Transoesophageal aortic velography in man. An ultrasonic probe placed in the oesophagus of anaesthetized patients was used to observe the velocity of the blood flow down the descending aorta. The operating principle of the technique was the Doppler shift of the reflection of a continuously emitted MHz beam of ultrasound. The human oesophagus took up to 15 minutes to accommodate to the presence of the probe in the oesophagus. Changes in the diastolic portion of the flow pattern were seen with small changes in peripheral resistance (produced by transiently obstructing a femoral popliteal by-pass graft) (Figure 1). Surgical stimuli also produced marked changes in the flow pattern (Figure 3) before arrhythmias occurred. Following a prolonged period of cardiac arrest the flow pattern was observed to return to normal very quickly (Figure 4). It is suggested that the ultrasonic trans-oesophageal probe could play a useful role in patient monitoring in anaesthesia.


Some pharmacological properties of althesin (CT1341) in man. Althesin in dose ranges of 40, 60 and 80 mul/Kg was administered to six healthy unpremedicated volunteers according to a balanced incomplete block design. Both subjective and objective changes resulting from the administration of the agent were studied and analyzed. In the dose ranges used, Althesin was found to have no deleterious effects on heart rate, respiratory rate or blood pressure and apnoea only occurred in one patient who had an end-expiratory CO2 level lower than normal, due to preanaesthetic hyperventilation. The onset of sleep is prolonged with Althesin at the injection rate of 1 ml/10 secs. The onset of anaesthesia is not influenced by the total dose, but the sleep time is directly proportional to the dose injected. Auditory evoked responses tended to lie on a curve which might indicate that with increasing dose the time to reappearance of these responses is not correspondingly prolonged. However, this last observation must be confirmed by studies on a larger scale.


Anaesthetic complications in surgical out-patients. This study reports retrospectively the post-anaesthetic complications in surgical out-patients. We have studied the incidence and severity of these complications during the first five post-operative days in 500 female patients who underwent tubal ligation by laparoscopy. The report shows that post-anaesthetic complications in surgical out-patients are frequent but of mild severity. Although they produced some discomfort for the patients most of them were of the opinion that the advantages of having the operation as out-patients made up for the discomfort.


A rapid and sensitive auxin binding system for detecting N6-substituted adenines, and some urea and thiourea derivatives, that show cytokinin activity in cell division tests. A selective, sensitive and rapid (2 min or less) method for detecting compounds with potential for cytokinin activity is described. The method does not measure cytokinesis; instead, it determines the ability of cytokinin-active agents to (i) activate the intake of either L-tryptophan or indoleacetic acid by germinated spores of the water-mould Achlya, while inhibiting the energy-dependent transport of all L-amino acids usually found in proteins; (ii) inhibit the energy-dependent transport of nucleosides and sugars by the same organism. The compounds with cytokinin activity generally activate auxin (tryptophan) intake at 10(-8) M or greater and inhibit at 10(-6) M or greater. The most effective activating compounds were N6-(delta2-isopentenyl)adenine, N6-benzyladenine. N6-furfuryladenine, and N6-(trans-hydroxy-3-methyl-but-2-enyl)adenine. These compounds are classed generally as cytokinins in plant growth studies. A cell membrane - localized glycopeptide of molecular weight 6000 was isolated from this organism and shown to be the site at which cytokinins, auxin, and tryptophan bind. An earlier study had also established that calcium ions bind to this entity as well. Tryptophan binding to the glycopeptide was enhanced by cytokinins, suggesting that this may be the way in which whole cells display enhanced tryptophan binding in the bioassay. On the other hand, calcium binding was antagonized by cytokinin. The results suggest that this may be an important experimental system for use in studying one possible way in which cytokinin may regulate plant growth.


Partial characterization of a histone acetyltransferase from trout testis. Histone acetyltransferase activity of trout testis was studied both in intact nuclei, and in high salt nuclear extracts. With intact nuclei, the distribution of incorporated [14C]acetate in the various histones was similar to that observed in vivo; the arginine-rich histones H3 and H4 showed the highest specific activities, and lower amounts of label were detected in histones H2a and H2b. Histone H1 incorporated little or no label. Acetyltransferase activity could be detected in purified, sheared chromatin after the addition of MgCl2 or KCl, suggesting that the enzyme is bound to chromatin. Treatment of nuclei with 0.4 M NaCl caused the dissociation of acetyltransferase activity. Most of this solubilized activity failed to bind to DEAE Sephadex and behaved as a high molecular weight heterogeneous complex on Sephadex G-100, suggesting that the enzyme is present as an aggregate with other proteins in the extract. The pH optimum of this preparation was approximately 8.5, and the enzyme showed a preference for histones H3 and H4 as substrates.


Studies on the fatty acid binding proteins in cytosol of rat liver. Gel filtration on Sephadex G-75 of crude rat liver supernatant preincubated with [1-14C]oleic acid yields three peaks of radioactivity which are attributed to the presence in these fractions of fatty acid binding proteins. We have confirmed these observations with binding assays by phase partition, polyacrylamide gel electrophoresis, and thin layer electrofocusing. Peak I (mol. wt. 60,000 pI 5.01 was shown to be albumin, which mainly arises from a contamination of the liver preparation by blood. Peak II (mol. wt. 10,000, pI 5.9) is a fatty acid binding protein. Finally peak III (mol. wt. 1500, pI 5.7) is a fatty acid binding component, the chemical nature of which was not elucidated. These fatty acid binding fractions have no effect on the reaction of acyl-CoA synthetase whereas the crude liver supernatant does stimulate the activation of fatty acid as shown earlier. In consequence, the physiological role of these fatty acid binding fractions is not yet elucidated.


Epidemiologic features of cerebrovascular disease in Manitoba: incidence by age, sex and residence, with etiologic implications. To determine the incidence of and risk factors in cerebrovascular disease in Manitoba, all 1367 new cases in defined areas (population, 660 391) in an 18-month period were studied. Pertinent data were collected from hospital records, death certificates and autopsy reports. The annual incidence of cerebrovascular disease in these areas was 138/100 000 and the incidence was generally higher in men than in women. The incidence of cerebral infarction (INF) and that of hemorrhage (HGE) were similar in men and women less than 50 years old; thereafter the incidence of INF increased faster with age than did that of HGE, the disparity being greater in men than in women, whereas the incidence of HGE increased at similar rates in the two sexes. The incidence of INF was significantly greater in men than in women in urban areas, and in men it was greater in urban than in rural areas. Elevated concentrations of serum lipids and smoking are implicated as risk factors in INF, and hypertension as a risk factor in HGE.


An Ontario solution to medically underserviced areas: evaluation of an ongoing program. In 1969 a program was established to place physicians in area of Ontario deemed to be medically underserviced. The main features of the program are area designation, physician subsidies, student bursaries, community participation and physician recruitment. From 1969 to March 1973, 162 communities were designated as underserviced and 196 physicians placed. As the program became active the rate of increase of numbers of  physicians practising in northern rural areas (population, less than 15 000) increased sharply, exceeding that for the entire province. Fifty-three percent of bursaried students have honoured their commitment. Seventy-five communities have built modern medical centres that have been an important factor in attracting physicians. Still unanswered are whether the physicians will stay and whether the health of the population will be improved.


Poisoning and poison control centres in Canada. Poisoning is a major and increasing health problem in the Western world. In 1972 the 310 poison control centres in Canada reported 53 531 enquiries about poisoning, 40% in adults. In 1964 the numbers of hospital admissions and deaths due to poisoning in this country were 2446 and 38, respectively, but in 1972 the figures were 6263 and 319, respectively. Most of the hospitalizations and deaths were among adults. Of 100 Canadian poison control centres two thirds were staffed by "any nurse in the emergency room", most of whom had received no training to answer the phone enquiries. However, two thirds agreed a training program is needed. Only 6.7% of 223 parents surveyed stated they would call a poison control centre if their child had accidentally swallowed a large amount of a  poisonous substance. Regionalization of centres, a training program for personnel answering telephone enquiries, the need for crisis intervention as part of poison control programs, and public education about poisoning and poison control centres are the new challenges facing those providing health services.


Correction of severe facial deformity.

Correction of severe facial deformity. A craniofacial team has been developed to corrdinate the treatment of patients with severe facial deformity and to minimize the surgical risks. Two hundred patients have been evaluated in the last 4 years and more than 100 treated by this team to correct orbital hypertelorism, oxycephaly and plagiocephaly with exophthalmos, features of Crouzon's disease and Apert's and Treacher Collins syndromes, hemifacial microsomia, and severe lower facial deformity and malocclusion. Surgical principles include extensive subperiosteal stripping of bone, osteotomy as necessary, and repositioning maintained by bone grafts. Postoperative evaluation is being maintained for 5 years or to maturity in younger children. Although many of the results are less than perfect, there has been sufficient improvement, especially psychologic and functional, to warrant continuation of the surgical program under closely controlled conditions.


Experience with Yersinia enterocolitica at The Hospital for Sick Children, 1972-74. Thirty-six cases of Yersinia enterocolitica infection were detected in the years 1972-74. The form of the illness in young children was acute gastroenteritis and in older children "appendicular syndrome". Improved isolation and identification techniques have increased the laboratory recognition of this enteric pathogen.


Cranial computed tomography in infants and children. Cranial computed tomography has been performed in adults for the past 2 years but relatively few children have undergone this procedure. The specific uses in children are in detecting intracranial mass lesions and identifying the character of the lesion, and evaluating congenital cranial diseases such as cerebral dysplasia, tuberous sclerosis and leukodystrophies. This safe, rapid, noninvasive technique will soon replace or supplement standard neuroradiologic techniques in infants and children.


Cystic fibrosis: present status and future prospects in detection of patients and carriers. Development of a sensitive, easily performed, reliable test would be an important advance in detecting cystic fibrosis, improving genetic counselling and providing early effective treatment. The sweat chloride test, which is reliable in diagnosis, is technically too difficult for a screening program, and only reliably detects homozygotes. In contrast, the meconium test for detecting homozygote newborns is simple, inexpensive, reasonably specific but its general application has yet to be evaluated. Detection of serum components is the basis of two new tests to distinguish patients with cystic fibrosis and carriers. The effect of these serum components on ciliary activity is the principle of one test, an extremely difficult procedure that is subjective and lacks sufficient specificity for routine use. The second test, in which serum components are separated by isoelectric focusing, may provide an objective biochemical means of detecting both homozygotes and heterozygotes.


Breast cancer report.

Breast cancer report. The recent increased public awareness of the necessity for early diagnosis of breast cancer has been accentuated by an intense exposure by the news media centering about the disease. This publicity includes the unfortunate but timely clinical sources of the wives of the President and the Vice President of the United States, Mrs. G.F. Ford and Mrs. N.A. Rockefeller. This paper attempts to quantitate in a subjective manner the impact of the events on the American public by comparing the incidence of operative procedures in similar populations in the Nashville community during October through December, 1973, and October through December, 1974, the latter period following the operative procedures upon Mrs. Ford and Mrs. Rockefeller. A statistically significant increase was noted in patients seen, biopsies performed, and cancers detected.


Combination chemotherapy in metastatic carcinoma of the breast. Results with a three-drug combination. Forty-two patients with Stage IV carcinoma of the breast were treated with an oral program of combination chemotherapy consisting of three drugs: methotrexate, 5-fluorouracil, and cyclophosphamide (substituting 1, 3-bis (2-chloroethyl)-1-nitrosourea in cases with central nervous system involvement). Sixty-four percent of the patients responded to the therapy, with a mean and a median duration of remission of 10.7 and 10.0 months, and a mean and median survival of 12.3 and 13 months. This therapeutic program is equally effective for pre- and postmenopausal patients and does not appear to be influenced by prior response to hormonal manipulation, single or combination drug therapy, or duration of disease. The results are comparable to those shown by previous authors. Toxicity in this group, however, was minimal, and patient acceptance excellent.


Single and combination chemotherapy for primary murine bladder cancer. Single and combination chemotherapy was evaluated for antitumor activity against N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide (FANFT)-induced bladder carcinoma in syngeneic mice. Two hundred fifty C3H/He mice having ingested FANFT for 10 months were randomly divided into groups of 30, and the following regimens initiated: cyclophosphamide (Cy), cis-diam-minedichloroplatinum (cis-Pt-II), dactinomycin, adriamycin, Cy plus cis-Pt-II, Cy plus 5-fluorouracil, and Cy plus adriamycin. The drugs were administered for 3 weeks. Each regimen was capable of producing a significant reduction in the mean bladder weight (MBW) when compared to a groups not receiving therapy (108.3 mg). Adriamycin (MBW equal 69.5), dactinomycin (49.6), and cyclophosphamide (42.9) were the best single agents, but the greatest inhibition of tumor growth was achieved by the combination of cyclophosphamide with 5-fluorouracil (38.3) or adriamycin (37.3). These combination chemotherapeutic regimens were able to effect a significant reduction in the number of bladders with Stage C tumors. It is hoped that information gained from this new animal model which allows evaluation of many antitumor drugs within a relatively short period of time will lead to therapeutic trials in patients with locally advanced or metastatic bladder cancer.


Interrupted vs. continued maintenance therapy in childhood acute leukemia. A total of 313 patients with childhood acute leukemia received a combination of vincristine (2 mg/m2/week) and prednisone (60 mg/m2/day); 86% of 276 evaluable patients achieved a complete bone marrow remission in a median of 35 days. When a complete bone marrow remission was achieved, patients were randomized to one of three oral maintenance therapies: 6-mercaptopurine (6MP) (75 mg/m2/day), methotrexate (MTX) (25 mg/m2/twice weekly), or cyclophosphamide (CYC) (100 mg/m2/day). Patients receiving maintenance therapy were further randomized at 2 and 6 months after the start of maintenance either to continue or discontinue therapy. tthe median lengths of subsequent bone marrow remission for patients randomized at 2 months to continue vs. discontinue therapy were: 37 vs. 19 weeks for 6-MP patients; 25 vs. 14 weeks for MTX patients; and 29 vs. 13 weeks for CYC patients. The median lengths of subsequent marrow remissions for patients receiving maintenance therapy for 6 months and randomized to continue vs. discontinue were: 57 vs. 17 weeks for 6-MP patients; 60 vs. 40 weeks for MTX patients; and 23 vs. 10 weeks for CYC patients. Results indicate a significant advantage for continuing maintenance therapy at 2 and 6 months after the start of complete bone marrow remission.


Delayed hypersensitivity in patients treated by curative radiotherapy. Its relation to tumor response and short-term survival. Delayed hypersensitivity, as determined by skin reactivity to 2-4 dinitrochlorobenzene (DNCB), was tested in 112 patients prior to their undergoing curative radiotherapy. Of the strong DNCB reactors, 84% had an excellent radiation tumor response, while only 48% of the negative reactors had an equivalent response. Almost twice as many strong DNCB reactors were alive and free of disease (NED) at 6 months (70% vs. 38% for nonreactors). Similarly, the positive DNCB reactors had a median survival of 18 months, compared to 10 months for the nonreactors.


Incidence and sites of bone lesions detected by 99mTc-polyphosphate scans in patients with tumors. The value of bone scanning with 99mTc-polyphosphate was assessed in 186 patients with various types of tumors. The sensitivity of this technique was greater than that of metastatic roentgenographic series and the reported results of 85-Sr-bone scans, in the detection of osseous involvement by tumors. Three cases with normal bone scans and abnormal roentgenographic studies illustrated the necessity and complementary value of comparing bone scan findings with radiographic studies. Patients with carcinoma of the breast, lung, or prostate displayed characteristic patterns of bone involvement by their tumors. The importance of clinical information, including bone symptoms, antecedent bone disease, and serum calcium and alkaline phosphatase, was stressed in the detection and interpretation of bone scan abnormalities.


Six families prone to ovarian cancer.

Six families prone to ovarian cancer. Six families are presented with multiple cases of ovarian cancer, mainly serous cystadenocarcinoma. Three families had concomitant aggregation of breast cancer, suggesting genetic determinants common to both tumors. The exceptional cancer risk in these families prompted prophylactic oophorectomy in 14 asymptomatic women from four families. Review of the original microscopic sections from 8 women revealed that 3, representing two families, had abnormalities of ovarian surface epithelium and mesothelial tissue, which may be of etiologic significance and portend neoplastic changes. To enable early detection and prevention of ovarian cancer, new diagnostic techniques and etiologic studies should be applied whenever possible to high-risk families.


The urinary excretion of nucleosides of ribonucleic acid by patients with advanced cancer. By means of a sensitive and specific method utilizing gas-liquid chromatography, the excretion levels for three nucleosides, degradation minor base products of ribonucleic acid, primarily transfer ribonucleic acid, were determined in 24-hour urine specimens from over 200 patients with solid tumor malignancies. These nucleosides were N2,N2-dimethylguanosine, l-methylinosine, and pseudouridine. When compared to normal control values, elevated levels of these compounds were found for patients in each of several tumor types studied. Increases in pseudouridine excretion suggest increased tumor transfer ribonucleic acid turnover; in addition, for the methylated nucleosides, higher than normal values may reflect enhanced transfer ribonucleic acid methylase activity of the neoplastic cells.


Insular carcinoid primary in the ovary. A clinicopathologic analysis of 48 cases. Forty-eight cases of primary insular carcinoid of the ovary were analyzed from a clinicopathologic viewpoint. Sixteen (33%) were associated with preoperative clinical evidence of the carcinoid syndrome. At operation only one ovary was usually enlarged, but in 16% the contralateral ovary was also enlarged by either a dermoid cyst or a mucinous cystadenoma or cystadenocarcinoma. The volume of the carcinoid was the most important determinant of whether the carcinoid syndrome was present. No patient had the syndrome whose carcinoid formed only a small portion of a teratoma. Pure tumors or components of teratomas between 4 and 7 cm in diameter were associated with the syndrome in one-half, and larger carcinoids in two-third of the cases. Prominent acinar differentiation also correlated with the presence of the syndrome. Although the prognosis was nearly always favorable after the removal of the tumor, tricuspid valve damage continued to progress and led to cardiac decompensation in one patient; fatal recurrences developed in two others. The primary insular carcinoid should be distinguished from carcinoid metastatic to the ovary, which is nearly always bilateral, is usually associated with the presence of peritoneal metastases, and has a poor prognosis.


Malignant histiocytosis with massive splenomegaly in asymptomatic patients. A possible chronic form of the disease. Four patients with malignant histiocytosis (MH) are described whose initial manifestation of the disease was massive splenomegaly without associated systemic symptoms. The diagnosis of MH was made after histologic evaluation of splenectomy specimens. Splenomegaly in an otherwise asymptomatic patient is unusual for malignant histiocytosis, but when such a clinical picture is seen, it may be confused with other diseases that often present with massive splenomegaly and that have a similar diffuse infiltrative pattern in the spleen. Although three of these patients did eventually develop systemic symptoms characteristic of MH 3, 6, and 10 months after the detection of splenomegaly, the 15-month asymptomatic survival of one patient who received no chemotherapy suggests that MH presenting with massive splenomegaly, rather than with constitutional symptoms, may have a protracted course.


Primary fibrosarcoma of the liver. Case report and review of the literature. A case of primary fibrosarcoma of the liver occurring in a 51-year-old man is added to 11 previously published cases. The neoplasm was moderately differentiated and occurred in a cirrhotic liver. Review of the literature revealed this to be the 3rd case of fibrosarcoma associated with cirrhosis. In 4 additional cases of cirrhosis-associated fibrosarcoma, a coexistent primary carcinoma was present in a different part of the same liver.


Breast cancer in brothers: case reports and a review of 30 cases of male breast cancer. Two brothers with breast cancer are presented. One died 8 years after diagnosis and the other is presently living at 1 year with metastatic disease. The courses of 28 other previously unreported male patients with carcinoma of the breast are reviewed, and the possibility of male breast carcinoma being metastatic disease from the prostate is discussed. Useful etiologic information might be obtained from following the offspring of male breast cancer patients to see if they are at increased risk of developing the disease.


Long-term spontaneous regression of malignant melanoma with visceral metastases. Report of a case with immunologic profile. A case of a 58-year-old woman with viscerally metastatic malignant melanoma is presented 12 years after spontaneous and complete regression of disease. Diagnosis of primary and metastatic lesions was confirmed by review of tissue sections. The presence and subsequent absence of visceral metastases were documented by open liver biopsies. Sections of metastatic lesions revealed extensive necrosis of tumor and infiltration of lymphocytes and plasma cells. Skin testing showed a strongly positive delayed hypersensitivity response to dinitrochlorobenzene (DNCB), to a standard battery of bacterial and fungal antigens, and to two of four preparations of allogeneic melanoma antigens. Values for cell- and serum-mediated cytotoxicity against melanoma cells and the response of the patient's lymphocytes to phytohemagglutinin were slightly above the normal range. A review of the literature reveals 13 other cases of long-term spontaneous regression of melanoma. None of these, however, had biopsy evidence of visceral disease. In each of the 13 cases, regression was associated with an event that might be inferred to have altered the patient's hormonal or immune status. This patient also provides evidence of a complete, spontaneous, and long-term remission of metastatic disease associated with the spontaneous development of host immunity.


Further observations on carcinoma in situ of the urinary bladder: silent but extensive intraprostatic involvement. Of seven patients with carcinoma in situ of the urinary bladder in the absence of an associated papillary carcinoma, five were found to have silent but extensive intraductal prostatic involvement. In three of these the carcinoma in situ was associated with microinvasion. The mean age at the time of diagnosis was 68 years. All had symptoms characteristic of carcinoma in situ, including hematuria, dysuria, and urgency. In three patients the prostatic involvement was diagnosed on transurethral resection. In two it was discovered only after radical cystectomy. The prostatic involvement was neither suspected clinically nor has it been previously emphasized. Although three patients are alive, apparently free of disease up to 15 months postcystectomy, two have died, one of disease. The importance of prostatic assessment in the evaluation of the patient with carcinoma in situ of the urinary bladder is emphasized.


Studies concerning the regional lymph node in cancer. VIII. Effect of two asynchronous tumor foci on lymph node cell cytotoxicity. Results suggest that cytotoxicity by cells from nodes regional to a primary tumor is unique. While a primary tumor was present, A) cytotoxicity was displayed by cells from lymph nodes (RLNs) to that tumor, B) cells from nonregional lymph nodes regional (NRLNs) possessed lesser cytotoxicity which failed to increase in response to a second tumor focus in an area drained by those nodes, and C) the second focus attenuated cytotoxicity of cells from LNs regional to the primary tumor. Following removal of the primary tumor, cells from RLNs rapidly lost cytotoxicity and with passage of time were unable to regain that function in response to a second tumor focus. In contrast, cells from NRLNs demonstrated increased cytotoxicity at any time following removal of the primary tumor when exposed to a second focus. These observations suggest that nodes regional to a distant metastatic focus may be unable to react to it and thus contribute little to the host response generated by the primary tumor. In addition, since nodes regional to a primary tumor manifest diminished cytotoxicity in the presence of a distant tumor focus, tumor cells gaining access and lodging in those nodes subsequent to the development of other metastatic foci are likely to proliferate, resulting in the "positive" lymph node. The findings are in keeping with our contention that host factors responsible for metastases, and perhaps metastases themselves, are at least in part responsible for growth of tumor in RLNs. They also have relevance to the site of administration of specific immunotherapeutic agents and to the significance of the removal of RLNs with a primary tumor.


Papillary thyroid carcinoma in Denmark, 1943--1968. The material presented dates from a nationwide Cancer Registry, and covers all cases of papillary thyroid carcinoma (T.C.) diagnosed in Denmark from 1943 to 1968, including those based on postmortem examinations. Direct comparison with clinical data from hospitals elsewhere will therefore tend to show less favorable results. In general, Danish cases show a higher average age than those from American hospitals. For the younger age groups this may to some extent be explained by the fact that therapeutic x-irradiation of the thymus during childhood has never been practiced in Denmark. However, the later occurrence in life of Danish cases and the less favorable prognosis might suggest a failure to realize the malignant character of the lesion in the earlier part of its course, and a variable experience on the part of the surgeons and the variety of institutions from which the material was collected. The age-adjusted incidence rate, the mortality, and complications are discussed. It is concluded that the prognosis may be improved considerably by more extensive operations on the thyroid gland, avoiding complications such as paralysis of the recurrent laryngeal nerve and tetany. The surgical efforts should be supplemented with suppression of the TSH production. In the present retrospective study it was not possible to report 20- and 30-year survival rates. This is a task for the future, as is the planning of prospective studies which, in the case of a disease as rare as papillary T.C., should be established on an international basis.


Prognostic features of thyroid cancer. A long-term followup of 68 cases. Sixty-eight cases of thyroid cancer were followed for 10 to 38 years after diagnosis. A minimum followup period of 10 years was necessary because of the long natural history of low-grade thyroid carcinoma. The prognosis of the disease was evaluated with regard to several parameters: age, sex, histologic appearance of the tumor, extent of disease, and treatment. The best prognosis was found in women less than 40 years of age with papillary carcinoma in whom there was neither extrathyroid extension nor metastasis and who were treated by surgery alone. Extrathyroidal cancer in the neck treated by radical neck dissection had a 100% survival rate at 15 years postdiagnosis. The poorest prognosis was in male patients over 60 years of age with metastatic undifferentiated carcinoma.


Carcinoid tumors. An analysis of 2,837 cases. Two thousand eight hundred thirty-seven cases of carcinoid tumor from files at the National Cancer Institute were analyzed statistically. Tumors were found in the lung, ovary, and biliary and gastrointestinal tracts. Most were in the appendix, rectum, and ileum. Age-adjusted incidence rates were higher for black males, except for lung carcinoids. Carcinoids showed several differences from other kinds of tumor, including a low age for appendiceal and lung cases and low male/female and black/white ratios in the lung. Percentages of concurrent neoplasms and multiple carcinoids were low compared to other series. Five-year relative survival rates ranged from 99% (appendix) to 33% (sigmoid colon). Survival for colon cases was not so low as expected on the basis of the high rate of metastasis. Some appendiceal carcinoids were metastatic and may have killed 1 patient. Findings are compared with other studies.


Chondrosarcoma of the foot. A case report and review of the literature. Chondrosarcoma of the foot is a very unusual entity. A case arising from a solitary osteocartilagenous exostosis is presented and the literature is reviewed and discussed.


Metastases to the vertebral column.

Metastases to the vertebral column. Review of 643 autopsies revealed 374 cases of malignant neoplasms, of which 140 were found to have evidence of disease metastatic to the vertebral bodies of the thoracolumbar spine. A comparison is made of the proportion of cases detected by clinical radiographs antemortem vs. the cases of metastatic tumor of the spine detectable by radiographs of slabs of the spine and by histologic examination. A high degree of correlation was found between metastases detected by fine-detail radiography and those detected by microscopic examination. Thus, the incidence of neoplastic metastases to the thoracic and lumbar vertebral bodies is presented, and the reliability of fine-detail radiography is assessing the presence of neoplastic metastases at autopsy is indicated.


Primary retroperitoneal seminoma. Report of a case and review of the literature. A large retroperitoneal seminoma in a 42-year-old man is described, which appears to have arisen as a primary tumor at that site. The mechanism for the development of extragonadal germ cell tumors is discussed, and the criteria for their distinction from metastatic occult or regressed testicular neoplasms are re-emphasized. Awareness by clinicians of this entity may save individuals with this neoplasm from unnecessary orchiectomy.


Diffuse submucosal cysts and carcinoma of the stomach. Gastric submucosal cysts, carcinomas, and atypical hyperplasia have been observed in the superficial mucosa of 12 stomachs. It is thought that gastritis may give rise to these heterotopic glands, that the development of heterotopic cysts in the submucosa may make the surface mucosa prone to erosion, and that repeated erosion and regeneration may cause carcinoma or atypical hyperplasia.


Combining talents for the management of cancer patients. The combination of talents required to bring to all patients the maximum benefits of combined modality treatment is examined in the following steps: devising treatment strategy, carrying out treatment, extension widely to the community, and treatment research. The devising of strategy should rest upon the theoretical principles of cell kinetics and pharmacokinetics, which in most instances combine local removal in the primary tumor and anticipatory chemotherapy of occult metastases. The delivery of treatment involves implementation of these principles for each individual patient, and its success depends upon continual consultation among the various members of the treatment team. Wide extension of best treatment to all patients with cancer in the community will involve the good will and effective liaison of many individuals in federal, state, and local government, and many professional and lay people. Many problems of treatment are still unsolved, so research must provide new knowledge. While future advances will come in unexpected ways, the three most needed are a quantitative marder for cancer cells, better drug combinations for carcinomas, and an effective was to diagnose and repair immune deficits.


Chemotherapy in the treatment strategy of breast cancer. Although breast cancer presents as localized disease and is treated with local modalities, i.e. surgery and radiotherapy, patients die with metastatic disease. For patients with positive nodes, the recurrence rates are well known. It is this group of patients who should receive more aggressive treatment. Chemotherapeutic regimens are available that cause responses in patients with advanced disease in the range of 20% to 65%, with about 15% complete responses The current paper deals with the application of several chemotherapeutic regimens at the time of surgery in those patients at high risk. The preliminary results indicate a significant decrease in the recurrence rates. Additional studies combining chemotherapy and hormonal procedures are mentioned.


Some surgical aspects of gynecologic cancer. The most important developments in gynecologic oncology in recent years have been the advent of supervoltage irradiation that allows the delivery of better and safer therapy; the diligent search for new cancerostatic drugs and hormones and their clinical application, singly and in combination; and studies suggesting the possibility of immunotherapy. Conversely, few noteworthy developments have emerged in the operative management of gynecologic malignancy, even though refinements of surgical technique, improved preoperative and postoperative care, and better control of infectious problems gradually have decreased the operative morbidity and mortality rates and have improved the survival rates significantly. Surgery continues to be the dominant therapy. Irradiation, chemotherapy, and hormones are therapeutic adjuvants in the management of ovarian, endometrial, cervical, vulvar, and other genital malignancies. As a result of earlier diagnosis, with the greatly diminished incidence of far-advanced carcinoma of the cervix, primary surgery is having a larger role in the management of the early stages of this lesion. Aggressive surgical removal of advanced, dissemenated ovarian carcinoma is worthwhile; diminishing the volume of the lesion significantly improves the response of residual tumor to adjuvant therapy.


Advances in chemotherapy for gynecologic cancer. Considerable progress is being made in the chemotherapy of some gynecologic cancers. A random study comparing postoperative irradiation therapy with chemotherapy shows the two to be equally effective. Chemotherapy has the advantages of added safety and of being much less expensive for the patient. Postoperative chemotherapeutic treatment with VAC of patients with embryonal carcinoma of the ovary can prevent recurrence of this frequently fatal tumor. In some patients with advanced embryonal carcinoma of the ovary, chemotherapy with VAC may produce permanent remissions. Combined irradiation and chemotherapy and vincristine and actinomycin-D may be curative for some patients with advanced sarcomas in the pelvis or abdomen. This treatment combination is associated with severe complications; however, some are preventable.


Endoscopic polypectomy. Therapeutic and clinicopathologic aspects. The problem of the malignant potential of neoplastic colonic polyps is being, in large measure, resolved by newly derived techniques. Now most polyps may be removed endoscopically using the fiberoptic colonoscope. The largest world experience is at the Beth Israel Medical Center in New York, where over 2000 polyps have been endoscopically removed without a single death and with but one complication requiring operative intervention. Laparotomy is now reserved for polyps not suitable for endoscopic resection or where a question of residual cancer exists. Experience with endoscopic resection has called for: 1) re-assessment of colonic polyps in terms of their malignant potential; and 2) clarification of the indications for laparotomy and bowel resection subsequent to or instead of endoscopic removal. Among all polypoid lesions 0.5 cm or greater in size in the Beth Israel series, a variety of pathologic types was encountered. If only the neoplastic polyps were considered, the incidence of "malignant change" was 10.5% for 855 polyps analyzed. There is, however, a need to clarify terminology and to differentiate between carcinoma in situ and invasive cancer whenever possible. Superficial cancers (carcinomas in situ) do not recur or metastasize and require no treatment other than polyp removal. When "invasive" cancer is present (4.5% of neoplastic polyps) or the lesion is a "polypoid carcinoma" each case must be individually evaluted. Criteria for diagnosis, gross morphological features suggesting cancerous change, and current management of "malignant" polyps are discussed. Colonoscopy is an important component of the followup program whether malignant polyps are resected endoscopically or by the transabdominal route.


Preoperative radiation theration therapy in rectal cancer. This paper outlines progress being made in the use of preoperative irradiation as an adjunct to surgery in the management of cancer of the rectum and rectosigmoid. Studies have shown that the normal rectal mucosa has a marked capacity for repair during fractionated radiation treatments. There is evidence that the use of preoperative irradiation reduces the number of involved lymph nodes found at operation. No marked interference with the ability of the surgeon to perform an abdominal perineal resection has been observed. In patients who subsequently undergo such a procedure, there are some data indicating that longevity may be increased when surgery is supplemented with preoperative irradiation, although further comparative studies are needed. Two studies are now under way by national clinical investigative groups.


Intracavitary irradiation of early rectal cancer for cure. A series of 186 cases. If radical surgery is the only rational policy for most cases of rectal cancer, the problem of local treatment in poor surgical risk patients should be discussed in selected cases. Only limited, fairly-well-differentiated tumors, still confined to the rectal wall may have a sufficiently low probability of lymphatic spread to be amenable to local treatment. Rectal cancer, usually regarded as being slightly radiosensitive when treated by external irradiation, proves to be highly radiosensitive in the case of early cancer treated by intracavitary irradiation. This method is able to control a large amount of limited polypoid and ulcerative adenocarcinomas. In a series of 133 cases followed more than 5 years, the rate of death from cancer is only 9%, and the 5-year survival rate is 78%. As compared with local exision or electrocoagulation, intracavitary irradiation has several advantages. It does not require colostomy nor anesthesia. Contact x-ray therapy is an ambulatory treatment applicable even to elderly and fragile patients. There is no danger of fistula in the case of tumor of the anterior wall in female patients. It preserves all the chances of cure by subsequent surgery in case of failure.


Advances in rehabilitation of stoma patients. The rehabilitation of people with abdominal stomas depends upon a good stoma well placed, the guidance of an enterstomal therapist, and the availability of a clinic staffed with a multidisciplinary group to recognize and meet the continuing needs of stoma patients.


Surgery of prostatic carcinoma.

Surgery of prostatic carcinoma. Seven surgical treatments for the management of prostatic cancer are briefly reviewed. A transurethral prostatic resection is of value, not only for the relief of bladder outlet obstruction, but also in the definitive management of Stage A lesions. The long-term survival for patients with Stage C disease treated by radical prostatectomy plus interstitial irradiation demonstrates the efficacy of this mode of therapy. Pelvic lymphadenectomy has yielded valuable information on the stage of the disease; long-term survival was related to the presence of lymph node metastases. Lymphadenectomy may have contributed to the 5-year survival rate of those with regional lymph node involvement, but there is no direct evidence to support this view. The early results in patients treated by cryosurgery indicate that this mode of therapy can be very effective in the ablation of the local lesion and may very well have a useful place in the surgical armamentarium for the management of prostatic cancer.


Carcinoma of the bladder T3NxMo treated by preoperative irradiation followed by cystectomy. Eighty-nine patients with bladder cancer T3NxMo have been treated by preoperative external irradiation (4000 rads in 4 weeks) followed by cystectomy. Five-year survival is 50%. Of patients with T-reduction (T3 becomes P0, P1, or P2) the 5-year survival is 70%. Treatment mortality has been reduced to 3% during the last 2 years. T-reduction cannot be predicted by histologic grade. A second staging by palpation under general anesthesia ("T" 4000) is reliable when T-reduction is felt; however, fibrosis can simulate a persisting T3 mass.


Radiation therapy for head and neck cancers. A general review of the therapeutic experience of the management of carcinoma of the head and neck at the Massachusetts General Hospital and Massachusetts Eye and Ear Infirmary is presented. Early lesions are highly curable by radiation therapy alone; the advanced lesions are preferably treated by combined irradiation and surgery, with improved survival rates. Concepts of various approaches are discussed.


Radiation therapy of soft tissue sarcomas. Recent advances in radiation therapy in the clinical management of patients with sarcoma of soft tissue are discussed. Radical dose radiation therapy combined with limited surgery has been shown to be highly effective as treatment of early to moderately advanced sarcomas of the extremities. Desmoid tumors which are nonresectable have been treated with moderate to high radiation doses with regular success. The multimodality treatment of rhadbomysarcoma of childhood has yielded a dramatic improvement in 2-year survival figures. This approach includes radiation therapy, multidrug and multicycle chemotherapy, and surgery. Finally, the dominant importance of the histologic grade of sarcoma to the prognosis is discussed in terms of a proposed clinical staging system.


Chemotherapy of sarcomas.

Chemotherapy of sarcomas. The development of intensive treatment techniques with combination chemotherapy, radiation, and selected surgery has produced dramatic improvements in the treatment of soft tissue sarcomas. This has been best demonstrated in the long-term disease-free survival of a majority of children with inoperable or metastatic embryonal rhabdomyosarcoma treated with VAC chemotherapy (vincristine, actinomycin D, and cyclophosphamide). The addition of adriamycin and imidazole carboxamide to the combination therapy program for adults with soft tissue sarcomas has resulted in significant improvements in their response rates as well.


The management of Hodgkin's disease.

The management of Hodgkin's disease. This paper presents a destillation of the authors' current views concerning the optimal management of Hodgkin's disease in relation to site(s) and stage of disease, constitutional symptoms, histopathology, and prior treatment, based on experience with a series of controlled clinical trials under way at Stanford University Medical Center since 1962.


The treatment of non-Hodgkin's lymphoma. Much of the approach to evaluation and management of the non-Hodgkin's lymphomas has been modeled after Hodgkin's disease. However, as the name implies, they are quite different. The non-Hodgkin's lymphomas are a group of diseases and syndromes. These many different presentations, syndromes, and possibly different diseases must be distinguished and separated in order to evaluate results. Advances in pathologic classification attempting to relate the disease to physiological activities of lymphocytes are being made, but a simple, clinically relevant scheme is not available at present. We recognize large differences in nodular vs. diffuse histologic patterns. Non-Hodgkin's lymphoma is only infrequently restricted to a single anatomical area, but when it is, radiation therapy can result in a significant proportion of cures. More widespread disease requires systemic therapy. Most encouraging results are found with whole-body radiation used as a systemic agent with the use of multidrug combination chemotherapy. Perhaps whole-body radiation will be most useful when combined with combination chemotherapy as systemic therapy for some groups of non-Hodgkin's lymphoma.


Rehabilitation of children with cancer.

Rehabilitation of children with cancer. The majority of children with cancer can now be successfully treated with eradication of their disease of they receive the best therapy available in experienced cancer treatment centers. This has become possible due to five major factors: 1) the availability of new antitumor drugs, 2) the utilization of new therapeutic techniques, 3) improved supportive therapy, 4) the development of the cooperative, coordinated team approach, and 5) the philosophy of the therapeutic approach. With this increasing success, the long-term physical and emotional rehabilitation of the child with cancer becomes of great importance. The goal is a return of the child and his family to as normal in lifestyle as possible as quickly as possible. The achievement of this involves an aggressive and positive approach to the overall treatment plan, with involvement of all of the members of the treatment-rehabilitation team, including the patient and his family.


Fast- and slow-growing transplantable tumors derived from spontaneous mammary tumors of the DBA/2 Ha-DD mouse. Nineteen transplantable tumor lines were established from individual spontaneous mammary tumors of the DBA/2 Ha-DD mouse. Of these lines, 5 were classified as fast growing, 8 as medium growing, and 6 as slow growing, based on the time required for the tumors to reach a size of 10 mm in average diameter and on the average survival time of tumor-bearing syngeneic hosts. The relative differences in rate of growth among 5 of these lines remained stable during 11 to 19 transplant generations. In DBA/2J mice, a slow-growing and a fast-growing tumor line were cross-immunogenic. The differences in growth rate between these 2 tumor lines were not primarily related to differences in immunogenicity since they were not abolished in preirradiated hosts. The growth of cell populations from these 2 tumor lines in culture was comparable; however, cells from the fast-growing line had a plating efficiency about 4 times higher than those from the slow-growing line.


Gonadotropin-induced proliferation of endoplasmic reticulum in an androgenic tumor and its relation to elevated plasma testosterone levels. The development of gonadotropin-induced structural change in a testosterone-secreting Leydig cell tumor and its relationship to plasma testosterone levels were studied in castrate, tumor-bearing mice 2 hr after daily injections of human chorionic gonadotropin (HCG). Tumor cells from control animals were small, averaging less than 1.0 X 10(-9) ml in volume, and were poorly differentiated, having very little smooth endoplasmic reticulum (SER) in their cytoplasm. Average plasma testosterone levels in these mice were near 1.3 ng/ml. Although a five-fold rise in plasma testosterone was measured 2 hr after the first HCG injection, no changes in the endoplasmic reticulum were detected at this time. After the second injection, plasma testosterone rose to only twice control levels, while ultra-areas of mixed rough endoplasmic reticulum and SER. Modest amounts of SER had appeared in many tumor cells after the third injection, and plasma testosterone showed a six-fold rise. Between the third and fourth injections, cell volume increased by about 70% as large accumulations of SER appeared in the cytoplasm of most cells. Plasma testosterone again rose to five times control levels. Increased cell volume and abundant SER were maintained by continuing daily injections of HCG, while the 2-hr plasma testosterone response persisted at five to six times the control level. These findings show that a maximal elevation of plasma testosterone can occur prior to changes in the endoplasmic reticulum of Leydig tumor cells. However, they also suggest that daily repetition of the maximal functional response requires that the cells acquire large quantities of newly produced SER.


The metabolism of ethionine in rats.

The metabolism of ethionine in rats. The L-[ethyl-1-14C]ethionine metabolites soluble in trichloroacetic acid were studied in rats by the use of column chromatography. After p.o. application of ethionine, its absorption from intestinal lumen was rapid and was complete in less than 2 hr. Any unabsorbed ethionine was later excreted in the feces. During the passage through the gastrointestinal tract, a portion of ethionine was metabolized. The chemical nature and biological significance of these metabolites is not yet known. The fate of absorbed ethionine was investigated in the small intestine, liver, blood, kidney, and urine as a function of time after application. A great part of ethionine was quickly oxidized to ethionine sulfoxide. In liver and kidney, the concentration of ethionine sulfoxide was higher than that of free ethionine. In all organs, the presence of N-acetylethionine sulfoxide was also demonstrated. Ethionine sulfoxide can be reduced and N-acetylethionine can be deacetylated in vivo as demonstrated by the formation of S-adenosylethionine from ethionine sulfoxide and N-acetylethionine. In urine, 4 main components were observed: N-acetylethionine sulfoxide, S-adenosylethionine, ethionine sulfoxide, and free ethionine. Some minor components, as yet unidentified, were also present in the urine and in different organs. The probable site of origin of urinary S-adenosylethionine is the kidney.


A human squamous cell carcinoma cell line. An epithelial cell line COLO 16 has been established from a human squamous carcinoma, characterized and maintained for over two years. The cells produce a parathyroid-like hormone and carcinoembryonic antigen. The line is definitely not a "HeLa contaminant." The cell line is available to other investigators.


Carcinoembryonic antigen and humoral antibody response in patients with thyroid carcinoma. Carcinoembryonic antigen and antibodies to thyroglobulin and to a microsomal fraction of thyroid were measured. Persons examined were normal volunteers, patients with thyroid cancer, and patients with a history of childhood irradiation to the thymus and/or tonsil who were otherwise normal. Elevated antigen and antibodies were most frequently found in the cancer thyroid group. Thyroid cancer patients with no previous history of childhood irradiation were more frequently positive for antigen and antibodies than all other categories studied. Thyroid cancer patients with a previous history of childhood irradiation showed normal frequencies of antigen and antibodies. The results suggest that the antigenic expression and host response to the tumor in patients with thyroid cancer depend on its pathogenesis. Mention is made of similar findings in animal model systems.


The therapeutic response of three human tumor lines maintained in immune-suppressed mice. Studies were made of the growth and therapeutic response of three lines of human tumor serially transplanted in immune-suppressed mice. They included a well-differentiated colonic carcinoma (HX 13), a poorly differentiated colonic carcinoma (HX 18), and undifferentiated small-cell carcinoma of the bronchus (HX 29). Their histological appearance and growth rates were stable, with volume-doubling times ranging from 6 to 12 days. Studies by the technique of labeled mitoses showed that the growth kinetics of the three tumor lines were very similar, with median intermitotic times in the range of 26 to 35 hr. An analysis of the incidence of single and double takes revealed evidence for variation in susceptibility among the recipient mice. One tumor (HX 18) was transplantable with single-cell suspensions but 10(5) cells were required for 50 percent takes. The response of the tumors to a range of chemotherapeutic agents was studied. There was evidence that drugs that are known to be effective in the treatment of patients did well, in particular 5-fluorouracil against the colonic tumors and cyclophosphamide against the bronchial carcinoma. Long-term regressions induced by cyclophosphamide in the bronchial carcinoma may reflect assistance from host defense mechanisms.


Inhibition of benzo(alpha)pyrene metabolism catalyzed by mouse and hamster lung microsomes. Induced and constitutive microsomal enzymes of mouse and hamster lungs catalyze both the hydroxylation of benzo(alpha)pyrene and reactions that lead to its irreversible binding to macromolecules. For mouse and hamster, the induced lung hydroxylases have Km values of 1.10 and 0.52 muM, respectively. The induced hydroxylases are strongly inhibited by 7,8-benzoflavone and are stimulated by cyclohexene oxide, an inhibitor of epoxide hydrase. Formation of the macromolecular product by the induced "binding" enzyme follows. Michaelis-Menten kinetics, except for substrate inhibition, and has Km values of 0.52 and 0.25 muM for lung microsomes from mouse and hamster, respectively. These reactions are also inhibited by 7,8-benzoflavone. The reaction catalyzed by the constitutive hydroxylase of mouse lungs is characterized by a brief lag period but proceeds in a linear fashion after the lag. The enzyme requires 60 muM benzo(alpha)pyrene to achieve maximum reaction velocity. Above this concentration, strong substrate inhibition is observed; accurate values for Vmax and Km cannot be derived. The constitutive hydroxylases are moderately inhibited by butylated hydroxytoluene, retinol, cyclohexene oxide, and 7,8-benzoflavone. The product of the constitutive "binding" enzyme is formed in a reaction that follows Michaelis-Menten kinetics. The Km value for enzymes from mouse and hamster lungs are 11.8 and 4.9 muM, respectively. Formation of this product is strongly inhibited by butylated hydroxytoluene and by retinol but not strongly by 7,8-benzoflavone or cyclohexene oxide. Since other evidence indicates that a constitutive enzyme may be involved in carcinogenesis by benzo(alpha)pyrene and since this reaction is inhibited by two known anticarcinogens, we suggest that it may be involved in this process.


Effects of human sera on reactivity of lymphocytes in microcytotoxicity assays. The effects of cancer patient and normal donor serum samples on the reactivity of patient and normal lymphocytes against both normal and malignant target cells were studied in microcytotoxicity assays. There were 17 of 140 cancer patient serum samples and 7 of 116 normal donor lymphocyte samples that selectively increased the growth of target cells in the presence of lymphocytes. This effect was most often noted with cancer patient serum against cultured tumor cells, but the effect was also noted against fibroblasts and with normal serum against both fibroblasts and tumor cells. Of 140 cancer-patient serum samples, 11 selectively decreased target cell survival in the presence of lymphocytes compared to medium and compared to other serum samples. In the absence of lymphocytes these serum samples were nontoxic. The effect was not observed with any of the normal serum samples studied. The lymphocyte-dependent serum toxicity appeared to be selectively directed against tumor target cells.


In vitro binding of N-acetoxy-N-2-acetylaminofluorene to DNA in chromatin. The binding of N-acetoxy-N-2-acetylaminofluorene to DNA in native and partially dehistonized chicken erythrocyte chromatin was studied. The amounts of carcinogen bound to DNA were measured, after removal of proteins with phenol, by using the absorption ratio A305/A260 or by counting the radioactivity of 14C-labeled carcinogen. Measurements of uncovered zones of DNA in chromatin were made by comparison of results obtained with free DNA and with chromatin at increasing ratios of carcinogen/nucleotide. The proportion of DNA accessible to the carcinogen was found to be 15% in native chicken erythrocyte chromatin and about 22% in native calf thymus chromatin. The amount of accessible DNA increases to 55% in chicken erythrocyte chromatin depleted of histones H1 and H5. Formaldehyde unwinding performed on DNA extracted from chromatin after modification showed an increasing number of defects in the double helix with the amount of DNA-fixed carcinogen. At high ratios of carcinogen/nucleotide, the recoveries of DNA (by phenol method) and of histones (by acidic extraction) decreased with increasing ratios. This suggests a covalent linkage between proteins and DNA.


Ultrastructure of spontaneous and urethan-induced thymomas in buffalo rats. Normal thymuses from Buffalo and Long-Evans rats of various ages, and spontaneous and urethan-induced thymomas in Buffalo rats, were examined by electron microscopy. Histological variabilities among thymomas of the lymphoid, mixed, and epithelial cell types were a reflection of the number of lymphoid cells within the network composed of neoplastic epithelial reticular cells. In the cytoplasm of these cells, development of tonofilaments and membrane-bound bodies and inverse development of the rough-surfaced endoplasmic reticulum were recognized in the sequential process from the lymphoid cell type to the epithelial cell type. An important role of the development of the rough-surfaced endoplasmic reticulum for thymic function was suggested. Phagocytic activity of the neoplastic epithelial reticular cells was revealed, and some of the membrane-bound bodies in these cells, especially those with moniliform structures, were regarded as remnants of damaged lymphocytes. Evidence for neoplastic epithelial reticular cell-lymphoid cell transformation could not be established from study of the thymoma tissue. No virus-like structures were observed in these thymomas.


Chemotherapy of a human malignant melanoma transplanted in the nude mouse. The effects of single agent therapy with 1-(-chloroethyl)-3-cyclohexyl-1-nitrosourea, 5-fluorouracil, and 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide on a human malignant melanoma transplanted and passed serially in thymusless nude mouse were studied. Tumor response varied. A single dose of 1-(-chloroethyl)-3-cyclohexyl-1-nitrosourea induced initial tumor regression, but thereafter growth resumed at a rate similar to that in the untreated control animals. Wehn 1-(-chloroethyl)-3-cyclohexyl-1-nitrosourea was given in divided dosage at an interval of 8 days, marked and persistent tumor regression was observed. 5-Fluorouracil had no effect. Treatment with 5-(3,3 dimethyl-1-triazeno)-imidazole-4-carboxamide was always reflected by almost total regression of tumors, an effect that was independent of dose within the range tested in this study. The results resemble those reported from clinical practice in patients with disseminated malignant melanomas treated with the same agents. This suggests that the pattern of drug susceptibility is preserved after transplantation of tumors in the nude mouse. The human tumor-nude mouse system is advocated as a new in vivo model for determination of individual tumor response to chemotherapeutic agents, and its potential as a model for the proving of new chemotherapeutic agents is suggested.


Factors modulating benzidine carcinogenicity bioassay. An integrated series of studies was presented in which several factors were assessed as to their capability to influence the outcome of carcinogenicity of benzidine dihydrochloride in mice. In all studies C57BL/6J X C3HeB/FeJ F1 mice of both sexes were utilized. Animals were either 6 or 1 week of age at the beginning of carcinogenic treatment. Six-week-old mice were exposed to p.o. administration of carcinogen delivered either in food (50 or 100 ppm daily) or by stomach intubation at equivalent dose levels at twice-weekly intervals. In addition, a 150-ppm dose level in food was administered for 39, 54, or 84 weeks. A limited 3-week, daily intubation of benzidine (30 or 100 mug/mouse) was also explored in 1- and 6-week-old mice. Animals were killed in all studies at 90 weeks of age, at which time their tumor incidence was evaluated. Depending upon experimental conditions, benzidine treatment effected development of liver tumors, lung adenomas. Harderian gland cystadenomas, and lymphoreticular neoplasms. Continuous feeding of adult mice for 84 weeks at three dose levels of benzidine resulted in development of liver tumors with a positive dose-response relationship in both sexes. The analysis of data revealed a greater susceptibility of females than of males (94% versus 44% at 150 ppm). Twice-weekly administration of benzidine by stomach intubation was shown to be less hepatocarcinogenic than continuous feeding of equivalent amounts. In the series in which male mice were fed food containing 150 ppm of benzidine for only 34 or 54 weeks, in contrast to the above 84-week schedule, a negative relationship was observed between the incidence of liver tumors and the duration of treatment. Daily administration of 30 mug of benzidine to infants by stomach intubation for a 3-week period significantly enhanced development of liver tumors only in males (66%). Introduction of 150 ppm of benzidine into food offered to mother and offspring from delivery to weaning led to development of liver tumors in 95% of male mice and in 5% of females. No liver tumors developed following similar 3-week treatment of 6-week-old adults.


Ethionine-induced changes in rat liver transfer RNA methylation. We have confirmed the finding by Rajalakshmi that transfer RNA (tRNA) from livers of ethionine-treated rats can act as a substrate for homologous tRNA-methylating enzymes in vitro. This methyl-deficient tRNA from liver can be methylated in vitro by enzymes from normal or ethionine-treated rats. The in vitro inhibition of tRNA methylation that follows ethionine treatment can be at least partially relieved in vitro. The liver extracts from ethionine-treated animals contained a low-molecular-weight inhibitor of tRNA methylation. Dialysis of enzyme preparations from ethionine-treated, but not control, rats resulted in large increases in tRNA methylase activity, with either Escherichia coli or homologous tRNA's as substrate. Furthermore, the tRNA methylase activity of control rat liver enzyme extracts was greatly depressed by dialysate from liver homogenates of ethionine-treated rats. After 5 days of ethionine administration the liver tRNA methylase activities were significantly higher than those of control preparations despite the continued presence of the dialyzable inhibitor(s). The liver tRNA's from these animals were poorer methyl acceptors than those from 3-day-treated rats, although still better than tRNA's from untreated rats. These observations have been interpreted to indicate that ethionine causes the accumulation in the liver of inhibitors of tRNA methylation. Early in the course of ethionine administration, methyl-deficient tRNA can be isolated. When the period of ethionine treatment is extended, the organism attempts to maintain homeostasis by production of increased amounts of tRNA-methylating enzymes. The increased quantities of these enzymes are able to overcome, at least partially, the effects of the inhibitors and to decrease the extent to which methyl-deficient tRNA is produced.


Mechanisms of action of 6-thioguanine, 6-mercaptopurine, and 8-azaguanine. The effects of 6-thioguanine on purine biosynthesis and cell viability have been examined in H.Ep. 2 cells grown in culture. Toxicity is not reversed by aminoimidazolecarboxamide, suggesting that inhibition of purine biosynthesis de novo is not the sole mechanism of toxicity. Also, 6-(methylmercapto)purine ribonucleoside, a potent inhibitor of purine biosynthesis de novo, produces more marked reductions in cellular pools of purines than does 6-thioguanine without killing cells. There is no apparent inhibition by 6-thioguanosine 5'-monophosphate of other enzymes leading to the synthesis of guanosine 5'-triphosphate as determined in whole cells by measurements of radioactive hypoxanthine or guanine incorporation. Inhibition of DNA synthesis by 1 mM thymidine protects cells from 6-mercaptopurine or 6-thioguanine but fails to protect cells from 8-azaguanine toxicity. On the other hand, inhibition of RNA synthesis by 6-azauridine plus deoxycytidine protects cells against 8-azaguanine but does not protect against 6-thioguanine or 6-mercaptopurine toxicity. In agreement with the in vitro data, arabinosylcytosine (a potent inhibitor of DNA synthesis) fails to protect mice against 8-azaguanine but has previously been shown to protect mice from 6-mercaptopurine or 6-thioguanine toxicity. The results support the hypotheses of others that incorporation into DNA (as 6-thioguanine nucleotide) is a mechanism of toxicity for these thiopurines, whereas 8-azaguanine is toxic due to its incorporation into RNA.


Comparative enhancing effects of phenobarbital, amobarbital, diphenylhydantoin, and dichlorodiphenyltrichloroethane on 2-acetylaminofluorene-induced hepatic tumorigenesis in the rat. Earlier studies showed that phenobarbital feeding enhanced hepatic tumorigenesis in rats previously fed 2-acetylaminofluorene for a brief period. As part of an investigation of the mechanism of this enhancement, the present study evaluated the relative enhancing abilities of amobarbital, diphenylhydantoin, and dichlorodiphenyltrichloroethane (DDT), agents that resemble phenobarbital to varying degrees in their effects on liver structure and metabolism. A comparison of hepatic tumor yields in rats fed 2-acetylaminofluorene, followed by the test substance (sequential treatment), showed that amobarbital and diphenylhydantoin had no enhancing activity, whereas the enhancing effect of DDT was similar to that of phenobarbital. These results show that the sequential treatment technique readily distinguishes among substances differing in enhancing ability and should prove useful in screening additional substances for this activity. The comparative biochemical effects of these substances in the liver can then be correlated with their relative enhancing abilities to provide information on the molecular events specifically associated with enhancement. Such correlations were initiated in this study by comparing the effects of the four test substances on liver weight and DNA synthesis. The results showed that the enhancers, phenobarbital and DDT, each stimulated liver DNA synthesis and increased liver weight, whereas the nonenhancers, amobarbital and diphenylhydantoin, had neither effect. Phenobarbital and DDT both increased the early tumor incidence rate and maintained an increment in tumor incidence over that in the other treatment groups throughout the experiment, although it is not clear whether this increment would persist indefinitely. In addition, although the spectrum of tumor types observed ranged from highly differentiated to poorly differentiated in all treatment groups, DDT and phenobarbital selectively increased the incidence of highly differentiated tumors throughout most of the experiment.


Differences in the incorporation of bromodeoxyuridine by human lymphoblastoid cell lines. Long term human lymphoblastoid lines differ in their ability to grow in medium containing bromodeoxyuridine (BrdU) and to incorporate analog into their DNA. Eight Burkitt's lymphoma cell lines divided at least twice in BrdU-containing medium and made DNA in which over 90% of the thymidine residues were substituted with analog in both strands. Three infectious mononucleosis-derived lines and 24 lines transformed in vitro were inhibited by BrdU after one cell division and made only hybrid DNA in which one strand was substituted with analog.  One out of eight normal individuals from whom long term lines were prepared gave cell lines which divided at least twice in BrdU and gave DNA in which both strands were substituted with analog. It would appear that intrinsic cellular factors regulate the response to BrdU and that Burkitt's tumor lines are characterized by their ability to make stable doubly substituted DNA containing a high proportion of halogenated analog.


An electron microscopic study of mouse foldback DNA. Foldback DNA is defined by its rapid, concentration-independent renaturation, consistent with intramolecular base pairing of inverted repeat sequences. Foldback DNA, isolated from renatured mouse main band DNA by hydroxyapatite chromatography, is spread for electron microscopy by the formamide isodenaturing technique. A large fraction of the molecules can be recognized as intramolecular "hairpins"--structures in which complementary sequences on a single DNA strand form base-paired "stem" regions analogous to tRNA stems. The stem regions of the hairpins have a wide distribution of lengths, averaging about 1000 base pairs. About 60% of the stem regions terminate in single-stranded loops, ranging from 400 to many thousands of nucleotides in length, while 40% of the hairpins do not have discernible loops. There are about 40,000 hairpin-forming sequences in the main band portion of the mouse haploid genome. They appear to be either clustered in groups or confined to about one third of the DNA, rather than uniformly or randomly distributed. Another large fraction of the molecules seen in foldback DNA consists of linear structures, some of which are probably also hairpins. The electron microscopic results, along with simple theoretical considerations, make possible a better interpretation of our previous studies of the yield and S1 nuclease resistance of mouse foldback DNA.


Structure and activity relationships of platinum complexes with anti-tumour activity. A number of complexes of platinum(II) and platinum(IV) have been prepared, characterised and tested for their ability to cause regression of a mouse plasma cell tumour. All active compounds possess two cis amine ligands but the oxidation state of the platinum is not critical. Relatively minor structural and substituent changes in the amine can lead to major and dramatic changes in the therapeutic index, generally, but not necessarily, associated with changes in toxicity. Some preliminary results on the relationship between structure and solubility are also reported.


Isotope effect on the carcinogenicity of 3-methylcholanthrene in mouse skin by selective deuteration of the 1-methylene group: biological evidence for a mechanism of tumor initiation. 3-Methylcholanthrene (MC) in chloroform and trifluoroacetic acid-d1 yielded 3-methylcholanthrene-d4 (MC-d4), a compound selectively deuterated at the 1-, 5-, and 6-carbon atoms. In turn, the protodedeuteration of the labeled hydrocarbon at the 6-carbon atom led to 3-methylcholanthrene-d3 (MC-d3). A comparative test for carcinogenicity between MC and MC-d3 by repeated skin painting on female Swiss mice showed a significantly lower tumorigenic activity of the latter. The result implies that the 1-carbon atom of the hydrocarbon is a critical binding-site to cellular targets in the tumor-initiating process.


The Golgi complex. III. The effects of puromycin on ultrastructure and glycoprotein synthesis. The effect of puromycin has been investigated on protein and glycoprotein synthesis and on ultrastructure of the Golgi complex from rat liver. Incorporation of [14C]leucine into protein in Golgi fractions and into serum proteins was depressed rapidly after puromycin treatment. In the serum proteins, incorporation returned to normal levels at 2 h whereas in Golgi fractions it continued to rise to 200% of the control levels at 3 h and was still elevated at 24 h after puromycin treatment. Incorporation of [14C]glucosamine into glycoprotein was depressed in Golgi and serum fractions in a similar manner but slightly later than that of leucine. Leucine labelled material found at 3 h was a poor acceptor for carbohydrate, since [14C]glucosamine incorporation was not elevated above control values. Galactosyl transferase activity was not depressed in the Golgi membranes and, at 3 h, was elevated implying that an adequate supply of enzyme was available at all times. The activity of the galactosyl transferase in serum appeared to be depressed suggesting that transport of enzyme from Golgi complex to serum was defective. Ultrastructural changes in the Golgi complex were observed to occur rapidly after puromycin treatment. The cisternae became irregular, compressed, and degenerated progressively from central region towards the periphery. Irregular tubular structures formed at the expense of cisternal membrane and showed accumulation of low density lipoprotein. Vesiculation and degenerative changes of the Golgi membranes continued from 2-12 h while more typical arrangements of the Golgi complex were observed between 24-48 h. The morphological changes correlated with changes in glycoprotein synthesis.


Evaluation of a new model to detect bladder carcinogens or co-carcinogens; results obtained with saccharin, cyclamate and cyclophosphamide. A sensitive rat model has been designed to detect potential weak bladder carcinogens or co-carcinogens. The test compound is given to animals which have received a single initiating, but non-carcinogenic, dose of N-methyl-N-nitrosourea (MNU). The model has been used to investigate two compounds currently under suspicion as weak bladder carcinogens, namely sodium saccharin and sodium cyclamate, and one compound known to be cytotoxic but not carcinogenic for the bladder epithelium namely cyclophosphamide. For comparison, these three compounds were also tested as solitary carcinogens in animals not pre-treated with MNU. At the very high dose levels used, sodium saccharin and sodium cyclamate were weak solitary carcinogens producing 4/253 and 3/228 bladder tumours respectively, and the first of these tumours did not appear for more than 80 weeks. When tested in the MNU/rat model more than half the animals receiving either sodium saccharin or sodium cyclamate developed bladder tumours from 10 weeks onwards. By contrast, cyclophosphamide failed to produce any tumours when tested either as a solitary carcinogen or in the MNU/rat model. It must be emphasized that the doses of saccharin and cyclamate used were far higher than those consumed by man, including diabetics, and these results should not be directly extrapolated to man without careful consideration of many other factors including negative epidemiological findings. The theoretical basis of the model is discussed and also the relevance, in terms of environmental human exposure, of detecting compounds which have a synergistic effect with other known bladder carcinogens. It appears that this model can be used to detect a carcinogenic or co-carcinogenic potential in compounds which are organotropic for the bladder more rapidly and with fewer animals than if the compounds are tested as solitary carcinogens by more conventional methods. It is suggested that it could be used to detect those compounds which require further investigation.


Effect of increased vascular pressure on lung fluid balance in unanesthetized sheep. In 20 unanesthetized sheep, we measured lung lymph flow and lymph and plasma protein concentrations during steady-state base-line conditions and during steady-state elevations of pulmonary microvascular hydrostatic pressure (range 3 to 23 cm H2O). In every sheep there was a base-line lung lymph flow (average 5.7 +/- 2.5 (SD) ml/hour), demonstrating that net fluid filtration occurred. The base-line lymph-plasma total protein ratio averaged 0.69 +/- 0.05, indicating a high protein osmotic pressure in the interstitial fluid at the filtration site. Lymph flow increased and lymph protein concentration decreased approximately linearly whenever hydrostatic pressure rose. A new steady-state condition was reached in 1-2 hours. The difference in plasma-to-lymph protein osmotic pressure increased by half the hydrostatic pressure increment (50% negative feedback regulation). Extravascular lung water content, measured post-mortem, did not change significantly until microvascular hydrostatic pressure more than doubled, indicating a large safety factor that protects the lungs against fluid accumulation normally. The major contributions to the safety factor appeared to be a sensitive and efficient lymph pump coupled to a washout of interstitial protein. The fluid filtration coefficient, whose calculation required many assumptions, averaged 1.64 +/- 2.65 ml/(cm H2O times hour) in the base-line condition and did not change significantly over the pressure range studied.


Bronchopulmonary arterial shunting without anatomic anastomosis in the dog. The effects of bronchial arterial administration of vasoactive substances on the pulmonary circulation were studied by a new technique for selective catheterization of a  bronchial artery in intact dogs. In most experiments, this technique permitted pressor agents to be distributed mainly to one lung with smaller amounts to the other lung. The intercostal arteries were avoided, and in all but 2 of 23 experiments only microscopic quantities of injected India ink could be identified in the distribution of the esophageal and mediastinal branches. These studies indicate that serotonin, angiotensin, histamine, and norepinephrine injected selectively into a bronchial artery increase lobar arterial pressure. Since blood flow was constant and left atrial pressure did not change, the increase in pressure suggests active pulmonary vasoconstriction. Additionally, the responses to bronchial and lobar arterial injections of pressor agents were similar. The contribution of bronchopulmonary shunt flow to pulmonary flow was small, since, under conditions of controlled lobar blood flow, changes in bronchial flow elicited by 65-75-mm Hg changes in bronchial arterial pressure produced little if any change in pressure in the perfused lobar artery or small vein. Bronchoconstriction contributed little to the response to bronchial administration of pressor agents, since responses were similar in the ventilated and the collapsed lobe. Injection of vasoflavine dyes into the bronchial artery showed the close proximity of bronchial and pulmonary arteries and confirmed the bronchial arterial origin of the vasa vasorum of pulmonary arteries. No vasa venorum were identified. Although no direct anatomic bronchial artery-pulmonary artery shunt was identified, ascorbic acid and 5-hydroxydopamine diffused rapidly into intrapulmonary arteries from the bronchial artery. These data suggest that the pulmonary pressor response results from passage of the vasoactive agents from the bronchial artery to the lobar artery through the vasa vasorum and by diffusion. Since no vasa venorum were found, pulmonary venoconstriction probably resulted from pressor agents reaching the veins by way of bronchopulmonary shunt flow. These results suggest a mechanism by which pressor substances present or liberated in the bronchial vascular bed can affect tone in the pulmonary vascular bed.


Sarcomere length-tension relations in living rat papillary muscle. Small papillary muscles about 2 mm long and 0.2 mm thick were dissected from the right ventricles of 16-19 day-old rats. Resting (between twitches) and active (at twitch peaks) striation patterns were photographed in living muscles using a light microscope. External muscle length was varied from Lmax, the length at which peak twitch tension was maximum, to 0.75Lmax, the length at which peak twitch tension was about 10% of maximum. Resting and active tension versus muscle length curves were similar to those obtained from other papillary muscle preparations. Resting average sarcomere length at Lmax was about 2.23 mu; it decreased with decreasing muscle length in the range between Lmax and 0.75Lmax. Near 0.75Lmax, resting average sarcomere length was about 1.5-1.6mu. Considerable internal shortening occurred during contractions, and the active average sarcomere lengths measured at the twitch peaks were less than the resting values. At Lmax, the active average sarcomere length was 1.98mu. At 0.75Lmax, there was only about a 3-6% decrease in average sarcomere length at the twitch peaks. However, at external muscle lengths between Lmax and 0.75Lmax more internal shortening was present than there was at Lmax, since average sarcomere length decreases of about 15% were observed. The finding that peak active tension decreases as sarcomere length decreases below about 2.0mu suggests that some of the factors limiting force generation at short lengths in skeletal muscle may also limit it in mammalian cardiac muscle.


Direct effect of beta-adrenergic stimulation on renin release by the rat kidney slice in vitro. Controversy exists regarding the mechanism by which catecholamines stimulate renin secretion in vivo. A sensitive rat kidney slice system was utilized to study the direct effects of adrenergic agonists and antagonists on renin release in vitro. Catecholamines were protected from degradation by the addition of ascorbic acid to the incubation medium. Significant dose-related stimulation of renin release was observed with epinephrine and norepinephrine in concentrations from 1.5 times 10(-9) to 1.5 times 10(-7)M and with isoproterenol in concentrations from 2 times 10(-9) to 2 times 10(-7)M. No significant stimulation was seen with 10(-10)M concentrations of the three agents. Methoxamine (10(-6)M) stimulated renin release significantly (P less than 0.01). The stimulation observed with epinephrine, norepinephrine, or isoproterenol was blocked by d,l- and l-propranolol (2 times 10(-4)M) but not by d-ropranolol (2 times 10(-4)M) or phentolamine (9 times 10(-4)M). Methoxamine-induced stimulation was abolished by d,l-propranolol but not by phentolamine. These data  that the in vitro kidney slice system is responsive to physiological concentrations of catecholamines when they are protected from degradation. The results further demonstrate a direct stimulatory role for beta-adrenergic agents on renin release and suggest that alpha-adrenergic effects seen in vivo are mediated indirectly by hemodynamic, vascular, or functional changes in the kidney.


Effects of potassium ion on the microcirculation of the hamster. The vasoactive properties of potassium were assessed in the microcirculation of the hamster cremaster muscle and the muscular and epithelial portions of the hamster cheek pouch. Tissues were transilluminated and suffused with a physiological salt solution whose potassium concentration varied from 0 to 20 mM. Vessel diameters were measured and normalized as a percent of the control diameter (+/- SE) observed during exposure to 4.7 mM K+. Altering the potassium concentration in the suffusion solution caused a transient vascular response. The peak changes in the vascular diameter of the arterioles supplying striated muscle varied directly with the suffusion solution potassium concentration from a minimum of 78 +/- 3% in 0 mM K+ to 155 +/- 15% in 15 mM K+. Vascular diameter increases were sustained for the full 5-minute test period only in 15 mM K+. In the epithelial portions of the cheek pouch, only the constrictor component of the potassium response was observed. The data indicate that potassium is sufficiently potent to participate in initiating functional hyperemia in striated muscle and might cause as much as a 6.3-fold increase in flow. Functional hyperemias exceeding approximately 3 minutes cannot be due to potassium ion, since the dilation induced by this agent is transient.


Altered ion transport in aortic smooth muscle during deoxycorticosterone acetate hypertension in the rat. Change in aortic water and electrolyte distribution and in ion turnover were studied during the development of deoxycorticosterone acetate (DOCA) hypertension in the rat. Treatment with DOCA plus saline during the prehypertensive phase was associated with increases in 42K turnover (0.0142 +/- 0.0005 vs. 0.0102 +/- 0.0003 min-1), cell water (0.89 +/- 0.03 vs 0.76 +/- 0.02 kg/kg dry weight), and the ratio of weight to length. These parameters were further increased during the development of hypertension. Significant increases were also observed in total K, Ca, and Mg contents and in Na and C1 contents corrected for the extracellular space. The turnover of 36Cl was increased (0.230 +/- 0.006 vs. 0.136 +/- 0.004 min-1) in DOCA hypertensive rats as was the content of slowly exchanging Cl. Removal of extracellular Ca greatly increased the steady-state turnover of 42K. For control rats, a Ca concentration of 0.1 mM reduced the rate of 42K turnover to less than 50% of the Ca-free value (0.063 +/- 0.004 min-1), whereas DOCA hypertensive rats exhibited only a 10% reduction. At the highest Ca concentration, 5 mM, the 42K turnover was greater in DOCA-treated rats with the hypertensives operating at 67% of maximum efflux or about twice the efflux in controls. It is concluded that significant alterations in ion transport by vascular smooth muscle occur before and during the development of hypertension induced by treatment with DOCA plus saline. Such changes may result from a reduced ability of Ca to stabilize the membrane. It is proposed that such alterations contribute to the changes in vascular reactivity and the hypertrophy associated with hypertension.


Selective inhibition by des-1-Asp-8-lle-angiotensin ii of the steroidogenic response to restricted sodium intake in the rat. Angiotensin III (des-1-Asp-angiotensin II) is a potent steriodogenic agent in many species. The effects of the heptapeptide in the adrenal zona glomerulosa are resistant to blockade by C-terminally substituted analogues of angiotensin II (1-Sar-8-Ile- or 1-Sar-8-Ala-octapeptides). For this reason, the effects of 7-Ile-angiotensin III, a C-terminally substituted analogue of the heptapeptide, and 1-Sar-8-Ile-angiotensin II on aldosterone biosynthesis in rabbit adrenal cortical cell suspensions and on urinary aldosterone excretion in sodium-deprived rats were studied. In the vitro studies, 7-Ile-angiotensin III was a better antagonist of angiotensin II- or angiotensin III-induced steroidogenesis than was 1-Sar-8-Ile-angiotensin II. In the rats, subcutaneously administered 1-Sar-8-Ile-angiotensin II (0.9 mumoles/kg) produced prolonged blockade of the pressor responses to exogenous angiotensin II. 70Ile-angiotensin III (0.9 mumoles/kg) had no effect on resting blood pressure or on blood pressure responses to angiotensin II infusions. At the doses studied, however, 7-Ile-angiotensin III caused a marked decrease (50%) in aldosterone excretion in sodium-deprived rats, but 1-Sar-8-Ile-angiotensin II had no effect on aldosterone excretion. In the sodium-deprived rats, the administration of 7-Ile-angiotensin Ile was not associated with an acute increase in plasma renin activity, but treatment with 1-Sar-8-Ile-angiotensin II resulted in a sixfold increase in plasma renin activity, but otensin III was not associated with an acute increase in plasma renin activity, but treatment with 1-Sar-8-Ile-angiotensin II resulted in a sixfold increase in plasma renin activity. These results are consistent with a role for angiotensin III in the control of aldosterone biosynthesis.


Effect of exercise on dilution estimates of extravascular lung water and on the carbon monoxide diffusing capacity in normal adults. Previous studies in exercising animals have demonstrated that the extravascular lung water accessible to measurement by dilution methodology increases in the transition from rest to low-level exercise and thereafter does not change with progress to high-level exercise. In normal humans, similar systematic examination is essential to provide a background for the interpretation of changes in measured extravascular lung water in pathophysiological states. Moreover, such an examination might provide new insight into the mechanisms underlying the change in the pulmonary diffusing capacity with exercise. We therefore measured both the pulmonary extravascular lung water (by use of the triple indicator-dilution technique) and the diffusing capacity for carbon monoxide in 11 subjects, seated on an exercise bicycle, at rest and usually during two levels of exercise. The central blood volume increased by 50% with a tripling of the cardiac output. The accessible lung water increased from an average of 2.16 g/kg to 2.55 g/kg in the transition from rest to low-level exercise, but it did not increase further at the higher level of exercise. The simultaneously measured diffusing capacity for carbon monoxide (single breath and steady state) continued to increase over the whole range of cardiac outputs. We infer that the proportion of the pulmonary parenchyma perfused by blood flow increases slightly in the transition from rest to low-level exercise but increases no further at the higher level of exercise. The continued increase in the pulmonary diffusing capacity over the range in which the estimated lung water values do not change appears to imply that part of this increase may be blood flow dependent rather than dependent on the recruitment of additional surface for exchange.


Valve replacement and myocardial revascularization. Results of combined operation in 59 patients. Fifty-nine patients (mean age 57 years) underwent aortic valve replacement or mitral valve replacement combined with saphenous vein bypass grafting (39 single, 19 double, 1 triple) between May, 1970 and January, 1974. The hospital mortality for aortic valve replacement was 4.7% (2 of 43 patients) and for mitral valve replacement 6.3% (1 of 16 patients). There was a 21% incidence of postoperative myocardial injury in the patients with aortic valve replacement and a 6.2% incidence in the patients with mitral valve replacement. Variations in operative technique and in the methods of intraoperative myocardial preservation (coronary perfusion or profound hypothermic ischemic arrest) did not affect hospital mortality or the incidence of myocardial injury. Prolonged periods of ischemic arrest (greater than 50 minutes) were not used. The late mortality for aortic valve replacement was 16.3% (seven patients) and for mitral valve replacement 25% (four patients). There was symptomatic improvement in the majority of survivors. Operative mortality rates for the combined procedures are comparable to those from our institution for valve replacement alone.


The spectrum of exercise test and angiographic correlations in myocardial revascularization surgery. Maximal exercise tests and angiographic evaluations were obtained in a group of patients before and after myocardial revascularization. Patients were classified on the basis of angiography and operative records. Two primary groups of 33 patients with complete revascularization and 95 patients with postoperative residual ischemia were studied. The residual ischemia subgroups included patients with partial revascularization, progressive coronary atherosclerosis, or graft failure. Patients with complete revascularization had statistically significant improvements in work capacity, maximal heart rate, maximal rate-pressure products, abnormal exercise electrocardiograms, exercise-induced angina pectoris, and atrial gallop sounds. A spectrum of lesser improvements in these measurements was observed in the subgroups with residual ischemia. Total graft failure resulted in no significant improvements in exercise-test parameters. Maximal stress tests provide a useful adjunct to routine clinical follow-up of myocardial revascularization patients. Myocardial revascularization is associated with significant patient palliation as determined by serial stress testing.


Effect of blood flow rate on subendothelial proliferation in venous autografts used as arterial substitutes. The effect of augmented and reduced blood flow rates through autogenous vein grafts (AVG) on the histological characteristics of veins used for arterial substitutes was studied in 22 dogs. In each animal autogenous jugular veins were implanted as conduits to replace excised segments of both iliac arteries. In one group (control) blood flow through the AVG conduits was not modified, but in the remaining animals blood flow rate was either augmented by a distal femoral arteriovenous fistula or reduced by a distal arterial stenosis. In the control group in which there was no modification of blood flow, subendothelial proliferative lesions (SEPL) were found in the vein graft, and typical SEPL were found at each anastomosis. However, in those animals in which blood flow was reduced by an average of 44% through the graft, SEPL were more numerous throughout the length of the vein graft, and the anastomotic SEPL were more prominent. In contrast, those animals in which a unilateral distal arteriovenous fistula augmented blood flow through the AVG (average 6.7-fold increase), no SEPL were detected along the length of the graft. Although SEPL were present at the suture lines, the lesions were much less prominent. These findings suggest that the magnitude and distribution of SEPL in AVG are determined, in part, by the rate of blood flow through the graft.


Ascending aortic aneurysms. Review of 100 consecutive cases. Aneurysms of the ascending aorta, if undiagnosed or untreated, may result in left ventricular failure from aortic valvular insufficiency. Aortic rupture, dissection, or compression of adjacent vital structures may also occur. The application of refined cardiopulmonary bypass devices, prosthetic heart valves, and synthetic grafts now allows successful surgical management of this disorder. This report presents our current diagnostic methods, surgical techniques, and the early and late results of 100 consecutive patients undergoing surgical treatment of aneurysms of the ascending aorta. There were 72 males and 28 females, ranging in age from 25 to 72 (ave 51.2) years. All patients had angiographic studies to demonstrate precisely the location of the aneurysm and the presence or absence of aortic valvular insufficiency. Sixty-three patients required concomitant aortic valve replacement, and the remaining 37 patients had only aneurysm resection and replacement. Pathological studies revealed 69 aneurysms were atherosclerotic, 22 were secondary to cystic medial necrosis, with the remaining 9 considered to be possibly leutic in origin. Despite the magnitude of the surgery and the advanced ages of some of these patients, the overall operative and hospital mortality rates were 4% and 9%. Survival rates by actuarial representation in 82 patients at 2, 4, 6, and 8 years were 82.9%, 78%, 70%, and 69.5%, respectively.


Depressed cardiac performance after mitral valve replacement. A problem of myocardial preservation during operation. Our experimental studies since 1972 show that the heart is preserved best during cardiopulmonary bypass when it is in the beating, nonworking state. Results after mitral valve replacement (MVR) from 1968 to 1974 using various techniques of cardiac preservation were compared. In group I were 47 patients (1968 to 1972) in which either profound, topical hypothermia with prolonged ischemic arrest (19) or ventricular fibrillation with continuous coronary perfusion (28) was used. In group II there were 22 patients (1972 to 1974) in whom the heart was in a beating, nonworking state between brief periods of ischemic arrest. In group I 55% (25/47) required inotropic support postoperatively, and 17% (8/47) died. In group II 5% (1/22) required inotropic support postoperatively, and this patient died (5% mortality). Extended periods of ischemic arrest were necessary because of intraoperative complications in this patient. These data show that depressed postoperative myocardial performance occurs rarely when the heart is preserved in the beating, nonworking state during MVR and ventricular fibrillation and prolonged topical hypothermic anoxic arrest are avoided.