histologic examination, treated animals with acute pancreatitis exhibited significantly less lung injury and apoptosis than did untreated animals with acute pancreatitis. Leukocyte sequestration and MPO activity were significantly reduced in the treated animals with pancreatitis compared to untreated animals with pancreatitis (P <.0001) or acute pancreatitis treated controls (P <.03). CONCLUSIONS: Blocking VCAM-1 on pulmonary vascular endothelium decreases leukocyte adherence and recruitment into the lung, hence reducing lung injury in severe acute pancreatitis. Clinically, VCAM-1 antagonism may be an important adjunct to evolving therapy for distant organ injury in severe acute pancreatitis.     

Long-term effects of mustard gas on respiratory system of Iranian veterans after Iraq-lran war： a review

To review long-term respiratory effects of mustard gas on Iranian veterans having undergone Iraq-Iran war. Electronic databases of Scopus, Medline, ISI, IranMedex, and Irandoc sites were searched. We accepted articles published in scientific journals as a quality criterion. The main pathogenic factors are free radical mediators. Prevalence of pulmonary involvement is approximately 42.5%. The most common complaints are cough and dyspnea. Major respiratory complications are chronic obstructive pulmonary disease, bronchiectasis, and asthma. Spirometry results can reveal restrictive and obstructive pulmonary disease. Plain chest X-ray does not help in about 50% of lung diseases. High-resolution CT of the lung is the best modality for diagnostic assessment of parenchymal lung and bronchi. There is no definite curative treatment for mustard lung. The effective treatment regimens consist of oxygen administration, use of vaporized moist air, respiratory physiotherapy, administration of mucolytic agents, bronchodilators, corticosteroids, and long-acting beta-2 agonists, antioxidants, surfactant, magnesium ions, therapeutic bronchoscopy, laser therapy, placement of respiratory stents, early tracheostomy in laryngospasm, and ultimately lung transplantation. High-resolution CT of the lung is the most accurate modality for the evaluation of the lung parenchyma and bronchi. The treatment efficacy of patients exposed to mustard gas depends on patient conditions (acute or chronic, upper or lower respiratory tract involvement). There are various treatment protocols, but unfortunately none of them is definitely curable.     

Hypertonic saline-dextran resuscitation of acute canine bile-induced pancreatitis

In this study, we examined the effects of hypertonic saline-dextran resuscitation (2,400 mOsm of sodium chloride, 6 percent dextran 70) on cardiopulmonary function and extravascular lung water in acute canine pancreatitis. Acute pancreatitis was induced in 21 dogs by injecting 0.5 ml/kg of autologous bile into the pancreatic duct. In 10 dogs, resuscitation was begun with a 4 ml/kg bolus of hypertonic saline-dextran solution; 11 dogs received no bolus. Lactated Ringer's solution was infused in all dogs to maintain mean arterial pressure and cardiac output at baseline values. Pulmonary hypertension accompanied by a significant increase in pulmonary vascular resistance and a decrease in lung blood flow occurred in those dogs resuscitated with lactated Ringer's solution alone. By contrast, dogs in the hypertonic saline-dextran group maintained pulmonary artery pressure and pulmonary vascular resistance at baseline values while nutritive blood flow to the lung decreased progressively. Our data suggest that hypertonic saline-dextran resuscitation effectively restores cardiac function while it significantly reduces fluid requirements, as well as the pulmonary hypertension and pulmonary edema that frequently accompany lactated Ringer's resuscitation of acute pancreatitis.     

Long-term effects of mustard gas on respiratory system of Iranian veterans after Iraq-Iran war: a review

To review long-term respiratory effects of mustard gas on Iranian veterans having undergone IraqIran war. Electronic databases of Scopus, Medline, ISI, IranMedex, and Irandoc sites were searched. We accepted articles published in scientific journals as a quality criterion. The main pathogenic factors are free radical mediators. Prevalence of pulmonaryinvolvement is approximately42.5%. The most common complaints are cough and dyspnea. Major respiratory complications are chronic obstructive pulmonary disease, bronchiectasis, and asthma. Spirometry results can reveal restrictive and obstructive pulmonary disease. Plain chest X-ray does not help in about 50% of lung diseases. High-resolution CT of the lung is the best modality for diagnostic assessment of parenchymal lung and bronchi. There is no definite curative treatment for mustard lung. The effective treatment regimens consist of oxygen administration, use of vaporized moist air, respiratory physiotherapy, administration of mucolytic agents, bronchodilators, corticosteroids, and long-acting beta-2 agonists, antioxidants, surfactant, magnesium ions, therapeutic bronchoscopy, laser therapy, placement of respiratory stents, early tracheostomy in laryngospasm, and ultimately lung transplantation. High-resolution CT of the lung is the most accurate modality for the evaluation of the lung parenchyma and bronchi. The treatment efficacy of patients exposed to mustard gas depends on patient conditions (acute or chronic, upper or lower respiratory tract involvement). There are various treatment protocols, but unfortunately none of them is definitely curable.     

Cardiopulmonary bypass reduces pulmonary surfactant activity in infants.

OBJECTIVE: Infants younger than 1 year of age undergoing cardiopulmonary bypass surgery often have severe lung injury necessitating increased postoperative respiratory mechanical support. Inasmuch as the mechanisms may involve an impairment of the pulmonary surfactant system, our aim was to determine whether changes of surfactant occur in such infants. METHODS: From the day of the operation to day 7 after the operation, serial tracheobronchial small-volume lavages of 19 infants (aged 166 +/- 29 days) were fractionated into a small and a large surfactant aggregate fraction and compared with those of 13 infants without lung disease (aged 203 +/- 33 days). RESULTS: After cardiac operations with cardiopulmonary bypass surgery, total protein in lavages was increased 3-fold to 4-fold and decreased linearly with time. Surfactant protein A was increased on day 1 and day 2 and then decreased, whereas surfactant protein B and total phospholipids were increased on day 1. The ratio of phospholipids in small and large surfactant fractions was unchanged, but the surface activity of the large-aggregate surfactant was impaired on days 1 to 3. CONCLUSIONS: Lung injury in infants after cardiopulmonary bypass surgery involves significant biochemical and functional disturbances of the pulmonary surfactant system. Inasmuch as substitution with natural surfactant might correct these deficiencies, the potential of this approach to reduce postoperative morbidity needs to be investigated.     

肺表面活性物质治疗新生儿呼吸窘迫综合征疗效观察

目的 观察肺PS治疗新生儿呼吸窘迫综合征的疗效.方法 对笔者所在医院新生儿特护病房收住的22例新生儿呼吸窘迫综合征患儿使用PS,观察其治疗后的临床反应、血气变化及胸片肺透亮度的变化情况.结果应用PS后,可发现患儿皮肤迅速转红,血氧饱和度上升,不进行机械通气的患儿呻吟、气促情况缓解,呼吸困难、三凹征、紫绀症状减轻或消失 辅助机械通气的患儿用药后30min均下调呼吸机参数,生命体征监测平稳,6～12h复查胸片,肺透亮度明显好转.用药前与用药后2h查血气,pH、PCO2、PO2均有显著差异.结论 使用外源性PS替代疗法治疗新生儿呼吸窘迫综合征,减少了NRDS的发病率及疾病的严重程度,降低了呼吸机使用条件,降低了病死率,疗效较好.     

Pharmacologic strategies in acute respiratory distress syndrome

Treatment of the acute respiratory distress syndrome includes both supportive measures and correction of the underlying cause. Various pharmacological interventions have been proposed to limit the severity of lung injury and enhance the healing process, including exogenous surfactant, inhaled vasodilators (mainly nitric oxide), corticosteroids, prostaglandin E1, antioxidants (N-acetylcysteine), ketoconazole and other substances. Some of these interventions are administered via the airways, for example inhaled nitric oxide or liquid ventilation with perfluorocarbons. Some have beneficial effects on surrogate end-points such as pulmonary gas exchange. However, in large prospective trials none of these pharmacological approaches have resulted in significantly improved survival in acute respiratory distress syndrome patients.     

Surfactant inactivation and surfactant replacement in experimental models of ARDS

Lung structure and function, and the effect of surfactant replacement, were studied in three animal models of adult respiratory distress syndrome (ARDS): surfactant depletion by repeated lung lavage, proteinaceous pulmonary edema induced by prolonged exposure to hyperoxia, and inoculation with hybridoma making an antibody to the hydrophobic surfactant-associated protein, SP-B. Surfactant replacement therapy restored normal gas exchange in respiratory failure induced by repeated lung lavage but was ineffective in animals with severe lung parenchymal lesions induced by hyperoxia or antibody to SP-B. Lung edema fluid from animals exposed to hyperoxia inhibited surfactant function in a concentration-dependent manner. These observations indicate that, in experimental ARDS, the effect of surfactant replacement depends on the type of animal model and, especially, on the degree of lung injury present at the time of therapy.     

The pathogenesis of pulmonary edema in acute pancreatitis.

Acute pulmonary edema appeared 3 or more days after the onset of acute pancreatitis in 7 patients, an approximate incidence of 8%. The severity of pancreatitis in these patients was characterized by massive requirements for intravenous colloid and by marked hypocalcemia. In addition, at least 5 of the 7 patients had very high serum levels of triglycerides at the time of hospital admission. Hemodynamic studies during pulmonary edema showed normal central venous pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, and pulmonary vascular resistance. Cardiac index was appropriately elevated. Respiratory treatment, consisting of endotracheal intubation and controlled ventilation with PEEP, was successful in allowing reversal of the pulmonary injury and recovery of respiratory function within 1-2 weeks in all cases. Two patients died later from pancreatic abscesses. The findings indicate that a distinct form of pulmonary injury may occur in acute pancreatitis, characterized by loss of integrity of the alveolar-capilllary membrane, leading to pulmonary edema. The mechanism of injury is not known but may be caused by circulating free fatty acids, phospholipase A, or vasoactive substances. The pulmonary membrane lesion appears to heal during the period of intensive respiratory support.     

Atelectasis--an unusual and late complication of lung transplant

We report a previously unrecognized late complication of allograft lung transplantation - persistent recurrent atelectasis of the transplanted lung. The patient developed sudden, severe respiratory distress about 2 yr after a right lung transplant, because of acute atelectasis of her transplanted lung. Multiple transbronchial biopsies at the time revealed minimal inflammation and no evidence of rejection. She was treated with surfactant replacement therapy, and her collapsed lung fully expanded following surfactant installation. To eliminate the possibility of acquired deficiency of surfactant lipids or proteins, ultrastructural examination and immunostains for surfactant proteins were performed in a transbronchial lung biopsy. No deficiency of surfactant lipids or proteins was found. On ultrastructural examination of the lung biopsy, the number of Type II cells per alveolus and the number of lamellar bodies per square micron of Type II cell cross-sectional area was increased compared with an age-matched control. We conclude that synthesis of surfactant lipids and proteins was unimpaired and because of the patient's response to surfactant replacement therapy, that the increase in number of lamellar bodies could reflect a compensatory mechanism for a surfactant functional defect. The patient later developed breast carcinoma to which she succumbed. We raise the possibility that the functional surfactant defect is a hitherto unrecognized non-metastatic manifestation of malignancy.