The prevention of invasive cancer of the rectum. The results of the 25+ year Cancer Detection Center study, including 20,000 participants and 100,000+ patient-years experience, demonstrate the obviation of appearance of most lower bowel cancers associated with a program of proctosigmoidoscopy and adenomatous polyp removal. Once on a schedule of periodic examinations, study participants developed only a fraction of the anticipated number of rectal cancers; most of the cancers which did develop were detected while at an early stage and with involvement of only the mucosa. Not a single death from lower bowel cancer has occurred among active study participants or for 7+ years following the most recent examination at the Center.


Plasma cell neoplasm involving the thyroid. Involvement of the thyroid gland by plasma cell neoplasms is very rare. On review of 248 cases, we found 4 cases in which pathological evidence of plasma cell neoplasm in the thyroid was verified. This was a heterogeneous group of patients; the thyroid involvement was clinically recognized as a site of extramedullary plasma cell neoplasm in one patient and as a part of generalized disease in two patients. In another patient with generalized disease, the thyroid involvement was discovered at autopsy.


Clinicopathologic correlations and significance of clinically occult mammary lesions. Experience with 189 clinically occult, i.e., nonpalpable breast lesions is presented. The described technique of localization and excision all but guarantees removal of even the smallest radiographically suspicious findings with an inconspicuous incision and minimal breast deformity. The incidence of carcinoma encountered in these 189 biopsies is 27.5%. Axillary node metastases were present in less than 25% of the invasive nonpalpable cancers, approximately half of what might have been expected if the lesions had been discovered in the usual manner. There were no patients with axillary node metastases among those with in situ ductal or microinvasive ductal carcinomas. This implies a better prognosis and lower death rate from breast cancer in these patients. Screening programs employing mammography, designed to detect breast cancers in this pre-palpable stage, are encountered as a means of uncovering a higher proportion of such cancers at an earlier stage in their natural histories.


Lack of prognostic significance of the pretreatment labeling and mitotic indices of marrow blasts in acute nonlymphocytic leukemia (ANLL). The prognostic significance of the pretreatment growth characteristics of marrow blasts was examined in 37 patients with acute nonlymphocytic leukemia (ANLL) treated with a similar therapeutic regimen. Initial mitotic index (MI) and in vitro 3H-thymidine labeling index (LI) were broadly distributed showing no correlation to other initial variables, such as age or absolute blast count. No relationship whatsoever was observed between the pretreatment LI, MI and either the likelihood of achieving a complete remission or the remission and survival length. We conclude that the initial growth characteristics of marrow blasts do not play a significant role in predicting the therapeutic response in ANLL; age, modality of therapy and, possibly, the dynamic perturbations of the proliferative activity of the blast cells induced by treatment should be regarded as more reliable prognostic indicators in ANLL.


Patterns of relapse and survival following radical mastectomy. Analysis of 716 consecutive patients. The records of 716 consecutive patients with breast cancer randomized from January 1964 to January 1968 between radical and extended radical mastectomy not followed by postoperative radiation therapy were reviewed. Relapse and survival rates were related to different patterns with the intent to define, on clinical basis, the high-risk groups in whom systemic adjuvant treatment can be attempted. The 10-year relapse rate was 52.9% for the whole series. In patients with negative axillary nodes (N-) this finding was 27.9% compared to 75.5% for patients with positive nodes (N+ 1-3: 66.5%, N+ greater than 3: 83.6%). The relapse rate was also affected by concomitant involvement of internal mammary nodes (IMN): N- IMN+: 60%, N+ IMN+: 96.7%. The corresponding 10-year survival rates were as follows: 59.7% (total), 81.9% (N-), 39.6% (N+), 53.7% (1-3), 25.6% (greater than 3), 45.8% (N- IMN+), 20.5% (N+ IMN+). In N+ patients relapse and survival rates were directly proportional to the size of primary tumor, while this trend was not present in N- patients. Location of primary tumor as well as menopausal status showed no direct effect on relapse and survival. In both nodal groups the sites of first relapse were documented to occur preferentially in distant organs and tissues.


Myelopoietic abnormalities in patients with metastatic carcinoma. Myelopoiesis was assessed in 41 untreated patients with widespread cancer without evidence of infection. None of these patients had neutropenia, although leukopenia due to decreased concentrations of blood lymphocytes was observed in two. Sixteen patients (39%) had neutrophilia and 12 patients (29%), 5 of them with neutrophilia, had decreased marrow granulocyte reserve. Neither the blood neutrophil counts nor the marrow granulocyte reserve correlated significantly with the marrow myeloid mitotic indices, myeloid to erythroid ratio or the number of marrow colony-forming cells. There was no difference in the duration of the disease, the extent of systemic metastasis and the degree of malnutrition between patients with or without myelopoietic abnormalities. Our findings suggest that decreased marrow granulocyte reserve and neutrophilia are common in untreated patients with disseminated carcinoma.


Implications from SEER data on breast cancer management. From the SEER files of the NCI, 8,587 cases of breast cancer diagnosed in 1975 were analyzed. Of these cases, 5.3% were noninvasive. Of the invasive cancers under 0.5 cm in diameter, 17.2% had positive axillary lymph nodes. Where the physician recorded no palpable axillary lymph nodes, 34.5% were found to be positive.


The use of antiestrogens tamoxifen and nafoxidine in the treatment of human breast cancer in correlation with estrogen receptor values. A phase II study. Twenty-five patients with measurable metastatic breast cancer and assays for estrogen receptor (ER) were studied. Of the 16 ER positive patients on anti-estrogen therapy, one had complete disappearance of all tumor for seven months and seven patients had more than 50% reduction in their measurable tumor for an average duration of 8.8 months. Seven other ER positive patients had stabilization of their tumors for an average interval of 8.4 months. Only one of the 16 ER positive patients progressed promptly. Conversely there was only one partial response in the nine ER negative patients and only two ER negative patients had stabilization of disease. Six out of nine ER negative patients progressed promptly. Correlation existed between the duration of response and absolute estrogen receptor level of the tumor. There may be a positive correlation between the response to antiestrogen therapy and response to endocrine ablation but prospective studies must be done to further define the role of antiestrogens in this regard.


Keratocysts of the jaw. Clinicopathologic study of 79 patients. A study of 79 patients with keratocysts of the jaws revealed that 72% of the cysts were in the mandible, predominantly in the ramus. The most common symptom was a painful swelling in the jaw. Enucleation was used in 69.2% of the cases. The recurrence rate was 39%. Total removal of the lining of the keratocyst is essential to prevent recurrence.


Effect of adriamycin and high-dose methotrexate chemotherapy on in vivo and in vitro cell-mediated immunity in cancer patients. Adjuvant chemotherapy with adriamycin (ADR) and high-dose methotrexate (HDM) with citrovorum rescue appears to hold promise for preventing recurrence of sarcomas following surgery. However, the effect of prolonged treatment with these agents on both in vivo and in vitro cell-mediated immunity (CMI) is unknown. To assess in vitro CMI, cryopreserved lymphocytes from 18 patients, collected before and at monthly intervals following initiation of biweekly ADR and HDM therapy, were tested simultaneously for stimulation to phytohemagglutinin, poke-weed mitogen, Concanavalin A, and pooled allogeneic lymphocytes by a micro-test technique. In vivo CMI was determined by serial skin-testing with 2,4,-dinitrochlorobenzene (DNCB). No significant overall change was noted for any of the in vitro lymphocyte function tests. DNCB skin test ratings, peripheral leukocyte counts and absolute lymphocyte counts did not change significantly during the study. Lymphocytes from a second group of patients were tested before, at 24 and 48 hours after HDM therapy. In vitro lymphocyte function tests were significantly depressed 24 hours following treatment, but returned to pretreatment levels at 48 hours. Long-term adjuvant ADR and HDM therapy does not appear to alter in vivo and in vitro CMI, although transient depressions were noted. The preservation of intact CMI may account in part, for the effectiveness of these agents as surgical adjuvants.


Halothane, surgery, immunosuppression and artificial pulmonary metastases. C57B1/6 mice were given intravenous tumor cells on day O. Mice were then given either a brief exposure to halothane anesthesia or given halothane and then underwent a hind limb amputation. Immune testing was done at varying time intervals and correlated with the development of artificial pulmonary metastases. The effects of a single 15 minute exposure to halothane on the immune system are probably short-lived and no effect on cell-mediated cytotoxicity was seen on day 7, nor was an increase in pulmonary metastases observed. However, when anesthesia was combined with surgery, cell-mediated cytotoxicity was impaired and an increase in pulmonary metastases was seen. The use of thiabendazole (TBZ), an nonspecific immunopotentiator, in the perioperative period restored the cell-mediated cytotoxic response and resulted in a significant decrease in pulmonary metastases.


The contribution of surgery to the management of carcinomatous pulmonary metastases. The presence of carcinomatous pulmonary metastases is a common clinical problem viewed by many physicians as beyond the realm of definitive surgical considerations. However, a number of patients dying with pulmonary metastases will have the totality of their disease confined to the lungs. In this select population, there is some potential for long term control or effective palliation through aggressive surgical management. This study quantitatively assesses the value of surgery in this setting and examines the prognostic effect of several important clinical variables. A single set of criteria were adhered to in the selection of patients. Cases were stratified in accordance with the intent of surgery, namely, 1) complete control and ablation of all known disease, or 2) reduction of total tumor burden to examine the possibilities for enhanced control by adjunctive therapeutic modalities.


Results of combined chemo-surgical therapy for pulmonary metastases from testicular carcinoma. Between 1966 and 1976, 34 patients had 42 thoracotomies for resection of recurrent or residual metastatic germinal cell carcinoma primary in the testes in addition to chemotherapy. Of the 34, 18 (53%) are alive and well free of evidence of disease from 4 months to 104 months. Systemic chemotherapy of this group of tumors has improved markedly and many patients are now rendered free of disease and are potentially cured. In some however, an occasional pulmonary nodule did not completely respond or recurred after complete disappearance. The surgery was done to remove the last evidence of disease, and to establish the histology of the metastases.


The value of diagnostic aids in detecting pancreas cancer. By contract with the National Cancer Institute, the accuracy of diagnostic techniques was assessed in 184 patients suspected of having pancreas cancer. Of 138 patients who were operated upon, 89 were found to have pancreas duct cancer, 30 had cancer of a different site of origin in the head of the pancreas region and in 19 there was no evidence of cancer at operation. All of the 46 patients who were not operated upon, 13 proven to have cancer and 33 patients discharged as free of cancer, were followed in our clinic. The majority of our patients presented with signs and symptoms of biliary obstruction. Computerized transaxial tomography (CTT) gave a "correct" diagnosis in 31 of 33 patients (94%) with proven cancer, there were 2 patients with a false negative report and a false positive diagnosis occurred in 8 of 20 patients (40%) without cancer. Celiac angiography (CA) gave a correct diagnosis in 78 of 94 patients (83%) with cancer, a false negative in 17%, and a false positive in 32%. 76Selenomethionine pancreas scan correctly diagnosed 27 of 36 patients (75%) with cancer, gave a false negative in 25% and a false positive in 31%. Ultrasonography gave a correct diagnosis in 18 of 27 patients with cancer (67%), a false negative in 33% and a false positive in 28%. Endoscopic retrograde cholangiopancreatography diagnosed correctly 8 of 11 cases (73%) of cancer, there were false negative diagnoses in 3 cases (27%) and false positives in 3 of 14 patients (21%). Duodenal aspiration techniques gave a very low percentage of correct diagnoses. Chronic pancreatitis most commonly gave rise to a false positive diagnosis. Serum alkaline phosphatase was elevated in 82% of patients, gave 18% false negatives and 33% false positives. Carcinoembryonic antigen (CEA) was elevated (greater than 2.5 ng/ml) in most of the pancreas cancer patients but also in patients with other cancers and with non-cancerous diseases. In our hands, CTT, CA, alkaline phosphatase, 75Se-methionine and ultrasonography, in descending order, have given the highest percentage of correct diagnoses but false positive and false negative diagnoses prevented any single test from being conclusive.


Curability of Ewing's sarcoma and considerations for future therapeutic trials. Twenty previously untreated children with primary Ewing's sarcoma and 8 children with primary tumor and metastatic disease were treated with surgery or radiation therapy (6,000-7,000 rads) for their primary tumor and T-2 chemotherapy. Of the 20 children with primary Ewing's sarcoma treated with T-2 "adjuvant" chemotherapy, 15 had no evidence of recurrent disease for from 31+-82+ months (median 46+ months) from the start of treatment. The actuarial 5-year disease-free survival rate for this group of patients was 75%. Eight patients presenting with metastatic disease had complete responses to T-2 chemotherapy, but 7/8 with metastatic disease eventually had tumor recurrence. Examination of the treatment failures, both those patients relapsing after adjuvant chemotherapy for primary Ewing's sarcoma (5), and those relapsing after having a complete response of metastatic disease (7) to T-2 chemotherapy, revealed that all relapses occurred at the end of the second year of T-2 chemotherapy or after chemotherapy was stopped. In addition, of 23 patients receiving "curative" radiation therapy to their primary tumor, 5 had local recurrence (22%) and 6 (26%) had severe functional debility secondary to combined radiation therapy and T-2 chemotherapy. The conclusions drawn from this experience have led us to consider a new approach to the treatment of Ewing's sarcoma, namely: 1) more aggressive initial or "induction" chemotherapy with subsequent T-2 "maintenance" chemotherapy to eradicate more completely all metastatic microfoci of disease presumed to be present in patients with primary tumor at the time of diagnosis, and ostensively present in patients with metastatic disease; 2) the use of surgery alone or in combination with moderate doses of radiation therapy in those patients in whom we can predict a high frequency of local recurrence (pelvic lesions) or a high percentage of "functional failures" (young children with lower extremity lesions). Preliminary results with this latter approach are encouraging with 11/13 patients with primary Ewing's sarcoma free of disease at 12+-26+ months. A longer follow-up of this more aggressive treatment is needed to determine the superiority of this approach for both increased survival and improved late physical rehabilitation.


Inguinal node metastases.

Inguinal node metastases. Twenty-two hundred and thirty-two patients with inguinal node metastases were reviewed. The primary site of malignancy was determined in 2210 (99%) of these patients and was, in order of frequency, skin of the lower extremities, cervix, vulva, skin of the trunk, rectum and anus, ovary and penis. The determinant three-year survival rate for the remaining 22 patients with metastatic disease from an unknown primary site was 50%. The source of the primary (stomach) was discovered in only one of the 22 patients; however, the treatment of choice was superficial groin dissection, and if surgical excision was adequate, radiation therapy did not appear to be necessary to obtain local control.


Acinic cell carcinoma of salivary origin. A clinicopathologic study of 67 cases. This study reviews a 30 year experience with acinic cell carcinoma. The tumor arose in the parotid gland in 64 patients, the submaxillary gland in one and minor salivary glands in two. In untreated patients with small tumors, clinical findings usually suggested a benign mixed tumor and a subtotal parotidectomy which spared the facial nerve was highly effective therapy. In contrast, local recurrence and death was the rule in those few who had locally extensive disease, regardless of how radical an operation was performed. Determine "cure" rates for the entire group were 76, 63 and 55% at 5, 10 and 15 years, respectively. Cervical lymph node metastasis occurred in 16% of the patients, and distant metastasis in 12%. Survival was most directly influenced by the clinical extent of the primary tumor, and also correlated with certain histologic features which are described.


Adjuvant chemotherapy.

Adjuvant chemotherapy. In this brief presentation, an attempt was made to illustrate why it is not possible to carry over chemotherapeutic trial results from one animal cancer to another or one human cancer to another without corrections for differences in (a) staging, (b) dose response, and (c) tumor regrowth rates. Interrelation of quantitative information on these same three variables has provided useful guidance in the planning and interpretation of experimental therapeutic trials. For example, such integration analyses show that selection and overgrowth of specifically and permanently drug-resistant tumor cells is a major cause of chemotherapeutic failure in cancers that initia-ly respond. Surgery followed by optimum chemotherapy improves the "cure rate" of all metastatic solid animal cancers that have been studied to date. However, surgery followed by chemotherapy fails in those animals in which the residual tumor cell burden (after surgery) is too large for the chemotherapy now available.


Adenocarcinoma of the stomach: review of 1,497 cases. The records of 1,497 patients with histologically proven adenocarcinoma of the stomach were reviewed from Charity Hospital over the 25-year period, 1948 to 1973. The operability rate was 82% and the resectability rate was 48%. In this series gastric carcinoma predominated in males and Negroes. Necropsy studies indicate a similar frequency of involvement of various organs in patients not operated upon as well as those subjected to a prior operation, which suggests the need for some therapeutic endeavors aimed at a wider base than the primary organ. The five-year survival rate, 7.4 overall, varied from 2.0% after esophagogastrectomy to 22.1% after radical subtotal gastrectomy, and to 30.3% for those with localized disease. One hundred one patients survived five years or more, and 5.4% survived ten years or more after the diagnosis of gastric cancer. Radical subtotal gastrectomy gave the best results in this series, whether measured in terms of median survival, five-year survival, or operative mortality. Esophagogastrectomy and by-pass procedures had high mortality and low survival rates, and should be reserved for special conditions.


A prospective randomized study of the efficacy of routine elective lymphadenectomy in management of malignant melanoma. Preliminary results. To determine whether immediate or delayed lymphadenectomy is more beneficial than none in cases of localized (stage I) melanoma, we undertook in 1972 a prospective randomized study. Patients with midline trunk lesions were excluded as well as patients with lesions situated directly over the node-bearing area. In addition, because of the low risk of metastasis, the protocol was changed to exclude level 2 lesions. Of the 173 patients studied, 63 were randomized to no lymphadenectomy, 56 to delayed (3 months) lymphadenectomy, and 54 to immediate lymphadenectomy. None of these regimens differed significantly from the others in its effect on length of survival or interval to metastasis. And of the 110 patients who underwent elective lymphadenectomy, 103 were without nodal involvement. Our preliminary conclusion is that elective node dissection is not beneficial in management of melanoma. However, disease progression was advanced significantly by age of the patient (greater than 60 years) and by invasiveness (level 4 or 5) and thickness (greater than 1.5 mm) of the melanoma.


Cryosurgery in the treatment of giant cell tumors of bone. A report of 52 consecutive cases. Cryosurgery combined with routine "second look" biopsy has been previously reported in our initial series of 25 cases and has been demonstrated to be a promising modality in the treatment of giant cell tumors of bone. Further refinement of this surgical technique by more careful preliminary curettage has now significantly improved the rate of local tumor control and has markedly reduced the incidence of associated complications. While the problems of infection, fracture, delayed bone healing and local tumor recurrence have not been completely eliminated, our experience with 27 additional cases shows that it has been possible to develop a highly reliable procedure for the eradication of tumor while usually preserving joint motion and avoiding arthrodesis or amputation. The 1.9% malignancy rate is much lower than the previously reported papers by Hutter and Jaffe.


Results of treatment of early stage I carcinoma of the uterine cervix with intracavitary radium alone. A total of 151 patients with Stage I carcinoma of the uterine cervix received treatment with intracavitary irradiation alone between 1948 and 1971. All patients had a minimum follow-up of five years. There were no local failures. No patient with microinvasive carcinoma (Stage IA) had a regional failure. A maximum of 4% (4/93) of patients with invasive cancer less than 1 cm in diameter (Stage IB-Small Volume) had regional failures. The five year determinate survival rates for patients with Stage IA and IB (Small Volume) lesions were 100% and 96% respectively. The incidence of severe complications was low, with a fistula developing in only one patient. Treatment with intracavitary radium alone is sufficient for patients with invasive cancer less than 1 cm in diameter who have adequate anatomy that allows effective irradiation of the primary lesion and paracervical lymphatics.


The treatment for dysgerminoma of the ovary. Thirty-six patients with pure dysgerminoma of the ovary were treated at the University of Texas System Cancer Center, M.D. Anderson Hospital and Tumor Institute between 1947 and 1974. Twenty-six of these patients had their initial surgery at the M.D. Anderson Hospital or were referred to the M.D. Anderson Hospital shortly after surgery at another hospital. The remaining 10 were referred after developing a recurrence of their tumor. Five of the 26 patients who were treated initially at the M.D. Anderson Hospital had only a unilateral salpingo-oophorectomy and are alive and well at the present time. The remaining 31 patients have received postoperative radiotherapy. Ninety-two percent of the patients receiving initial treatment at M.D. Anderson Hospital, and seventy percent of those referred for treatment after recurrence, are surviving at the present time without evidence of disease. The selection of treatment for the individual patient is discussed.


The use of electron beams in treating local recurrence of breast cancer in previously irradiated fields. A retrospective study was performed to assess the efficacy of using electron beam therapy to treat locally recurrent breast cancer in previously-irradiated fields. In a group of patients who received postmastectomy nodal and chest wall megavoltage photon therapy to doses of 4000-5000 rads, an additional 4000-5000 rads were delivered to chest wall recurrences with 7-10 MeV electrons. Good tumor responses were obtained without unacceptable concomitant normal tissue damage. With a follow-up time of 9 months to 5 years, 62% (8 of 13) are alive and clinically free of disease in the irradiated volume. Two patients died at respective times of 5 and 6 months after retreatment, with only one showing evidence of chest wall recurrence. One patient showed no response to therapy and the remaining two patients recurred in the treated volume at 10 and 59 months. Morbidity was limited to dry and/or moist desquamation with no evidence of soft tissue necrosis. These results demonstrate that the first course of irradiation did not select for a subset of radioresistant tumor cells, and indicate that a second course of radiation therapy may have much to offer in controlling locally recurrent breast cancer.


Carcinoma of the endometrium: effect of stage and grade on survival. Of 523 patients with endometrial carcinoma, 324 were FIGO stage Ia, 85 stage Ib, 24 stage II, 44 stage III, and 46 stage IV. High-grade lesions were present in 7.1% with stage Ia, 18.8% with stage Ib, 37.5% with stage II, 29.6% with stage III, and 55.3% with stage IV. There was no significant difference from expected survival at 5, 10, and 15 years for patients with IaG1 or IbG1 disease. Patients with IaG2 and IbG2 disease showed similar survival, as did patients with IaG3 and IbG3 disease. Thus, uterine size seemed to make no difference in patient survival at comparable grades of disease. Deaths due to cancer at 5 years increased from 63% for stage Ia disease to 100% for stage IV disease. By absolute measurement of penetration, with increasing stage of disease there was greater penetration whether the disease was low or high in grade. Also, as the grade increased within a given stage, so did penetration of the myometrium.


Synergistic action of high-dose hydroxyurea when used with cyclophosphamide and certain new organoplatinum complexes in treatment of advanced L1210 leukemia. Seven new organoplatinum (Pt) compounds, cyclophosphamide (CY), and hydroxyurea (HU) were used singly and in combination in treatment of advanced L1210 leukemia in C57BL/6 X DBA/2 mice. In each experiment the Pt + CY combination was supra-additive, as has been shown with other Pt compounds when used with CY. HU at the dose used (1000 mg/kg) was only minimally effective when used alone. However, six of the seven Pt + CY + HU combination regiments enhanced markedly the increased life span of treated mice when compared with the corresponding dual Pt + CY combination. The triple drug regimen yielded cure rates (760-day survival) up to 70% in individual experiments. Collectively, the cure rate was 11% with the various Pt + CY combinations, and was increased to 53% upon inclusion of HU in the regimen. It is suggested that HU may inhibit a process whereby potentially lethal DNA damage produced by Pt + CY would otherwise be repaired. A reduced efficacy of HU when used at a single, high-dose level was also noted, and a possible mechanism and potential significance of this observation are discussed.


Adriamycin and 1-(2-chlorethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in the treatment of metastatic breast cancer. Adriamycin every three weeks and CCNU every six weeks were given to thirty patients with metastatic breast carcinoma. Most patients had received prior chemotherapy. The overall response rate was 40%, with three patients obtaining complete remission. Survival was significantly prolonged in responders versus nonresponders. Three patients developed CNS metastasis while on treatment. Prior chemotherapy was a major factor in determining response rate; all patients without prior chemotherapy responded. The combination appears to be inferior to adriamycin alone in patients who have received prior chemotherapy.


Hemorrhagic cystitis with MOPP therapy.

Hemorrhagic cystitis with MOPP therapy. After 12 cycles of MOPP therapy for Hodgkin's Disease, an adolescent black male developed hemorrhagic cystitis, which clinically and histologically was similar to that induced by cyclophosphamide. At that time he had a normal platelet count and had never been irradiated below the diaphram. The markedly contracted bladder returned to normal approximately one month following cessation of therapy.


Long term effect of cis-diamminedichloride platinum (CDDP) on renal function and structure in man. To examine CDDP induced nephrotoxicity in patients with testicular carcinoma, we measured renal function prior to therapy and at six month intervals for twelve months in fifteen patients and twenty-four months in seven patients. CDDP was given iv at 20 mg/M2 per day for five days at three week intervals. Eight patients received three courses, four received four courses and three received more than four courses. The mean creatinine clearance +/- SD prior to treatment was 112 +/- 12 ml/min. By six months, it had decreased to 68.5 +/- ml/min (p less than 0.01) and it remained at that level. Plasma creatinine and blood urea  nitrogen increased significantly. Subjects receiving other potential nephrotoxins in addition to CDDP developed a greater decrease in creatinine clearance (p less than 0.05). Proteinuria and functional tubular disturbances were not observed.  Microscopic features were characterized by hydropic degeneration of the renal tubular epithelium, thickened tubular basement membranes and mild interstitial fibrosis. Electron microscopy revealed phagolysosomes filled with flocculent material. CDDP resulted in a permanant, nonspecific renal injury in our patients. Although the renal injury has remained subclinical, future courses of CDDP may lead to clinically important chronic renal failure.


Immunochemotherapy in advanced neuroblastoma. Twenty-two children with advanced (Stage III and IV) neuroblastoma have been treated in a nonrandomized fashion, half with a three-drug regimen consisting of vincristine, adriamycin, and cyclophosphamide, and half with this same drug combination plus the nonspecific immunostimulatory agent, MER/BCG. The addition of MER to the three-drug combination appeared to improve the duration of survival in this pilot study. The median duration of response was less than one year in the combination chemotherapy alone arm. The median duration of complete remission in children treated with the addition of MER has yet to be reached at 24 months.


Phase I studies of C. parvum given intravenously: effects of dexamethasone on its biologic and toxic properties. Three biologic effects were clearly associated with C. parvum infusions: a) granulocytosis with lymphomonocytopenia, b) increase in responsiveness to  phytohemmagglutinin and c) increase of specific antibodies to C. parvum antigens. Addition of dexamethasone moderately altered the kinetics of leukocyte changes without affecting other properties. Side effects after intravenous administration of C. parvum (2.5 mg/m2) consisted primarily of chills and fever which lasted for periods of 6-24 hours. Side effects occurred in 77% of the infusions. Addition of dexamethasone (4 mg IVP) reduced significantly the frequency (only 22% of patients) and intensity (fever 102 F and chills for only 30-60 minutes) of side effects. Clearly, dexamethasone of the dosage employed did not abrogate C. parvum effects while reducing significantly its toxic properties.


Radiotherapy in the treatment of carcinoma of the male urethra. Carcinoma of the male urethra is an uncommon tumor. Four patients are reported in this investigation. All the patients belonged to the middle age group under the age of 45 years. None of them suffered from preivous urethral structure. The most unusual presentation was impotence due to the involvement of the corpus spongiosum of the penis. Urethrogram and urethroscopy with biopsy are the most useful aids in the diagnosis. All of them had epidermoid carcinoma nad were treated with external radiation therapy. Two patients with distal urethral lesions without metastases responded well with a 4 and 5 years survival and disappearence of the tumor. Two patients with extensive bulbomembranous lesions had palliation with relief of pain and partial regression of  the tumor. Radiation therapy in a properly selected patient with an early lesion gives gratifying result.


Selective uptake of 75Se-selenomethionine by thymoma with pre red cell aplasia. Red cell aplasia and an enlarging anterior mediastinal mass developed in a patient being followed for thyroid carcinoma. Differential diagnosis included thymoma and metastatic thyroid carcinoma. Preoperative scanning demonstrated significant uptake of 75Se-selenomethionine whereas 67Ga-galiium citrate failed to visualize the mass. Subsequent thoracotomy revealed a lymphocytic thymoma which was resected, resulting in reversal of the red cell aplasia. The use of 75Se-selenomethionine scanning maybe a useful adjunct in the preoperative evaluation of suspected thymomas.


Gray scale echography of the lung and pleural space: current applications of oncologic interest. B mode gray scale echography is not useful in evaluation of the normal lung and pleural space. The presence of abnormal fluid collections in the chest change the acoustic properties of the thorax and pleural fluid collections may be detected and localized with precision. Lesions abutting the chest wall may be characterized as cystic or solid. Echography can be used to assess the motion and morphology of the diaphragms. Sonographic examination of the thorax is particularly useful in determining whether a large area of radiographic opacification such as an opaque hemithorax is due to fluid, tumor, or intrinsic pulmonary disease such as atelectasis or consolidation.


Chromosome abnormalities in patients with hairy cell leukemia. We evaluated chromosomes from 20 patients with hairy cell leukemia (HCL) to ascertain the frequency and type of consistent chromosomal abnormalities. Samples from 17 patients were obtained from peripheral blood cultures grown 24 and 48 hours without phytohemagglutinin, or from bone marrow samples. Two male patients had similar, consistent abnormalities; one patient's karyotype was 46,X,+12; that of the second was 46,X,+C marker. In the latter case, the distal long arm of the C marker most closely resembled chromosome No. 12 from band q14 to q terminal, but the short arm and proximal long arm were of undetermined origin. Both karyotypes lacked the Y chromosome. A third patient had, in one sample, a single abnormal cell with an extra No. 3 and an extra No. 12 (48,XY,+3,+12), and in a later sample, a second cell of poor morphology which also could have been trisomic for no. 12. The two patients with consistent chromosome abnormalities had rapidly progressive disease and a relatively short clinical course from the time of diagnosis (5 and 7 months, respectively). Further data are needed, but the results thus far suggest that patients with consistent chromosome abnormalities could be considered as candidates for aggressive combination chemotherapy.


Clear cell sarcoma with melanogenesis.

Clear cell sarcoma with melanogenesis. An example of clear cell sarcoma, from the great toe of a young woman having an otherwise classic history and appearance is described, and a malignant giant cell component is reported for the first time. Histochemical and electron microscopic studies clearly demonstrate melanogenesis. The controversy over tissue of origin of this uncommon neoplasm is discussed and evidence in support of neurectodermal derivation is presented.


Primary yolk-sac (endodermal sinus) tumor of the prostate. A primary yolk-sac (endodermal sinus) tumor of the prostate occurring in a 51-year-old man is described, and the difficulties associated with classification of this tumor are discussed. Yolk-sac tumors have been reported to arise in several extragonadal sites, but to our knowledge this is the first documented case of a germinal cell tumor occurring the the prostate. This tumor in extragonadal sites  carries a grave prognosis. Despite radical surgery, radiotherapy, and chemotherapy, this patient died 10 months after the tumor was diagnosed.


Intraepithelial neoplasia of the uterine cervix in the teenager. One hundred and seventeen teenagers with abnormal cervical cytology were evaluated using colposcopy and directed biopsies. Eighty-eight cases of cervical intraepithelial neoplasia were discovered including 24 cases of severe dysplasia or carcinoma in situ. Erradication of these lesions is essential as a preventative measure. The importance of routine cytologic screening and early evaluation of abnormal Papanicolaou smears in the teenager is emphasized.


Glycogen-containing neuroblastoma with clinical and histopathologic features of Ewing's sarcoma. The differential diagnosis is difficult in cases of metastatic neuroblastoma, Ewing's sarcoma, lymphoma, and rhabdomyosarcoma, the common so-called small round cell tumors of childhood. The distinction between Ewing's sarcoma and neuroblastoma in bone with no soft tissue mass in the adolescent is especially difficult. Ewing's tumor is usually characterized by its content of glycogen, neuroblastoma by its absence. A case of glycogen-containing neuroblastoma initially misdiagnosed as Ewing's tumor is presented. Diagnostic implications, including the role of electron microscopy in diagnosis, are discussed. Glycogen alone is unreliable as a diagnostic aid due to 1) its presence in several tumors other than Ewing's including neuroblastoma, and 2) its absence in some cases of Ewing's sarcoma.


Lack of usefulness of bone marrow enzymes and calcium in staging patients with prostatic cancer. Bone marrow acid phosphatase has been reported to be a sensitive indicator of early bony metastasis from adenocarcinoma of the prostate. In order to evaluate this hypothesis, we measured bone marrow acid and alkaline phosphatase, lactic dehydrogenase, and calcium levels in a group of 84 patients with a variety of problems, including 18 with cancer of the prostate. We found that the bone marrow acid and alkaline phosphatase and lactic dehydrogenase were elevated and calcium was depressed in most patients. Among patients with prostate cancer, bone marrow acid phosphatase was not significantly different between those with or without bone metastases. In addition, the patients with prostatic cancer did not have higher levels of bone marrow acid phosphatase than subjects with other malignant and nonmalignant conditions. The level of acid and alkaline phosphatase, lactic dehydrogenase and calcium varied predictably with the aspiration technique used and was independent of sex, disease state or method of chemical determination. Due to this variation, we believe that bone marrow enzyme and calcium levels are of no value in the detection of metastases in patients with prostate cancer.


Serum selenium and reticuloendothelial tumors. Serum selenium levels were determined by neutron activation analysis on 59 patients with a variety of reticuloendothelial neoplasms. Correlations were attempted between the widely variable range in the serum concentrations of the trace element with the parameters employed in this study. Therapy, particularly less than six weeks initiation, produced elevations in the serum selenium levels.


Epithelioid sarcoma: an analysis of 22 cases indicating the prognostic significance of vascular invasion and regional lymph node metastasis. Twenty-two cases of epithelioid sarcoma seen and/or treated at Memorial Hospital are presented. With the exception of one tumor which occurred in the neck, all the sarcomas arose in the upper (15 cases) or lower extremities (6 cases). Ten originated in the hand. At the time of initial treatment, 14/22 patients were between 20 and 40 years of age. The tumor most commonly presented as a nodular lesion and involved dermis, subcutaneous tissue, fascia and tendons, and when it recurred (13 cases) it tended to grow proximally along tendons and fascial planes. Of special interest was the finding of vascular invasion in surgical specimens removed from 5 patients. Four of these represented recurrent tumor, and in two cases the vascular invasion was massive. Two of these patients also demonstrated tumor emboli in pulmonary vessels and cardiac involvement at autopsy. Metastasis to regional lymph nodes occurred in eight cases (42%). Follow-up ranging from 2 to 34 years (average of 8 years) was obtained for 19 cases (86%). Eleven patients are alive with disease or died as a result of their sarcoma (58% of the follow-up group). Adverse prognostic factors included recurrence after initial local excision, vascular invasion and lymph node metastasis. All of the patients with intravenous extension of tumor and 6 of 8 patients with lymph node involvement died with pulmonary metastases. Our data suggest that cure may best be achieved by amputation or by an exceptionally wide en bloc excision as early as possible, depending upon the location and extent of the original tumor.


Serum sialic acid elevations in malignant melanoma patients. Elevated membrane sialic acid (n-acetyl neuraminic acid) concentration may be a general phenomenon associated with malignant or transformed cells. In this study, sera from 30 normal persons and 25 melanoma patients were examined to determine first, if serum sialic acid elevations were associated with malignant melanoma, and second, if there was a relationship between tumor burden and serum sialic acid level. Significantly elevated sialic acid concentrations were found in the melanoma patients (p less than 0.005), and levels tended to be greater in those with a large tumor burden (p less than 0.05). Thus, increased serum sialic acid could prove to be a valuable clinical monitor of change in tumor burden as a result of therapy or change due to recurrence of disease following treatment.


Cytomorphological grading and Feulgen DNA-analysis of metaplastic and neoplastic bronchial cells. Quantitative determinations of nuclear DNA were made on squamous metaplastic and neoplastic cells from sputum cytology specimens. The cellular material was processed by destaining diagnostic smears, restaining by the Feulgen method and relocating the cells for measurement. Adventitious leucocytes were used as internal controls. There was good correlation between increasing degree of aneuploidy as judged from DNA values, and increasing degree of morphologic nuclear atypia. The data indicate a progressive aberration from normality of nuclear DNA content in squamous metaplastic and neoplastic cells exhibiting a progressive degree of atypia. This implies that squamous bronchial carcinoma is preceded by sequential changes of the cellular composition which may be recorded by both quantitative DNA analysis and cytology.


Ectopic production of salivary type amylase by a pseudomesotheliomatous carcinoma of the lung. A pseudomesotheliomatous carcinoma of the lung which appeared to be ectopically secreting large quantities of salivary (S) type amylase is described. This unusual variant of adenocarcinoma may mimic a mesothelioma, but is distinguished from mesothelioma by its histiological and histochemical features.


Mucinous cystadenoma, serous cystadenoma and benign cystic teratoma of the ovary: clinico-pathologic differences observed in a Malaysian hospital. A study of 207 benign ovarian tumors seen at the University Hospital, Kuala Lumpur between 1968 and  1975 was made to evaluate the clinical features that might be useful in the preoperative differentiation of mucinous cystadenoma, serous cystadenoma, and cystic teratoma of the ovary. This study indicated that the pertinent information included the mean age of the patient, the marital and menstrual status, and the estimated tumor size. The racial background was an additional factor in serous cystadenoma. Features like parity, the location of the tumor, and ABO blood group pattern were of no value in the preoperative differentiation.


An analysis of the benefits of serial screening for breast cancer based upon a mathematical model of the disease. A model of breast cancer is developed that consists of hypotheses about the age-specific incidence of the disease, the rate of disease progression, the tendency of the disease to be detected without benefit of regularly scheduled screening examinations, and prognosis related to the extent of disease at treatment. Parameters for the model are estimated from published data. The model is validated by comparing model predictions to data not used in parameterization. The model, under a variety of assumptions, is then used to analyze questions of interest about breast cancer screening strategies. These include the following: the benefits from screening with mammography and clinical examination as a function of the frequency and starting age of screening, the effect of different assumptions about radiation risks on the benefits of screening, the benefits from screening with mammography if yearly clinical examinations are performed, and the benefits from screening with mammography and clinical examination if self-examinations are performed.


Rupture of a renal cell carcinoma in a child: five-year tumor-free survival and literature review. The third case of presumably spontaneous rupture of a hypernephroma in a child is reported. This patient remains free of disease more than 5 years following radical nephrectomy, radiation and chemotherapy. Although renal adenocarcinoma in children remains a rare disease, more than 80 cases have appeared in the literature, making it necessary now to consider this tumor in the differential diagnosis of all childhood abdominal masses. Equally significant is the observation that presentation as an acute abdominal crisis in a child can occur, making it important that diagnostic considerations in such situations include hypernephroma, as well as Wilms' tumor. Review of the literature shows that occasional cures from spontaneous retroperitoneal rupture of hypernephromas have been reported in adults, but not in children, although this child has survived in spite of tumor spillage in the free peritoneal cavity.


Survivorship from large bowel cancer among Caucasians and Japanese in Hawaii. From 1960 through 1973, the Hawaii Tumor Registry identified 781 Caucasian and 1073 Japanese cases of large bowel cancer. Survivorship analysis revealed that Japanese patients had a 32% higher 5-year relative survival rate than Caucasians. Further analyses showed that colon cancer cases did better than rectal cases, and patients diagnosed before 65 years of age fared better than cases diagnosed at an older age. As expected, patients with localized disease lived much longer than those who had more advanced disease. Men and women were similar in their survival from large bowel cancer. Histologic grade of the lesion, socioeconomic variables, behavioral practices and other factors which may affect survivorship by race could not be included in this study. Until such factors are also incoporated in the analyses, the observed results are only suggestive of a racial difference in survivorship.


The association of body weight with recurrent cancer of the breast. Recurrence of carcinoma of the breast after radical mastectomy was associated with preoperative body weight among patients observed for up to 24 years. Patients who had no axillary lymph node metastases and who weighed 130 pounds or less had an accumulative recurrence free survival superior to that of heavier patients. The advantage was unassociated with significant differences in menopausal status, clinical stage, or tumor size. High fat diet and large body mass have been linked epidemiologically with high risk for breast cancer; whatever biologic mechanisms are involved may also promote growth of residual tumor after potentially curative surgery. Diet and weight reduction may represent empirical means for improving the prognosis of heavy individuals with early stages of breast cancer.


Inflammatory carcinoma of the breast.

Inflammatory carcinoma of the breast. Fifty-eight patients with clinical inflammatory breast carcinoma and 15 patients with "occult" inflammatory cancer (dermal lymphatic carcinomatosis without clinical inflammation) are grouped and reviewed to determine whether diagnosis is pathologic or clinical. All cases represent a retrospective study of records from the Ellis Fischel State Cancer Hospital, Columbia, Missouri. Lesions of clinically apparent and occult inflammatory carcinoma demonstrate similar gross and microscopic growth patterns, histologic types, axillary involvement and early widespread metastases. Regardless of pathologic evidence of dermal  lymphatic tumor, patients with clinical inflammation had rapid deterioration. Cases with only a pathological diagnosis were slightly less fulminant in progression. Either clinical or pathologic criteria justify use of the term "inflammatory breast carcinoma" to indicate short-term prognosis despite available treatment.


Malignant mediastinal teratoma in a 15-year-old girl. A well-differentiated anterior mediastinal teratoma was removed from the right hemithorax of a 15-year-old girl presenting initially with ascites. Death followed a precipitous clinical deterioration from widespread sarcomatous metastatic disease. The true malignant nature of this tumor was not apparent on initial resection and evaded detection until shortly before death. These unique features prompted a review of the pertinent literature on malignant mediastinal teratoma in children. A similar case had not been reported previously.


Endodermal sinus tumor: the Stanford experience and the first reported case arising in the vulva. A review of the histology, clinical findings and results of therapy in 9 females with endodermal sinus tumor (EST) is presented. Five patients had histologically pure EST; 4 had EST mixed with other germ cell components. The site of primary tumor was the ovary in 8 of the 9 females; the remaining patient with an extraovarian primary represents the first reported case of EST arising in the vulva. The addition of combination chemotherapy has prolonged survival over historical controls treated with surgery or surgery plus irradiation. Adjuvant chemotherapy appears warranted as treatment for occult metastatic disease; postoperative radiation therapy appears useful in providing local control of primary disease. There is a suggestion of increased sensitivity of EST to combination chemotherapy as compared to other germ cell histologies with which it is commonly admixed.


Preparation for disseminated intravascular coagulation by Yoshida sarcoma in rats. Five days following implantation of a Yoshida sarcoma, female rats developed an increase in plasma fibrinogen concentration and a decrease in the number of platelets. The endotoxin induced fibrinisation of the microcirculation, as measured in percent involvement of glomerula, was found to be five to ten times higher than in control animals. A single injection of endotoxin without infusion was sufficient in tumor bearing animals to induce glomerular capillary thrombosis. The Yoshida sarcoma induced pathophysiological changes with a "preparative" effect on the endotoxin-induced disseminated intravascular coagulation.


Acceleration of myeloid recovery from cyclophosphamide-induced leukopenia by pretreatment with Bacillus Calmette-Guérin. Treatment of C57BL/6 mice with Bacillus Calmette-Guérin i.p. 8 days prior to the induction of leukopenia by cyclophosphamide (300 mg/kg i.p.) significantly (p less than 0.002) increased peripheral granulocyte counts on each day during the recovery from leukopenia. The recovery of lymphocyte counts was unaffected by Bacillus Calmette-Guérin treatment. Further experiments indicated that the accelerated granulocyte recovery was the result of an earlier initiation of the recovery process rather than of the release of stored granulocytes. Bacillus Calmette-Guérin may have clinical value as a stimulator of myelopoiesis in patients rendered leukopenic by antineoplastic chemotherapy.


Serial sacrifice study of pathogenesis of 210Po-induced lung tumors in Syrian golden hamsters. The pathogenesis of 210Po-induced tumors in the peripheral lung of Syrian golden hamsters has been studied in a serial sacrifice experiment utilizing both plastic (glycol methacrylate) and routine paraffin embedding procedures for lung sections. A rapid progression from hyperplasia of bronchiolar-type cells that appear in the alveolar region to malignant tumors was documented. Tumors began appearing as early as 15 weeks after the first intratracheal instillation of 210Po.


Defective and enhanced postreplication repair in classical and variant xeroderma pigmentosum cells treated with N-acetoxy-2-acetylaminofluorene. Xeroderma pigmentosum (XP) cells proficient in the excision repair of pyrimidine dimers (XP variants) were also found to be proficient in the excision repair of N-2-acetoxyacetylaminofluorene (AAAF)-induced lesions in their DNA, as assayed by the photolysis of 5-bromodeoxyuridine incorporated during repair. However, the time in which the small segments of newly synthesized DNA, made immediately after treatment of cells with AAAF, were joined together to form DNA of parental size by a process called postreplication repair was long in the XP variant and classical cells. Although increasing doses of AAAF increased the time for making daughter DNA of parental size for variant and classical XP cells, AAAF did not appear to affect this process in normal human cells. Treatment of variant and classical XP cells with a relatively small dose (2.5 micron) of AAAF or 2.5 J/sq m of UV radiation several hr before a 2- to 3-fold-larger dose decreased the time for the pulse-labeled DNA to appear as parental size.


Delayed cutaneous hypersensitivity to oxazolone in mice with tumors. A murine model of immune responsiveness had been adapted to study anergic conditions associated with neoplasia. Marked anergy observed in mice bearing L1210 leukemia and P-388 lymphoma is contrasted to the minimal immune depression associated with B-16 melanotic melanoma and Sarcoma 180J. The ability of N,N-bis(2-chloroethyl)-N-nitrosourea chemotherapy to reduce tumor burden without prolonged suppression of delayed cutaneous hypersensitivity is compared to the profound suppression of the cutaneous response observed with Adriamycin cytoreductive therapy. The applications of our model are discussed in relation to tumor-associated anergy, new approaches to the evaluation of pharmaceuticals, and studies of combined chemoimmunotherapy regimens.


Influence of interferon preparations on the proliferative capacity of human and mouse bone marrow cells in vitro. The toxicity of interferon to bone marrow was studied by the use of in vitro colony forming assays for hemopoietic cells. In the same study the relative inhibitory effects of two clinically common interferon preparations, leukocyte and fibroblast interferons, were compared with regard to their effect on both myeloid [colony-forming unit, culture (CFUc)] and erythroid [colony-forming unit, erythroid (CFUe)] progenitor cells. CFUe formation in human bone marrow cells in vitro appeared to be fairly resistant to both interferons. Only high doses of both interferons gave a marked inhibition of CFUe. However, the toxicity of leukocyte and fibroblast interferon was divergent for CFUe in human bone marrow. Leukocyte interferon appeared to be considerably more inhibitory for CFUe than was fibroblast interferon. The effects of mouse interferon, induced in L929 cells, on the growth of CFUc and CFUe in murine bone marrow cells were comparable with those of fibroblast interferon on human cells. The toxicity of human and murine interferon was species specific. Except for the toxicity of leukocyte interferon to CFUc in human bone marrow, the toxicity of interferon was marked only with concentrations on interferon far exceeding the amount necessary to produce an antiviral state in vitro.


Tumor-promoting activity of 2,3-dihydrophorbol myristate acetate and phorbolol myristate acetate in mouse skin. Phorbolol myristate acetate (PHMA) had been previously prepared from the potent mouse skin tumor promoter phorbol myristate acetate (PMA) by sodium borohydride reduction of the C-5 carbonyl group in PMA to a secondary alcohol. PHMA was shown to have an inflammatory effect in mouse skin equal to that of PMA. 2,3-Dihydrophorbol myristate acetate (DPMA), a new compound, was prepared from the 3-aldehyde of PMA by catalytic hydrogenation. DPMA exhibited no detectable inflammatory effect in mouse skin. Both DPMA and PHMA were tested on the dorsal skins of female ICR/Ha Swiss mice (30/group) for 433 and 380 days, respectively, in separate experiments. The tumor-promoting activity of both compounds was reduced significantly, compared with that of equimolar doses of PMA. For each treatment the number of mice with tumors per total number of tumors was: DPMA, 9/17; PMA, 29/553 at 10 microgram/mouse; PMA, 30/317; PHMA, 24/69 at 2.5 microgram/mouse. The results suggest that specific binding requirements influence the tumor-promoting and hyperplastic activity of PMA and its closely related derivatives in mouse skin.


Arrest of synthesis of specific proteins at the onset of mammary tumor regression. MTW9 mammary carcinoma regressing after removal of mammotropin stimulation was used as a model to test the hypothesis that the augmented activity of lysosomal enzymes observed during regression may be triggered by a modification of the protein composition of the cytoplasm. In support of the hypothesis, we observed that: (a) the pattern of leucine incorporation into cytosol proteins differs between growing and regressing tumors; (b) the difference is localized in three bands of the electrophoretic pattern; and (c) the change in pattern appears within 6 hr after hormone removal, about 4 hr after prolactin levels in blood were below the concentration needed by MTW9 to grow. These observations are in line with our previous finding of an increased susceptibility of cytosol proteins to proteolytic digesion during MTW9 regression.


Familial aggregation of urinary system tumors in a region with endemic nephropathy. In hyperendemic villages in the Vratza district of Bulgaria, 193 patients with urinary system tumors (UST) were diagnosed during 1965 to 1976. A tendency towards familial aggregation was revealed when the patients were compared with two groups of controls, namely, patients with tumors other than UST and healthy persons. Each control group consisted of 193 persons matched by sex, age, and place of birth. This tendency was observed in all relatives who lived together as well as in those related by blood. The probability of having relatives with UST was 2.5 times higher than could be expected as chance occurrence among UST patients than among the controls. The UST cases also had significantly more relatives with endemic nephropathy than did the controls. The familial clustering of both UST and nephropathy in the endemic region is considered another clue to their common etiology.


Solubilization and developmental distribution of embryonic antigen of the chick red blood cell plasma membrane. An antigen(s) on the surface of embryonic and newly hatched chick red blood cells was studied with antiserum absorbed with adult red blood cells. Because of the reappearance of the antigen or some cross-reactive antigen during myeloblastosis, attempts at solubilization and characterization of the antigen were pursued. Antigen was solubilized from whole red blood cell lysates or from red blood cell ghosts with 0.01 M Tris:0.1% Nonidet P40, pH 8.0. Antigen was assayed with an enhancement of agglutination assay. Enhancement apparently occurs because of available specific receptors for the antigen on newly hatched chick red blood cells. Antigen was also found to be present in plasma, and both the membrane-derived antigen and the plasma antigen were excluded from Sephadex G-100. Isoelectric focusing of the antigen extract indicated the presence of more than one molecular species with antigenic activity.


In vitro metabolism of aflatoxin B2 by animal and human liver. The metabolism of aflatoxin B2 by postmitochondrial supernatant fractions of duck, rat, mouse, and human livers was studied in an in vitro system. Duck liver had a much higher level of activity than had tissues from other species. Postmitochondrial supernatant equivalent to 0.2 g whole liver metabolized 40 to 80% of the initial substrate in 30 min, compared to less than 6% for the other species. Among several metabolites formed by duck liver, aflatoxin B1 was produced in amounts equivalent to 2 to 8% of the initial substrate, and metabolites having chromatographic properties postualted for aflatoxicols 1 and 2 and aflatoxins M1 and M2 were also formed in small amounts. In contrast, rat, mouse, and human liver preparations produced no detectable aflatoxin B1 and only small amounts of compounds thought to be aflatoxins Q2 and P2. The greater susceptibility of duck liver to the toxicity of aflatoxin B2 may be attributable to its ability to form aflatoxin B2 may be attributable to its ability to form aflatoxin B1, which could then be activated through further metabolism.


67Ga and 59Fe uptakes by cultured human lymphoblasts and lymphocytes. Studies with spontaneously proliferating human lymphoblastoid cells have shown that cellular uptake of both 67Ga and 59Fe3+ (as citrates) become appreciably increased with small additions of purified human transferrin to the cultures. In many respects, their uptake responses were broadly similar to those previously reported for cultured mouse lymphoid tumor cells. Studies were also undertaken with cultured human lymphocytes, but transferrin promotion of tracer uptakes could not be detected for these cells. In addition, cellular uptakes for phytochemagglutinin-stimulated cultures were not significantly increased over their unstimulated controls.


In vivo monitoring of the death rate of artificial murine pulmonary micrometastases. A system is described for direct monitoring of the death rate of artificial murine pulmonary microscopic metastases in vivo. Metastatic fibrosarcoma cells or benign connective tissue cells labeled with [125I]iododeoxyuridine were injected i.v. Comparison of the long-term radioactive decay rate of these two cell types in the lung permitted identification of the portion of the decay curve reflecting the initial period of micrometastasis development and growth. About 5% of the injected tumor cells were retained in the lung in micrometastasis, and their average death rate could be monitored by loss of radioactivity from the lung. Systemic methotrexate (75.0 mg/kg) was administered as a single dose 80 hr after injection of tumor cells at a time when micrometastases had not yet become vascularized. This treatment killed about 60% of the micrometases and suppressed the appearance of gross metastases at 14 days.


Decrease in 5'-nucleotidase activity in malignant transformed and normal stimulated cells. Analysis of six different cell types of normal and transformed fibroblasts grown in vitro and of four different cell types of normal and leukemic lymphocytes grown in vivo have shown a marked decrease of 3- to 30-fold in the specific activity of 5'-nucleotidase in the malignant cells as compared to their normal parental cells. The results have also indicated that a serum stimulation of untransformed or normal fibroblasts and a stimulation of normal lymphocytes by concanavalin A resulted in a significant decrease in the specific activity of 5'-nucleotidase of the stimulated cultures as compared to the resting cells. In both the malignant cells and the stimulated normal cells, the decrease in 5'-nucleotidase activity was not accompanied by a similar decrease in the specific activity of acid phosphatase, indicating a specific enzyme alteration in the surface membranes of the transformed and the normal stimulated cells.


Antitumor activity of amidoximes (hydroxyurea analogs) in murine tumor systems. A series of amidoximes was prepared and evaluated for possible antitumor activity against L1210 leukemia. Three of the most active compounds in the L1210 system, formamidoxime, acetamidoxime, and 2-aminoacetamidoxime hydrochloride, were also active against P388 leukemia. Acetamidoxime was marginally active against Lewis lung carcinoma. The active amidoximes showed best activity against L1210 leukemia when given two times daily, 5 hours apart, for 8 days. Most of the amidoximes produced excessive central nervous system stimulation.


Ceruloplasmin as a marker of neoplastic activity in rabbits bearing the VX-2 carcinoma. The establishment of an experimental model with rabbits in which VX-2 carcinoma was implanted in the gastrocnemius muscle and subsequently successfully cured by a second tumor cell inoculation has been reported previously. Tumor growth and regression could be followed by manula palpation. The changes in serum ceruloplasmin (CP, EC 1.10.3.2) levels of individual rabbits during tumor development and regression were followed. CP levels increased 4- to 8-fold of normal during the progression of the malignant process, often before tumors could be detected by palpation. With tumor regression CP levels returned to normal. When metastasis developed, the CP levels remained high. This phenomenon seems to be related to the VX-2 carcinoma, since CP levels in rabbits challenged with various antigens and suffering from induced multiple s.c. abscesses did not change significantly, while in pregnant rabbits CP levels increased up to at most 3-fold. It is concluded that serum CP level can serve as a reliable biochemical marker of the activity of this malignant process. The practical application of this finding lies in the follow-up of malignant processes in humans and is now under investigation.


Modulatory effect of the sympathetic nervous system on neuroblastoma tumor growth. Growth of C-1300 neuroblastoma was markedly suppressed in mice chemically sympathectomized at birth with 6-hydroxydopamine. Growth of A-10 adenocarcinoma was also somewhat reduced. In newborn mice pretreated with nerve growth factor to induce sympathetic nervous system neuronal hypertrophy, neuronal maturation, and peripheral hyperinnervation, the growth of neuroblastoma was augmented.


Effects of dietary constituents on ultraviolet light-mediated carcinogenesis. The effects of several dietary supplements of antioxidants and enzyme inducers on ultraviolet light-mediated carcinogenesis were investigated. Glutathione (reduced) was without effect, but butylated hydroxytoluene, phenobarbital, and disulfiram all significantly suppressed the initiation and development of actinic lesions and tumors. On the basis of the present study and related previous ones, tumor inhibition appears to be due not to an umbrageous effect but rather to the induction of systemic physiological responses.


Effect of p-hydroxyacetanilide, sodium sulfate, and L-methionine on the leukemogenicity of N-[4-(5-nitro-2-furyl)-2-thiazolyl]acetamide. Dietary administration of N-[4-(5-nitro-2-furyl)-2-thiazolyl]acetamide to mice for 14 weeks followed by 16 weeks of control diet resulted in a high incidence of lymphocytic leukemia and a low incidence of forestomach squamous cell papillomas. The coadministration of p-hydroxyacetanilide at a dose of 1.0% with either 250 or 500 ppm of N-[4-(5-nitro-2-furyl)-2-thiazolyl]acetamide resulted in inhibition of leukemogenesis, whereas when p-hydroxyacetanilide was coadministered with 1000 ppm of N-[4-(5-nitro-2-furyl)-2-thiazolyl]acetamide the leukemia incidence was not significantly reduced, but the latent period was prolonged. When sodium sulfate was administered with p-hydroxyacetanilide and N-[4-(5-nitro-2-furyl)-2-thiazolyl]acetamide, leukemogenesis was partially restored. L-Methionine, fed in place of sodium sulfate, unblocked leukemogenicity inhibition by p-hydroxyacetanilide. None of these chemicals, p-hydroxyacetanilide, sodium sulfate, or L-methionine, significantly affected the incidence of forestomach papillomas induced by N-[4-(5-nitro-2-furyl)-2-thiazolyl]acetamide, although tumor incidences in all groups were low. p-Hydroxyacetanilide and sodium sulfate had no significant effect on the high incidence of stomach tumors induced by formic acid 2-[4-(5-nitro-2-furyl)-2-thiazolyl]hydrazide or bladder tumors induced by N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide.


Effect of glucan, a macrophage activator, on murine hemopoietic cell proliferation in diffusion chambers in mice. Pretreatment of mice with glucan, a potent macrophage activator, resulted in enhanced myeloid cluster and colony formation by bone marrow cells in diffusion chambers implanted into the peritoneal cavity. Simultaneously, erythroid colony formation was also augmented. In some experiments the plasma clots formed inside the chambers were dissolved, and the number of hematopoietic cells was determined. An increased yield of early proliferative cells, granulocytes, and macrophages was found in glucan-treated hosts. Concomitantly, higher leukocyte counts were noted in the peripheral blood of treated animals. These results suggest that glucan has a strong stimulatory effect on hematopoiesis. This stimulation is probably mediated by humoral factors of host animal origin rather than by direct interaction with proliferating hematopoietic precursors enclosed within the chambers.


Induction of plasminogen activator in cultured cells by macrocyclic plant diterpene esters and other agents related to tumor promotion. In vitro systems that are responsive to tumor-promoting agents may facilitate the identification of such agents and the analysis of their mode of action. We have previously reported that the potent tumor promoter phorbol-12-myristate-13-acetate induces the synthesis of the enzyme plasminogen activator in cultured chick embryo fibroblasts. We have, therefore, tested various compounds for their ability to induce plasminogen activator in chicken embryo fibroblasts. Among these, phorbol esters and other macrocyclic diterpene esters isolated from species of the families Euphorbiaceae and Thymelaeaceae were potent inducers of plasminogen activator. These compounds maximally induced enzyme to the same levels, although they differed in their relative molar potencies. Structural requirements for in vitro activity paralleled the requirements for activity in vivo. These results indicate that induction of plasminogen activator is a useful marker for the biologically active macrocyclic diterpene esters. On the other hand, tumor-promoting agents such as anthralin, cantharidin, Tween 60, and tobacco leaf extract failed to induce plasminogen activator.


Mammary tumors induced in rats by adriamycin and daunomycin. The two anthracycline antitumor antibiotics, Adriamycin and daunomycin (DM), induced a high incidence of mammary tumors, both fibroadenomas and adenocarcinomas, in female rats that received a single i.v. dose, thus confirming previous results. The incidence of DM-induced adenocarcinomas increased with the dose of the drug, whereas the incidence of Adriamycin-induced adenocarcinomas showed a plateau at 5 mg/kg and above. Adriamycin- and DM-induced fibroadenomas showed a peak at lower doses (about 5 to 6 mg/kg). With the highest DM dose (12.5 mg/kg) used, there was a slight prevalence of adenocarcinomas over fibroadenomas.


Apex-carotis diagram as related to systolic and diastolic time intervals in myocardial infarction. Simultaneous recordings of the electrocardiogram, phonocardiogram carotid pulse tracing and left apex cardiogram were obtained in 32 patients with myocardial infarction and 62 normal subjects. This allowed to measure systolic and diastolic time intervals and to construct the apex-carotis diagram (ACD), a new mechanocardiographic method which integrates the carotid pulse tracing and the apexcardiogram in an orthogonal coordinate system. In myocardial infarction, the ACD showed a decrease of the field of ventricular filling, a decrease of the field of ventricular ejection and an increase of the diastolic subsegment. A. The measurement of time intervals showed statistically significant information in those which were directly related to the deformation of the ACD in patients with myocardial infarction.


Pathogenesis of isoproterenol-induced myocardial lesions: its reation to human 'coagulative myocytolysis'. Animals develop 'infarct-like' lesions when injected with isoproterenol (ISP), a potent synthetic catecholamine. These lesions are morphologically similar to those of 'coagulative myocytolysis' (COAM) or myofibrillar degeneration, one of the findings described in acute myocardial infarction and sudden death in man. Wistar rats were divided into 8 groups: some were injected with 10 mg/kg ISP i.p. plus 5 muCi of tritiated ISP, while others served as control. Animals were sacrified at 5 and 30 min and 24 and 72 h. The ISP-induced lesions were studied by means of light microscopy, histochemistry, autoradiography and electron microscopy. Myofibrillar degeneration, positive tests for ischemia, increase of succinic dehydrogenase enzymes, hypercontraction and widening of Z bands of sarcomers were correlated with the rapid distribution of ISP. These lesions were minimized by prenylamine, a drug which inhibits catecholamine effects by slowing down Ca transport. It is concluded that myocardial necrosis induced by ISP is probably due to a primary act on the sarcolemmal membrane, followed by stimulation of adenylate cyclase, activation of Ca and Na channels, exaggreated Ca inflow, excess of excitation-contraction coupling mechanism, energy consumption and cellular death. The close resemblance of human COAM to ISP-induced lesions suggests that similar mechanisms may be involved.


Myocardial infarction with patent coronary arteries. A 62-year-old patient suffered an acute anterior wall infarction as documented by clinical, electrocardiographic and enzymatic evidence. His ECG returned to a near normal pattern on the 5th day. The next day the patient died suddenly. Post mortem examination revealed a transmural anterior infarction with a mural thrombus, and a fresh thrombus in the left renal artery, but the coronary arteries were patient with only slight arteriosclerotic changes. We assume that a coronary thrombus might have been the cause of the infarction, with subsequent lysis. Such early lysis (6 days after the infarction) has not yet been demonstrated in earlier reports.


Hemodynamic changes during hemodialysis. 35 patients with chronic renal failure were examined during the first 2 h of hemodialysis by invasive and non-invasive methods. The cardiac output was determined by the dye dilution technique in 11 of these patients and by Swan-Ganz catheterization in 5. In the patients without severe myocardial damage, the cardiac output during hemodialysis showed a significant increase (p less than 0.05), accompanied by a significant decrease of both mean blood pressure (p less than 0.05) and total peripheral resistance (p less than 0.05). Mean pulmonary artery pressure and pulmonary artery wedge pressure were reduced in all cases during hemodialysis. The increase in cardiac output during hemodialysis in patients with chronic renal failure may be attributed to the decrease in afterload.


Postmyocardial infarction syndrome. Unusual mode of presentation. The postmyocardial infarction syndrome usually presents weeks after acute myocardial infarction as pericarditis associated with fever, leukocytosis, high sedimentation rate and pulmonary infiltrations. The unusual feature of the case discussed here was severe left shoulder pain resembling subdeltoid bursitis. Subsequently signs of pleuritis appeared prior to the classical picture of Dressler's syndrome. There was a dramatic response of steroid therapy.


Haemodynamic effects of supraventricular tachycardias and their alterations by electrically and verapamil induced termination. The haemodynamic effects of electrically initiated supraventricular tachycardias were studied in 10 otherwise healthy patients. With the beginning of the dysrhythmia there was a sharp decrease of systemic arterial and left ventricular systolic pressure, dP/dtmax, cardiac index, and stroke volume. Then, these parameters except stroke volume exhibited an increase, but were statistically different from control until the tachycardia was electrically stopped at the tenth minute. Mean pulmonary artery pressure rose steadily and remained on an elevated level which was reached between the third and fifth minute. After cessation there was a short augmentation of systemic arterial and left ventricular systolic pressure as well as of dP/dtmax and cardiac index. Mean pulmonary artery pressure steadily decreased and for all parameters control values were reached at about the third minute. When the tachycardia was terminated at about the same time by an i.v. injection of 10 mg of verapamil the 'post-tachycardial potentiation' was less marked or even absent. Mean arterial and left ventricular pressure was lower and mean pulmonary artery pressure remained elevated as compared with the values observed after electrical termination. Cardiac index and dP/dtmax showed no significant differences. It can be concluded that verapamil in a dosage sufficient to terminate the arrhythmia did not exhibit additional negative inotropic effects.


Influence of alterations in sinus rate on determination of drug-induced changes in ventricular automaticity. The interrelationship between drug-induced changes in heart rate and drug-induced alterations in ventricular automaticity was studied in dogs with intact conduction systems and dogs with surgically-induced complete heart block. The effects of epinephrine (0.5 microgram-kg-1-min-1) and propranolol (1.0 mg-kg-1) on ventricular automaticity were shown to be partially concealed by heart rate changes produced by these agents. Partial concealment of ventricular automaticity changes was shown to result from an alteration in the degree of overdrive suppression secondary to rate changes. Changes in the degree of overdrive suppression have a masking effect on drug-induced alterations in ventricular automaticity and only when the degree of suppression was held constant could the full extent of drug effects on ventricular automaticity be determined. Following vagal stimulation or rapid pacing, the rate of recovery from overdrive suppression as measured by the number of ventricular beats in 30 s was shown to be a dependable index of ventricular automaticity. It was concluded that determinations of drug effects on ventricular automaticity should take into account changes in heart rate produced by the drug. A method for determining ventricular automaticity is described which matches overdrive suppression during the control period to that during drug action in order to cancel out the influence of changes in heart rate on ventricular automaticity.


Vasodilator mechanism of the intracerebral (non-sympathetic) adrenergic pathway. Stimulation of the intracerebral noradrenergic pathway causes a vasodilatation in the hypothalamus. We have investigated whether this vasodilatation is caused by a direct vascular innervation or whether it is secondary to an activation of hypothalamic neurons. Non-specific neuronal activation using glutamate increased the mean hypothalamic blood flow. Depression of neuronal activity using barbiturate reduced hypothalamic blood flow and blocked the glutamate and the intracerebral noradrenergic pathway-induced vasodilatation. These results suggest that stimulation of the intracerebral noradrenergic pathway increases hypothalamic neuronal activity which indirectly causes a vasodilatation.


Growth related changes in the content of heparin and 5-hydroxytryptamine of mast cells. Heparin and 5-hydroxytryptamine (5-HT) were quantitated cytofluorometrically in individual mast cells from rats of various ages and body weights. Mast cells were studied in animals 35-200 days of age (150-575 g) representing a period of major body growth and about a quarter of the life span of the rat. Mast cell numbers as well as the content of both heparin and 5-HT in the mast cells was found to be strongly related to body weight and age of the animals. The number of mast cells increased about 3.5 times, the content of heparin in mast cells was doubled and the content of 5-HT increased at least three times during the growth period studied. There were great variations in the content of heparin and 5-HT within the cell populations of both young and old animals. The heparin content in the mast cell populations appeared to be either approximately normally distributed or slightly positively skewed. The skewness was not as marked as in a log-normal distribution. The 5-HT distribution profiles, on the other hand, were more strongly positively skewed. Except in the youngest age group, the 5-HT content appeared to be log-normally distributed within the mast cell population. A strong positive correlation was found between the median values of 5-HT and heparin content in the mast cell populations of growing rats.


Cytochemistry and x-ray microprobe analysis of the midgut of Tomocerus minor lubbock (insecta, collembola) with special reference to the physiological significance of the mineral concretions. Histochemical and cytochemical analyses have been made on the mineral concretions within the midgut cells of Tomocerus minor. The classical histochemical methods are not specific and precise enough and have been supplemented with cytochemical techniques on ultrathin sections. The most interesting of these was the K-pyroantimonate technique combined with glutaraldehyde-osmium fixation. This technique shows the distribution of cations such as Ca++, K+, Mg++ and Na+ on the concentric layers of the concretions. Chloride ions can be detected by means of the silver lactate technique. The action of calcium chelators such as E.D.T.A. shows an important distribution of calcium ions in the concretions. The spectra obtained by electron probe microanalysis from areas of fresh, dried and carbon coated midguts as well as from carbon coated semithin or ultrathin sections reveal the presence of Ca, K, Mg, S, Cl and P principally. Other elements such as aluminium, silicon and manganese have also been detected. Iron is not always present. The chemical and X-ray analytical investigations indicate that the midgut concretions are mainly built up of calcium, potassium, magnesium and sodium phosphates, perhaps associated with chlorides and carbonates. An organic matrix formed by polysaccharides seems to join the different mineral layers. These concretions may be formed within the vesicles of rough endoplasmic reticulum. The midgut cells are highly differentiated and very active in transport. Extensive basal infoldings and apical microvilli as well as lateral membranes are a site of small cationic deposits. The possible pathway of ion transport in the cell and the physiological significance of the concretions are discussed. The principal function of these concretions seems to be the maintenance of the mineral balance and to trap foreign and excess ions.


An insect retina without microvilli in the male scale insect, Eriococcus sp. (eriococcidae, homoptera). Male scale insects of an undescribed Australian species of Eriococcus have no compound eyes but show an extraordinary arrangement of three pairs of ocelli: One pair is positioned dorsolaterally where most insects have their compound eyes. Another pair looks ventrally and is placed where insects usually have their mouthparts, and there are two small lateral ocelli. Corneal nipples and a spherical lens with an estimated F-number only 0.55 are structural adaptations considered to increase the overall light sensitivity in order to compensate for the poor quantum capture of the shallow retina whose rhabdomes are only 3 micrometer long. The outer segment of each receptor cell consists of a central core of cytoplasm containing mitochondria and a peripheral cylinder of about 16 "rhabdomeres". There is no optical separation between neighbouring outer segments. Uniquely in arthropod eyes, the light sensitive structures are not composed of cylindrical microvilli, but consist of membrane stacks whose configuration is analogous to the stacked plates of vertebrate cones. At present no conclusive answer can be given as to why the photoreceptors have plates instead of microvilli. Comparative calculations show that they do not contain more photosensitive membrane per unit volume than rhabdomeres of fly ocelli.


The junctional connections between the cells of the urinary bladder in the rat. The junctional connections between the cells of the urinary bladder epithelium in rat have been studied by freeze-fracturing. Tight junctions and desmosomes are known as structural features of the epithelium. In addition, gap junctions (nexus) have been found to connect the epithelial cells in an irregular distribution pattern. The junction size ranges from few assembled particles up to plaques with irregular forms. This may indicate that the gap junctions are mobile structures. The functional significance of the junctions in comparison with electrophysiological data is discussed.


Localization of glyoxylic acid-induced histofluorescence in surgically isolated medial basal hypothalamus of the rat. Examination of glyoxylic acid-induced catecholamine histofluorescence in the hypothalamic median eminence of adult male rats revealed a linear pattern of fine varicosities coursing through the ependymal and fibrous zones, suggestive of juxtaposition to tanycytes. In order to determine the origin of these terminals, adult rats were subjected to complete isolation of the medial basal hypothalamus, using a small Halasz-Pupp knife. As rapidly as 24h after this "deafferentation" degenerative axon profiles were observed dorsal, as well as anterior and lateral, to the knife track. Occasionally at three days postoperatively, and routinely by seven days after surgery, fine-sized new fibres were seen passing through the knife wound. The linear profiles of varicosities observed in the normal median eminence remained traceable in the experimental preparations; the site of origin for these terminals therefore appears to be neurons of the arcuate (A12) and rostral periventricular (A14) regions. The results also indicate that fibres innervating the isolated area are capable of morphologically demonstrable new growth. The observations bear functional implications in assessing endocrine regulation following MBH isolation of the type used in this study.


Light and electron microscopic immunocytochemical localization of thyroglobulin in the thyroid gland of the anadromous sea lamprey, Petromyzon marinus L., during its upstream migration. Antibodies made against thyroglobulin (TG) were used in an immunocytochemical study for the light and electron microscopic localization of TG in the thyroid gland of the anadromous sea lamprey, Petromyzon marinus, during its upstream migration. TG was found in the follicular lumen and in some colloid droplets within the follicular cells. Except for an immunoreactive product observed in a small portion of the interstitial connective tissue, the location of TG in the lamprey was similar to that in the thyroid of the rat.


The paramedial neurosecretory cells of the suboesophageal ganglion of the cricket, Teleogryllus commodus (walk.). Ovariectomy, performed immediately after the final hatch, caused a reduction of stainable (neurosecretory?) MATERIAL IN THE PARAMEDIAL NEUROSECREtory cells (PNC) (A-type) of the suboesophageal ganglion in 10 day-old females of Teleogryllus commodus (Walk.). A concomitant increase in nuclear volume and in the incorporation of 35S-cysteine indicates increased synthesis of neurosecretory material. From these findings it is concluded that more stainable material is secreted in the cerebral neurohaemal organ after ovariectomy. A functional relationship between the PNC and the ovaries is suggested.


The paramedial neurosecretory cells of the suboesophageal ganglion in the cricket, Teleogryllus commodus (walk.). II. Electron microscopic studies in normal and ovariectomized females. The paramedian neurosecretory cells (PNC) (A-type) in the suboesophageal ganglion of the cricket, Teleogryllus commodus (Walk.), have been studied by electron microscopy. In control animals (10 day-old virgin females) three different cell stages could be distinguished: Stage 1 shows a variable content of elementary granules and characteristics of actively synthesising cells. Stage 2 is characterised by the presence of numerous fusion bodies, which are formed by the coalescence of elementary granules, presumably for storage purposes. In stage 3 granules are degraded in lysosomes (?). While the production of material rich in cysteine increases after ovariectomy (Dürnberger et al., 1978), the fine structure of the cells is essentially unchanged. The only noted differences are an increased lysosomal synthetic activity and the existence of stages intermediate between 2 and 3, which were never found in control animals. The functional significance of the different stages is discussed.


Steroid transport through the surface of the prothoracic gland cells in Galleria mellonella L. Steroid transport through the cell surface of the giant polyploid prothoracic gland cells of Galleria mellonella L. was studied by an ultracytochemical method. The alkaloid digitonin, known to form a complex with all sterols having a free-OH radical in position 3, proved to be suitable for studying the interiorisation of moulting hormone precursors and the release of synthesized hormones. The results suggest that cholesterol uptake in the last larval instar occurs by macropinocytosis during the feeding period, while the release of the steroids produced by the gland occurs by reverse micropinocytosis mostly on days 5-7 of the instar. The two processes are not simultaneous. The intracytoplasmic localisation of the reaction product confirms the steroidogenic role of the prothoracic gland.


An ultrastructural study of the dermal papulae of the starfish, Asterias rubens, with special reference to innervation of the muscles. The ultrastructure of the dermal papulae of a starfish (Asterias rubens) is consistent with a respiratory function. The present study has shown no regions specialized for excretory mechanisms. The papulae consist of an outer ectodermal epithelium of sensory, support and gland cells and a small basiepithelial nerve plexus. A true basement membrane lies underneath the epithelium and regularly arranged longitudinal muscle bundles lie within the connective tissue. The coelomic cavity of the papulae is lined with ciliated endothelial cells, which overlie an irregular layer of circular muscles. A system of canals that are not lined by cells occurs at the base of the papulae with the circular muscles. The longitudinal and circular muscles show a different gross morphological arrangement and innervation. This paper proposes that there are "skeletal" and "visceral" types of smooth muscle in echinoderms and discusses this proposal at length.


The salivary glands of the cockroach Nauphoeta cinerea (Olivier). A study of its innervation by light and scanning electron microscopy. The innervation of the salivary gland of the cockroach Nauphoeta cinerea (Olivier) has been investigated with the use of light and scanning electron microscopy. Light microscopy of methylene blue stained glands reveals the presence of a dual innervation arising from the ventral nerve cord and the stomodeal nervous system; the principal innervation is that from the ventral nerve cord which passes to the gland via the reservoir ducts. Branches of these nerves form a plexus on the acinar surface, the axons of which exhibit swelling at irregular intervals. The presence of this surface plexus and the axonal swellings was confirmed by scanning electron microscopy both in normal glands and in those in which the basal lamina had been removed by means of an HCl-collagenase digestion method. No acinar plexus was seen to be formed by branches of the stomatogastric nerve that were associated with the gland. However, other branches of this nerve were clearly connected with a complex network of multipolar neurones on the surfaces of the anterior regions of both salivary reservoirs.


Responses of lysosomes in the digestive cells of the common mussel, Mytilus edulis, to sex steroids and cortisol. Estradiol-17beta and progesterone at physiological concentrations in vivo induced a reduction in lysosomal stability in the digestive cells of Mytilus edulis. Estradiol-17beta (10(-8) M) also reduced lysosomal stability within 15 min in vitro. Lysosomal stability was determined cytochemically as the labilisation period for latent N-acetyl-beta-hexosaminidase and this was shown to be inversely related to microdensitometric measurements of staining intensity for this enzyme. Estradiol-17beta did not appear to induce complete labilisation or cytochemical activation of lysosomal hexosaminidase and a second, much longer labilisation period could be determined for this hormone. The effects of estradiol-17beta were partially counteracted by cortisol (10(-2) M). There was an increase in PAS staining of secondary lysosomes and an increase in alcian blue staining of residual bodies in digestive cells of animals exposed to estradiol-17beta, while no changes could be observed in basophil cells. The significance of these results is discussed in terms of the physiological role of digestive cells and their possible function as target cells for estradiol-17beta and progesterone.


Nerve-Purkinje fiber relationship in the moderator band of bovine and caprine heart. The moderator band in the heart of the ox and goat contains bundles of Purkinje fibers and nerve fibers separated by connective tissue. The axons are mostly unmyelinated and embedded in the cytoplasm of Schwann cells. Small bundles of axons run close to the Purkinje fibers. The axons dilate into varicosities 0.5 to 1.6mu in diameter (mean 0.95mu), containing three types of vesicles: 1)agranular vesicles with a diameter of 400-500 A, 2) large dense-cored vesicles with a diameter of 800-1200 A, 3) small dense-cored vesicles with a diameter of 500 A. Most varicosities contain agranular vesicles together with a few large dense-cored vesicles. The gap between the varicosities and the nearest Purkinje fiber is unusually wide and normally varies between 0.3mu and 0.8mu. No intimate nerve-Purkinje fiber contacts, with a cleft of 200 A, were observed.


Influence of gonadotropic hormones on the ultrastructure of rat pinealocytes. The influence of gonadotropic hormones on the ultrastructure of rat pinealocytes was studied. Human chorionic gonadotropin (HCG) as well as pregnant mare serum gonadotropin (PMSG) caused a marked activation of pinealocytes. It is characterised by a conspicuous proliferation of the granular endoplasmic reticulum and Golgi apparatus as well as an increase in number of dense core vesicles, mitochondria, dense bodies, subsurface cisternae and vesicles in the terminal buds of pinealocyte processes. The changes after HCG administration were more pronounced than after PMSG.


Uptake of horseradish peroxydase by the testis of locusta migratoria during the last larval instar; relation with variations of ecdysteroid levels in haemolymph. By using horseradish peroxydase (HRP) as a tracer, it is shown that the gonial region of the locust testis is an "open" compartment which is almost always freely penetrated by the tracer. During the last larval instar, however, the penetration of HRP decreases and ceases at the time when high levels of ecdysteroids are detected in the haemolymph by radioimmunoassay. A cause and effect relationship between tracer uptake and hormonal level could not be demonstrated by the experiments carried out up to now. From ultrastructural observations of the testis, it is concluded that the temporary isolation of the gonial compartment is not based upon any morphological structure which could act as a barrier. Penetration of the macromolecule is considered as the expression of an active uptake by the testis and the short period of nonpenetrability as a state of inertia whose significance remains to be discovered.


Local degenerative changes in the drum muscles of piranhas (serrasalminae, characidae). In the posterior drum muscle of the piranha structural alterations are frequently observed. Electron microscopic studies revealed a disordering of the myofibrils in these regions, accompanied by conspicuous changes in the mitochondria. As the degree of disorder increases, the mitochondrial cristae initially swell to form vesicles. Eventually the mitochondria become filled with myelin-like lamellar structures, which in many cases coalesce to form a dense outer wall. A striking concentration of lysosomes into localized masses was also characteristic of these regions.


Observations on the cytolemma of the olfactory receptor cell in the newt. 1. Freeze replica analysis. The fine structure of the cytolemma of olfactory receptor cells in the newt was studied by the freeze-fracture replica method. Two kinds of receptor cells were recognized, namely ciliated cells (ciliary type) and non-ciliated cells (microvilli type). The cytolemma of olfactory knobs as well as their processes from both types of receptor cells showed an abundance of large membrane particles 80 approximately 110 A in diameter. The large square aggregation of membrane particles, 0.1 x 0.1 micron to 0.2 x 0.3 micron in size, consisting of 50 approximately 100 cuboidal subunits, were found in the cytolemma of the dendrite. A structural model of aggregation is presented. The soma of the receptor cell revealed large pitted membrane particles about 140 A in diameter. These particles are possibly the morphologic counterpart to ionophores which have been proposed by electrophysiological studies.