Prolonged Irritation Research Articles

Review : Laboratory Studies in the Prediction of Lung Cancer Risk

The value of studies involving the exposure of laboratory animals by the inha lation route in research aimed at identifying agents which might pose a risk of respiratory tract cancer in humans is reviewed. Among the problems encoun tered are: anatomical differences between species which affect aerodynamics; the higher efficiency of the rodent nose in removing particles before the air stream reaches the lungs; difficulties in imitating human exposure conditions while at the same time avoiding the absorption of test chemicals through the skin; the fact that prolonged irritation of respiratory tract epithelium by non genotoxic agents - if it causes necrosis followed by regenerative hyperplasia- can lead non-specifically to cancer development; and a tendency of mice of many strains to develop adenomatous tumours of the lung despite no deliber ate exposure to any known carcinogens. The value of laboratory rodents in relation to lung cancer risk from bis(chloromethyl) ether, cadmium, nickel, chromium, tobacco smoke, asbestos and other fibrous dusts, and general industrial air pollution is discussed in the light of the above considerations.

Exostoses of the external auditory canal.

Exostosis of the external ear canal is a disease unique to man. It has been identified in prehistoric man, affecting the aborigines of the North American continent. Aural exostoses are typically firm, sessile, multinodular bony masses which arise from the tympanic ring of the bony portion of the external auditory canal. These growths develop subsequent to prolonged irritation of the canal. The large, primitive jaw of prehistoric man placed great mechanical stress on the tympanic ring. Chronic aural suppuration seen in the preantibiotic era was soon followed by exostoses. Today, prolonged contact of the external ear canal with cold sea water is the most prevalent cause (aquatic theory). As a result the disease is now essentially limited to coastal regions. In this way we have seen exostoses appear in different stages of the evolution of man as a result of mechanical, chemical and now thermal irritation. The author is an otolaryngologist in a coastal region. In examining 11,000 patients during a ten-year period, 70 cases of symptomatic exostoses of the external auditory canal were identified. The incidence of exostoses was found to be 6.36 per 1,000 patients examined for otolaryngologic disease. It is a predominantly male disease. The development of these "irritation nodules" is painless until the tenth year of aquatic exposure to irritation, when symptoms of obstruction occur. The hearing loss associated with exostoses is usually a conductive type, secondary to occlusion of the canal by impacted cerumen or acute external otitis. The results of studying the thermal characteristics of the body of water used for such aquatic activities is presented.

Sleep cycle in rats with paroxysmal foci.

The present paper is an attempt to disclose further the changes occurring in the sleep cycle's phases following the implantation of cobalt epileptogenic foci into the intralaminary nuclei of the thalamus and the dorsal hippocampus.The effect of these epileptogenic foci upon the alternance and duration of the sleep cycle phases was studied and a statistically significant shortening of the telencephalic phase of sleep was observed. The rhombencephalic phase of sleep showed none or only a relatively minor shortening. The alternance of the sleep phases did not change as compared with normal or control animals. These effects are discussed in the light of an opposite effect obtained by prolonged irritation of mesencephalic activating structures.

Stimulation of the mechanoreceptors of the intestinal wall as a cause of dynamic intestinal obstruction

As demonstrated in chronic experiments on dogs, prolonged irritation of mechanoceptors of the intestinal wall caused development of dynamic intestinal obstruction. Inhibition of the motor function is accompanied by a characteristic triad — vomiting, anorexia and depression.

Leukoplakia of the renal pelvis

A case of leukoplakia of the renal pelvis is presented. The cause of this lesion is obscure, although it probably represents squamous metaplasia as a result of prolonged irritation and infection. The importance of attempting to discover its presence whenever possible is emphasized by the fact that it may be a precursor of malignant change.

CANCER BIOLOGY: VIRAL AND EPIGENETIC*

CANCER BIOLOGY: VIRAL AND EPIGENETIC*

Carcinoma of the Esophagus in Association with Achalasia of the Cardia

Prolonged irritation of the skin or mucous membrane has been accepted as an important exciting factor in the etiology of cancer. Yet, there are many conditions in which such irritation (chemical, thermal, bacterial, or traumatic) has existed for a long period without evoking a new growth. One such example is so-called cardiospasm or, more properly, achalasia of the cardia. The term “achalasia,” meaning “without relaxation,” is preferable in that it calls attention to the essential functional abnormality. The name achalasia serves, furthermore, to distinguish this disease entity from the truly spastic states of the esophagus occurring in association with ulcers and diverticula of its cardiac end or as a reflex mechanism when disease is present elsewhere in the gastro-intestinal tract. The term “cardiospasm” might be reserved for these latter conditions. Since neither the exciting agent nor the neuropathology of the disease entity under consideration has yet been established, one should stick to the characteristic demonstrable finding, namely achalasia. The constant irritation of stagnating food and saliva in the esophagus might be expected to be of sufficient degree and duration to be carcinogenic. Rake (1), indeed, describes the sequence of events as irritation by the products of stagnation → ulcerations of the mucosa → attempts at repair → islands of epithelial hyperplasia → papillomatous formation → malignant growth. It is on the basis of such a scheme of pathogenesis that he explains the high incidence of carcinoma in achalasia of the esophagus. In his series of 15 cases he found 3 patients with carcinoma. Similarly, Gottstein (2) urges early treatment because “experience has taught us that, aside from their suffering, the patients are subject to certain dangers.” He then cites 3 cases of carcinoma encountered among 33 patients suffering from achalasia. In sharp contradistinction to these series, showing an incidence of malignant change of 20 and 10 per cent, respectively, are the reports of 301 cases of achalasia by Plummer and Vinson (3) and later of 683 cases by Vinson (4) without any mention of an associated or complicating carcinoma. Walton (5), in his discussion of the surgical treatment of achalasia, asserts that carcinoma appears to be rare. Kornblum and Fisher (6) have recently reviewed the subject and added 2 cases of their own. They, too, are of the impression that cancer is an unusual complication of achalasia. They say: “While we have not tabulated the actual number of cases of achalasia of the cardia that we have examined roentgenologically, our experience no doubt is similar to that of hundreds of other roentgenologists working in a large city hospital.” Between 1931 and 1942, inclusive, 227 patients with carcinoma of the esophagus were admitted to the Edward Hines Hospital, Hines, Ill. In only one of these cases was achalasia associated with carcinoma. The rarity of such an occurrence appears to warrant the report of that case.

EARLY CARCINOMA OF THE COLON

It is now generally agreed that a cancer represents the ultimate phase of a definite series of changes rather than a mere fortuitous incident in the life of the tissues, and, although the nature of these changes is not yet completely understood, it is known that they result from developmental change, from reaction to prolonged irritation or from unsuccessful attempts at tissue repair. Evidence giving support to this has been accumulated by investigators in three separate fields—experimental workers, pathologists and clinicians. EXPERIMENTAL WORK Experiments have been carried out chiefly on the so-called tar cancer in mice. Cramer,1by applying one of the known carcinogenic substances to the skin of mice, was able to produce typical epithelioma in these animals. He observed that the process is not continuous but is composed of two phases: (a) a process of long duration inducing in the cells a condition of potential malignancy which

Roentgen-Ray Treatment of Skin Cancer

CANCER of the skin usually begins in abnormal tissue, such as a wart fissure, old scar, thickened skin, and from prolonged irritation due to dirt, dust, or wind. It is frequently found in elderly patients whose skin is thickened and in those individuals who have led lives exposed to the weather, as well as in persons living in rural districts who seldom use warm water and soap for cleansing purposes. If these pre-cancerous lesions are cured, no carcinoma will develop. Cancer of the skin is very often ignored as it causes very little discomfort. It is an appalling fact that four thousand deaths occur in the United States each year from skin cancer. I have noted with surprise that in certain rural communities skin cancer is permitted to reach the advanced stage before medical aid is sought. This is partly due to ignorance on the part of the patient who does not realize the gravity of the condition. This type of patient will treat a skin lesion with ointments and salves. He has no way of knowing that the irritating effect of such treatment aggravates his lesion. A few years ago I saw a patient with one-half of his face eaten away with carcinoma before he even consulted a physician. The case was so far advanced that it was impossible to do anything for him. If such cases are treated early, from 95 to 98 per cent can be cured permanently. Chronic irritation is recognized as probably the most important factor in the stimulation of abnormal cell growth. As the proliferation continues, the vitality of the part decreases and in the older center cells necroses and ulceration are produced. Ninety per cent of skin cancers develop on the face, neck, and hands. Areas not protected by clothing are especially vulnerable. About two-thirds are basal-cell type and one-third are squamous-cell carcinoma. Basal-cellcancer usually occurs in persons beyond middle age. It may begin as a papillomatous lesion, the so-called rodent ulcer which is slow in destruction of the surrounding tissues. The characteristic lesion is ulcerative, with a raised pearly border, and is common on the face, especially above the lip line. However, it may occur on the neck, arms, back, chest, legs, buttocks, and perineum. Basal-cell cancers seldom metastasize, but if they are of long standing, may develop to such an extent as to become incurable. Squamous-cell carcinoma is differentiated from the basal-cell carcinoma in that it forms prickle cells and epithelial cells with protoplasmic processes between them. There is a mixed cell type which has some basal and some squamous cells, which occurs in a small percentage of the cases. One method of grading malignancy of the skin cancer is based on the number of malignant cells or the amount of tumor cells as they approach the normal. As a rule, the more embryonic or lower cells present in the tumor or specimen, the quicker the response to radiation.

Two cases of bone formation in the postoperative scar of the abdominal wall

Histogenetically similar cells can sometimes undergo metaplasia under the influence of little-known reasons. In some cases, the transformation of one type of tissue into another occurs for no apparent reason, such as in various kinds of mixed tumors; in other cases, we observe the phenomenon of metaplasia in chronic tissue irritation (Podvysotsky). Our cases of ossification of the postoperative scars of the abdominal wall and can be interpreted in terms of prolonged irritation of the connective tissue of the aponeurosis of the abdominal muscles with silk sutures, for which, to a certain extent, the shape of the bone formations speaks.

The Action of Lipoid Solvents on the Organism and in the Production of Cancer

The study of the action of coal tar on the organism has been of interest not only from the light it has thrown on the cause of cancer, but also on the general action of fats in the organism, their storage, the general toxic effects an excess of certain of them may cause, and the nature of vitamins. Oils of various kinds have been used for centuries as curative agents in wounds and other diseases. The general action of these substances on the organism has never been explained. Clinical cases of cancer among chimney sweeps, workers in pitch, tar, etc., have been recorded since the original description by Potts (1). This as well as later observations stimulated a great amount of research into the causative factors of this condition. By painting crude coal tar on the skin at repeated intervals over a period of time a number of investigators have produced cancer in various parts of the body of animals. Many of these have been true cancers as they have been transplanted from generation to generation and the malignant proliferation has persisted for a long time after the coal tar painting has been stopped. Separation of the crude coal tar into its various substances has disproved the presence of a specific carcinogenic agent. Kennaway (2) showed definitely that it was the higher boiling fractions, the more viscid substances that produced cancer when painted on the skin of the laboratory animal. When my studies with coal tar were begun in 1923, no light had been thrown on the manner in which this substance produced the malignant change. Coal tar and other lipoid solvents had become considered to act merely as irritants; the cells underwent malignant transformation as a result of the prolonged irritation. Yamagiwa and Ichikawa (3) had appreciated that a single application of tar produced degeneration of cells and hyalinization of tissue and that repeated applications were necessary for the production of cancer.

ROENTGENOGRAPHY AND THERAPY WITH IODIZED OILS

Two proprietary iodine-oil compounds, lipiodol and iodipin, extensively used in recent years for roentgenography and therapy, are now known to produce two harmful effects which restrict their usefulness: first, because, virtually nonabsorbable, they may remain in the tissues for indefinite periods, for two years in one instance; and, second, they may cause by prolonged contact irritation and cicatrix formation.1 We have studied the therapeutic effects of these and other iodized oils after injection into the seminal ducts through vasotomy, usually bilateral, in sixty-seven men, with immediate roentgenograms in all; the viscosity of lipiodol and iodipin renders the filling of the vesicles difficult and at times incomplete (fig. 3). The failure of absorption, observed by others in various tissues, is shown in the persistence of lipiodol in the vesicles and in the connective tissue at the internal inguinal ring (Bogros' space), into which it was intentionally injected by way of

Types of Cysticercus Tumors

In October, 1919, the present authors (1) instituted a method of producing tumors of the liver of rats experimentally by employing Cysticercus fasciolaris , the larva of the cat tapeworm, Tenia crassicollis , as the agent of irritation. Infestation of the rat occurred through the natural channels following the oral administration of cat feces containing the eggs of this Tenia. From the beginning of the experiment to July 1, 1925, 1,400 rats have developed Cysticercus tumors of the liver, varying in size from microscopic growths in the cyst walls to massive neoplasms which largely replaced the liver or hung pendant from one of its lobes. The cysts from which the larger tumors originated were generally either buried to varying depths in the tumor substance or projected from the surfaces of the growths. Occasionally the cyst cavity was completely obliterated by an ingrowth of tumor tissue. The tumors were generally confined to a single cyst, although multiple primary tumors involving two or more cysts were fairly numerous. Metastasis formation was a common accompaniment of tumor growth and nearly all the large tumors produced generalized peritoneal metastasis. Sometimes the thoracic viscera and mediastinal lymph nodes showed metastatic tumor deposits. This experiment was a striking demonstration of the predisposition to neoplastic transformation of the mesoblastic tissues of the rat's liver in the presence of prolonged irritation. All the Cysticercus tumors which arose in the 1,400 rats were of mesothelial origin and all except one, a chondroma, were malignant. The liver cells, on the contrary, showed no tendency toward tumor formation and little or no proliferative activity except in the early stages of larval development during the formaation of the cyst wall. The apparent passivity of these cells to the irritation induced by older larvae may be due to a protective action of the cyst walls which are interposed between them and the organisms.

Tuberculous infection and tuberculosis as modified by experimental pneumonokoniosis

Tuberculous infection and tuberculosis as modified by experimental pneumonokoniosis

THE DIAGNOSIS AND TREATMENT OF CHOLELITHIASIS.

An early diagnosis of cholelithiasis is important for the welfare of the patient. When we consider the complications and sequelae that may arise after prolonged irritation from the presence of gall-stones in the bladder or ducts, this becomes more apparent. These complications may be septicemia, ulceration of the gall-bladder and ducts, permitting the calculi to escape into the adjoining viscera, derangement of the liver from obstruction or abscess, cancer from irritation, obstruction of the pylorus, various nervous phenomena, and general debility. Unfortunately there are no pathognomonic symptoms in the early stages that serve to make a positive diagnosis. From a careful study of 20 cases coming under my notice in the last few years, of which full clinical records are made, I have been able to make some deductions that may prove interesting and valuable to the profession. My records show quite a number of other cases in which the

THE IMPORTANCE OF EARLY OPERATION IN GALL-STONES.

It is well established that there is no more valuable life and health conserving operation than the removal of an offending appendix in the period of health. The analogy between the appendix and the gall-bladder is in many ways striking, but it is not perfect. The appendix always contains within itself elements of sepsis, which by their escape into the peritoneal cavity threaten life; the gall-bladder does not; its contents threaten life only when, after prolonged irritation, it has yielded to infections brought from more or less remote areas. The appendix often becomes completely infected without warning; the gall-bladder seldom does. The appendix often contains one or more fecal stones which, septic in themselves, cause ulceration of the mucous lining and give opportunity for direct infection from bacteria right at hand; the gall-bladder may also contain stones, but it is questionable whether they have within themselves bacteria capable of causing