The contribution of interstitial implants to treatment planning.

Delivery of radiation to a deeply located tumor site by external radiation is only accomplished by traversal of normal tissues. Even with the physical advantages of high energy radiation or heavy particles, this is still unwanted radiation. Even a tumor-seeking isotope, such as radio-iodine for carcinoma of the thyroid, must still have an initial total body distribution. While interstitial sources, removable or permanent, present a personnel exposure problem, the delivery and deposition of ionizing radiation in this way has unequalled simplicity, versatility, and availability. Although the method is as old as radiotherapy itself, three dimensional computer dosimetry has given it extended applicability, and extends an invitation to innovations in achieving ideal dose distribution.


Phase I study of ftorafur, an analog of 5-fluorouracil.

Ftorafur, a furanyl analog of 5-fluorouracil (5-FU), is reported to be five to six times less toxic and possibly more effective in cancer of the breast and colon than 5-FU. The drug was synthesized, formulated, and utilized in toxicologic studies, and then in 24 patients with advanced incurable malignancies. When Ftorafur is given by intravenous push, it results in immediate flushing, dizziness, nausea, retching, and in some cases transient hypotension. These immediate side effects are largely eliminated by administering the drug slowly by infusion. In patients, 60 mg/kg of Ftorafur given i.v. daily for up to 10 days resulted in mild toxicity. However, 80 mg/kg given i.v. daily for 7 days resulted in severe toxicity, with nausea, vomiting, stomatitis, leukopenia, and thrombocytopenia. These studies confirm those of the Russian investigators as to toxicity and dosage, even with a different method of administration more convenient for therapy. Phase II studies are presently being carried out to compare the effectiveness of Ftorafur and 5-FU.


Clinical and theoretical aspects of the treatment of surgically unresectable retroperitoneal malignancy with combined intra-arterial actinomycin-D and radiotherapy.

A small pilot series (eight patients) of surgically unresectable retroperitoneal tumors treated with radiotherapy and a selective, prolonged, continuous intra-arterial infusion of actinomycin-D is discussed, in addition to the possible theoretical advantages for this therapy. For such tumors, there is a very low probability of obtaining local control with conventional radiotherapy alone. However, on the basis of recent knowledge from radiobiology and molecular biology, the technique is a rational attempt to improve the local control probability. Geographic miss with radiotherapy portals is another major cause for local failure with such tumors. We also emphasize the importance of detailed tumor localization procedures. The local responses, some of the local controls, the palliation achieved, and the lack of significant morbidity with this technique have been encouraging. We therefore consider it worthy of further clinical investigation.


Comparison of continuously infused 5-fluorouracil with bolus injection in treatment of patients with colorectal adenocarcinoma.

In a randomized series of 70 patients with with colo rectal adenocarcinoma, a comparison of systemic 5-fluorouracil chemotherapy administered as a continuous 120-hours infusion vs. intravenous bolus injection daily for 5 days demonstrated superiority of prolonged intravenous infusion. The most striking advantage of prolonged infusion of 5-FU was the absence of myelotoxicity. Fifteen of the 34 patients treated with infusion and 8 of the 36 patients treated by bolus injection developed objective tumor responses. The difference in response rate at least in part is explainable by unequal distribution of patients with different characteristics between the two treatment groups.


Heparin and chemotherapy in the management of inoperable lung carcinoma.

Twenty-eight patients with inoperable or metastatic carcinoma of the lung who failed to respond to conventional chemotherapy and/or radiotherapy were entered in this study. All of them received repeated courses of multiple chemotherapy (cyclophosphamide, 5-fluorouracil, 6-thioguanine, methotrexate, and vincristine) with or without concurrent intravenous heparin anticoagulation. No tumor regression was noted in any of the 14 patients who received the multiple chemotherapy only. On the contrary, tumor progression was seen in all of them, and subsequently 12 died of their disease. The other 14 patients were anticoagulated with heparin, then received the same multiple chemotherapeutics while anticoagulated. Over 50% tumor regression was noted clinically and radiologically, and occasionally demonstrated histologically in 7 of them. Two patients in this group are alive and well for 1 1/2 years. No increase in toxicity or metastases was noted. The 2 patients who had progression of their disease while on the multiple chemotherapy program alone showed tumor regression when they received the same chemotherapy after heparinization.


Papillary cystadenofibroma of endometrium: a histochemical and ultrastructural study.

The light and electron microscopic as well as the histochemical characteristics of a papillary cystadenofibroma of the endometrium are described. The neoplasm arose in the lower uterine segment and was composed of a florid fibroblastic growth arranged in club-shaped papillae projecting into clefts and cystic spaces. The epithelium lining the plicae, recesses, and cysts was exclusively of the mucous-secreting type and bore identical histochemical and subcellular characteristics to that of the normal endocervical epithelium. Essentially similar papillary lesions were recently reported in the endocervix, endometrium, and fallopian tube. The pathogenesis and differential diagnosis of this distinct neoplasm are discussed in the light of the available morphological data.


Ultrastructure of primary and metastatic ovarian carcinoids: analysis of 11 cases.

The ultrastructure of 11 ovarian carcinoids was investigated. The 6 carcinoids with an insular pattern primary in the ovary or metastatic to it from the ileum displayed granules that were pleomorphic (dumbbell and reniform shaped) and varied from 90 to 410 mum, with an average diameter of 210 mum. Five trabecular carcinoids primary in the ovary or metastatic to if from the pancreas contained uniformly round granules with an average diameter of 185 mum and a range of 150-210 mum. These data confirm other reports that pleomorphic granules are typically associated with insular carcinoids of the midgut, and round granules with trabecular carcinoids of the foregut and hindgut.


Microinvasive carcinoma of the cervix. The significance of lymphatic invasion and confluent patterns of stromal growth.

Thirty examples of microinvasive carcinoma of the cervix were studied to determine the presence or absence of lymphatic invasion. Invasion of spaces resembling lymphatic spaces was demonstrated by step sections in more than half of the cases (57%). The pattern of invasion within the stroma, whether confluent or finger-like, did not correlate with the presence or absence of invasion of these spaces. All of the patients had been treated with a pelvic lymphadenectomy, and all of the lymph nodes were negative for metastasis. Thus, neither invasion of what have been considered to be lymphatics nor a confluent pattern of stromal invasion should be a criterion for excluding either the diagnosis of microinvasion or treatment by simple hysterectomy.


Phytohemagglutinin-induced lymphocyte transformation in newly presenting patients with primary carcinoma of the lung.

The transformation of peripheral blood lymphocytes in response to PHA was studied in 37 newly presenting patients who were subsequently proven to have carcinoma of the lung. When compared with healthy age- and sex-matched normal controls, no differences were noted in the thymidine uptake of the unstimulated lymphocytes in culture or in the response to any of the three dose levels of PHA used. Neither the extent of the spread of the carcinoma nor the type of its histology showed any correlation with the PHA response, but the PHA response was significantly depressed within 14 days of death in 7 patients. No evidence for serum inhibitory factors was found.


The influence of splenectomy on the invitro lymphocyte response to phytohemagglutinin and pokeweed mitogen in Hodgkin's disease.

Using tissue culture techniques, the 14C-thymidine incorporation of peripheral lymphocytes in 17 Hodgkin's patients was tested before and after splenectomy under stimulation with phytohemagglutinin and pokeweed. Incorporation under phytohemagglutinin stimulation about 10 days after splenectomy was not affected in Hodgkin's patients with pathologic Stages I and II, but was significantly (p less than 0.005) increased in those with Stages III and IV. The total PHA stimulation potency, i.e. the product of the lymphocyte count and PHA stimulation, increased slightly in both groups. Incorporation under pokeweed stimulation after splenectomy did not significantly differ from that before the operation in the two groups. Although the number of cases studied is rather small, it is concluded that splenectomy causes no demonstrable untoward effect on the cellular immunologic potency. The immunologic state is more likely to be favorably influenced than unfavorably.


Chromosomes and causation of human cancer and leukemia. XII. Banding analysis of abnormal chromosomes in polycythemia vera.

The chromosome constitution of bone marrow cells was determined in 13 patients with polycythemia vera (PV). In 5 of these patients definite karyotypic abnormalities were found: 3 with 46,XY,Fq-; 1 with 46,XY,11q-, 13q-; and 1 with missing Y. The latter cytogenetic finding is thought not to be related to the PV. The 4 patients with partial deletions of chromosomes had been treated with 32P, and 3 of them with chemotherapy also. Karyotypes from 2 of these patients, 1 with 46,XY,20q-, and another with 46,XY,11q-,13q- were examined with G and/or Q banding. From the results of the banding analysis, it appears that the abnormal chromosomes were due to simple deletions at specific sites on their arms, particularly in the cases with the F abnormality (20q11). The breaks occurred in the regions C11q and D12q. The portions missing from the original chromosomes could not be found on any chromosome. Most patients with PV do not develop chromosomal abnormalities through the course of their disease; when such abnormalities appear (20q- in particular), they seem to result exclusively from radiation (and possibly chemo-) therapy. Thus, cytogenetic changes do not appear to play a crucial role in the genesis of PV.


The incidence of yolk sac tumor (endodermal sinus tumor) elements in germ cell tumors of the testis in adults.

The incidence of yolk sac tumor (endodermal sinus tumor) elements was studied in 147 germ cell neoplasms of the testis in adults observed over a 4 1/2-year period. Excluding 79 cases of pure seminoma, yolk sac tumor elements were found in 26 (38%) of 68 tumors; in 8 tumors the yolk sac tumor was the predominant element. Yolk sac tumor elements were found admixed with all other germ cell tumor elements. Tumors composed entirely of yolk sac tumor were not encountered. Fifteen (57%) of the 26 patients with tumors containing yolk sac tumor elements have died of their disease during the period under study, compared with 13 (31%) of the remaining 42 patients, suggesting that the prognosis of adults with testicular tumors containing yolk sac tumor elements is unfavorable. This is in contrast to the relatively good prognosis of infants and young children with testicular yolk sac tumor, and similar to the prognosis of female patients with ovarian yolk sac tumor. The results of the present study give further support to the view that yolk sac tumor (endodermal sinus tumor) is not adistinctive neoplasm of the infant's testis, but a germ cell neoplasm differentiating in the direction of yolk sac or vitelline structures, and occurring in the testis, ovary and extragonadal sites in common with other germ cell neoplasms.


Clinicopathologic review of 88 cases of carcinoma metastatic to the putuitary gland.

Clinical and pathologic features of 88 cases of carcinoma metastatic to the pituitary gland were reviewed. In 61 (69.3%), metastases were localized either in the posterior lobe alone or in the posterior and anterior lobes together; only 12 (13.6%) involved the anterior lobe alone. Diabetes insipidus was present in 6 patients (6.8%), one of whom also had clinical panhypopituitarism due to metastatic tumor and necrosis in the anterior pituitary lobe. Breast and lung were the most frequent primary sites in women and men, respectively. Sixty-four (72.7%) of these glands were grossly normal at necropsy. Metastases to the pituitary gland occur more frequently in the posterior lobe than in the anterior lobe, and my ve reflected clinically by diabetes insipidus in patients with diseminated carcinoma. Clinical panhypopituitarism is a rare accompaniment of anterior lobe involvement.


Serum immunoglobulin levels in patients with breast cancer.

Serum immunoglobulin levels IgA, IgG, and IgM have been estimated in 92 patients with breast cancer and 50 control patients, 40 of whom had benign disease of the breast. In patients with breast cancer, IgA was significantly raised at all stages and IgG was significantly reduced, but the two abnormalities were not necessarily concomitant. These findings may suggest a disturbance in the secretory immune system, and immunologic defect even when the cancer is localized to the breast.


Proliferative kinetics of central nervous system (CNS) leukemia.

The proliferative kinetics of the leukemic cells in the cerebrospinal fluid (CSF) were studied in three adults with CNS leukemia after 18 and 8 months while receiving an intensive treatment regimen. One (J.L.) had acute myeloblastic leukemia and developed CNS disease after 5 years' treatment with arabinosylcytosine and 6-thioguanine. All were in marrow remission at the time of study. G.H. had had no therapy for CNS disease, A.K. had had intrathecal methotrexate 2 months previously, and J.L. had recently completed radiotherapy (1900 R) to the head. An Ommaya reservoir was placed in a lateral ventricle and 3H-thymidine was injected into the resrvoir every 12 hours for 10 days; samples of cells were obtained by lumbar puncture periodically for autoradiography. In all patients the flash 3H-thymidine labeling index (LI) of the leukemic cells was less than 2% (determined in vitro) and the mitotic index less than 0.1%. After 10 days of 3H-thymidine injections in vivo, the LIs of the leukemic cells were 55%, 36%, and 21% in G.H., A.K., and J.L., respectively. These findings indicate that leukemic cells may proliferate very slowly in the CNS, and stress the difficulty of eradicating CNS leukemia with chemotherapeutic agents which are only active against proliferating cells.


Extraskeletal neoplasm resembling Ewing's sarcoma.

This article reviews the pathologic features and the behavior of 39 small, round, or oval cell sarcomas occurring in the soft tissues and considered histologically indistinguishable from Ewing's sarcoma of bone. The tumors affected chiefly young adults (median age 20 years) and most commonly involved the soft tissues of the lower extremity and the paravertebral region. Microscopically, they consisted of solidly packed small, round, or ovoid cells of great uniformity, arranged in sheets or lobules separated by strands of fibrous connective tissue. The nucleus of the tumor cells contained finely divided chromatin, a distinct nuclear membrane, and frequently a minute nucleolus. The scanty ill-defined cytoplasm contained varying amounts of glycogen. Sometimes the histologic picture was dominated by a "peritheliomatous" pattern, or by large areas of necrosis or hemorrhage. Followup data ranging from 1 month to 14 years were available in 35 of the 39 cases (93%). Of these, 13 were alive  and 22 had died. In the majority of the fatal cases, the clinical course was rapid; metastatic lesions developed within a few months after the primary tumor was excised. The lungs and the skeleton were the two most common sites of metastasis. Cure may be achieved by wide local excision of the tumor at an early stage of the disease, combined with radiation therapy and chemotherapy.


Combination chemotherapy with adriamycin and cyclophosphamide for advanced breast cancer.

Fifty-five consecutive women with advanced breast cancer were treated with a combination of adriamycin (40 mg/m2 administered intravenously on day 1) and cyclophosphamide (200 mg/m2/day given orally in divided doses for 4 days on days 3-6). Courses were repeated at 21-28-day intervals. The mean age for the 55 patients was 55 years (range, 37-77 years); 20% of the patients were 65 years or older. All patients were evaluable. Objective response (at least a 50% decrease in the size of all measurable lesions lasting for at least 1 month) was noted in 40 (80%) of the 50 patients who received an adequate trial of chemotherapy (a minimum of two courses). Six of the 40 responses observed were complete. The median duration of response was 10 months. Actuarial survival for the entire group of 55 patients was 80% at 6 months after initiating chemotherapy and 70% at 12 months. Survival for the 40 responding patients was 95% at 6 months and 80% at 12 months. Response rates by site of involvement were: soft tissue, 20/25 (80%); lymph node, 15/19 (79%); bone, 21/25 (84%); lung, 15/18 (83%); pleural effusion, 6/8 (75%); and liver, 7/10 (70%). Eighty-three percent of the responses were apparent after two courses of treatment and 98% were apparent after four courses. Toxicity was acceptable and included nausea, myelosuppression, alopecia, and reversible congestive heart failure (in 2 patients who received 550 mg/m2 of adriamycin). Chemotherapy with adriamycin and cyclophosphamide proved to be safe and effective for out-patient treatment of advanced breast cancer.


Comparison of prednisolone, vincristine, methotrexate, and 6-mercaptopurine vs. vincristine and prednisone induction therapy in childhood acute leukemia.

This was designed to compare vincristine-prednisone (VP) vs. prednisolone, vincristine, methotrexate, and 6-mercaptopurine (POMP) with respect to response rates and toxicity for induction therapy in acute leukemia. Children with acute lymphoblastic, acute undifferentiated, or acute stem cell leukemia were stratified on the basis of initial leukocyte count and age, then randomly assigned to POMP or VP induction therapy. On the POMP regime, 19/34 (56%) achieved complete remission (CR), 7 achieved partial remission (PR), and 5 did not respond (NR). Three died prior to day 25 of the study. On the VP regime, 37/39 (95%) had CR, and 2 NR. On the VP regime neither sepsis nor toxicity were significant problems. The POMP regime had a higher incidence of sepsis and other toxicities frequently causing therapy interruption, but not enequivocally causing the poor response rate. Several other factors were evaluated as possible causes for the lack of response to POMP therapy.


An analysis of a multiple-drug program in the treatment of patients with advanced breast cancer utilizing 5-fluorouracil, cyclophosphamide, and prednisone with or without vincristine.

Ninety patients with advanced breast cancer received a polychemotherapeutic program composed of 5-fluorouracil, cyclophosphamide, and prednisone with or without vincristine as a control group in a series of four consecutive Phase II clinical trials of new drug programs. Objective regression rates were 59% without vincristine and 46% with vincristine. Projected mean length of regressions exceeds 1 year. Site of dominant disease, disease-free interval, or performance scale score (if score was 0, 1, or 2, ECOG scale) failed to influence response rates; decreasing response rates were noted as the length of time increased after menopause. No advantage existed in patients experiencing severe myelosuppression (nadir leukocyte count of less than 1,500/mm), and appreciable response rates occurred without significant myelosuppression. The addition of vincristine to the regimen failed to increase the response rates, and only increased toxicity. The program as outlined is reasonably tolerable and effective for this group of patients with advanced breast cancer.


The response of the local immunoglobulin system to malignant lesions of the stomach. A new diagnostic test.

The response of the local secretory immunoglobulin system to tumor antigens was studied in 71 patients suspected of harboring a gastric malignancy. Gastric aspirates were obtained by fiberoptic endoscopy and measured on single radial immunodiffusion plates (Behring Diagnostics). Patients with malignant neoplasms of the stomach were divided into Type I and Type II lesions, based on the extent and stage of the disease. Secretory IgA titers were elevated in all patients with a Type I malignant tumor confirmed by histologic examination; mean 6.1 mg/100 (SD +/- 3.7 mg/100). This leads us to believe that  the host's response to malignant cells of the gastrointestinal system is an altered and elevated secretion of IgA. Evaluation of local immunoglobulin titers may be of value when used in conjunction with other diagnostic modalities in determining the nature of gastrointestinal lesions, particularly when the lesion is not metastatic or massively involving the gastric wall.


CEA levels in patients with colorectal polyps.

Preoperative plasma CEA levels were measured in 93 selected patients with histologically defined colorectal adenomata removed at fibroptic colonoscopy in order to determine whether CEA levels are elevated in patients with colonic polyps, or vary with different histologic patterns. None of the patients had inflammatory bowel disease, previous history of carcinoma, or evidence of liver disease. Fifteen percent of the patients had elevated CEA levels (greater than or equal to 2.5 ng/ml; Hansen method), and two-thirds of these were between 2.5 and 4.0 ng/ml. Increased association of elevated CEA levels was noted with old age, villous adenomas (2- to 4-fold), and increased tumor size (greater than 2.3-cm diameter; 2-fold), but not with foci of dysplasia or carcinoma in situ as such. One-half (7/14) of the patients with elevated CEA levels showed the following: two patients had villous tumors with carcinoma in situ, one had a villous adenoma, two had mixed villous and tubular adenomas (with a high proportion of villous pattern), and two were subsequently shown to have carcinoma elsewhere in the colon. It is uncertain that the polyps were the source of the elevated circulating CEA levels; other factors including smoking and patient selection need to be considered. This preliminary study suggests that patients with colorectal adenomata and elevated circulating CEA may be at higher risk for the development of carcinoma. Further follow-up studies of the malignant potential of the polyp-bearing colon are essential.


Adenocarcinoma of the small intestine arising in Crohn's disease. Demonstration of a tumor-associated antigen in invasive and intraepithelial components.

A segment of small intestine surgically removed from a man with intestinal obstruction was found to have coexisting regional enteritis and an invasive adenocarcinoma associated with an area of intraepithelial neoplasia. The cells of the adenocarcinoma and the intraepithelial neoplasia contained a tumor-associated surface antigen capable of reacting with an antiserum prepared against a colonic carcinoma. The importance of thorough sampling of specimens of regional enteritis in accurate reporting of the incidence of carcinoma is stressed, as is the use of immunohistologic techniques as an adjunct to the morphologic diagnosis of preinvasive neoplasia.


End results of radiation therapy, alone and combination with 5-fluorouracil in colorectal cancers.

The authors retrospectively analyzed the results of irradiation in 148 cases of primary inoperable and recurrent adenocarcinoma of the colon and rectum treated at the Department of Radiation Therapy, Roswell Park Memorial Institute between 1962 and 1970. This group includes 95 recurrences and 53 inoperable primaries. Uninterrupted radiotherapy was used in 118 cases and split-course technique in 30 cases. Eleven patients received combined radiotherapy and surgery. Seventy-eight patients received a combination of 5-fluorouracil (5-FU) and irradiation. The response rate and survival of individual groups is discussed in detail. This study indicated that perineal recurrences should receive whole pelvic irradiation in addition to perineum field. Split-course technique appeared to yield a better survival than the uninterrupted course. The best 5-year survival rate (64%) is found in the group treated with a combination of radiation and surgery. For locally advanced, inoperable cancers, split-course technique, combined 5-FU and irradiation gave the best results, achieving longer palliation with improved quality of life and sometimes yielding cure (5-year survival).


Lymphographic demonstration of cyclic changes in lymph node size during Pel-Epstein fever.

Pel-Epstein fever cycles, consisting of 1-2 weeks of high fever separated by afebrile periods of the same duration, are classically characteristic of Hodgkin's disease. Clinical observation has determined that the lymph nodes enlarge during periods of fever and reduce in size as the fever subsides. To our knowledge, the waxing and waning of lymph nodes in tempo with the fever cycle in Hodgkin's disease have never before been documented by lymphography. The alterations we verified radiographically resemble cyclic swings in classic autoimmune diseases. Speculations are offered regarding the observed changes.


Primary malignant melanocytic tumors of the sympathetic ganglia, with an ultrastructural study of one.

Three cases of melanocytic tumors arising in the sympathetic chain were studied. A metastasis from one of them was studied with electron microscopy. Both light and electron microscopy demonstrated the presence in these tumors of true melanogenesis and autophagic activity in melanocytes as well as phagocytosis of mature melanin by associated histiocytes. Review of the embryology, biochemistry and in vitro culture of sympathetic nervous tissue showed a close relationship between it and pigmented cells in other parts of the body which are also derived from neural crest. These findings support the clinical and morphological conclusion that these rare pigmented tumors are true melanocytic tumors originating from the sympathetic chain. The malignant potential of these tumors is emphasized by the fact that the two patients who survived initial surgery later died of metastatic disease.


Induction of pulmonary metastases in both immune and nonimmune mice. Effect of the removal of a transplanted primary tumor.

In mice bearing a benzypyrene-induced fibrosarcoma tumor, the survival was determined of intravenously injected tumor cells at various intervals after previous immunization of experimental animals by induction and subsequent excision of a transplanted primary tumor in the soft tissues of the leg. Seven days after induction of a transplanted primary tumor, I.V. tumor cells produced fewer pulmonary metastases in immunized mice than in nonimmunized mice. When tumor cells were inoculated I.V. immediately following amputation of the transplanted primary tumor, the number of pulmonary metastases in the immunized and nonimmunized animals were similar; however, 6 hours, 7 days and 14 days after primary tumor excision, I.V. inoculated tumor cells produced a higher incidence of lung metastases in the immunized than in the nonimmunized mice. This increased survival of I.V. tumor cells following excision of the transplanted primary tumor may have relevance to the development of metastases after eradication of certain primary tumors in humans.


Prognosis in breast cancer utilizing histologic characteristics of the primary tumor.

A study was made of the inter-relationships and prognostic significance of structural characteristics found in primary breast cancers and their associated axillary lymph nodes. The prognostically favorable characteristics included the following. For the primary tumor: nuclear differentiation of the cancer cells, diffuse lymphoid cell infiltrations (LI) and perivenous lymphoid cell infiltrations (PVI). For the axillary lymph nodes: sinus histiocytosis (SH). Perivenous lymphoid cell infiltrations (PVI) in the primary tumor are found to be as important a prognostic factor as SH in the axillary lymph nodes; these two characteristics are found to be positively associated. Evaluation of the nuclear grade (NG), LI, and PVI in the primary tumor allows for the definition of association with cancer cells having a low (anaplastic) nuclear grade, and to be positively associated with follicular hyperplasia (FH) in the lymph nodes. We also found a positive association between the cellular responses to areas of in situ carcinoma and the cellular responses to accompanying invasive breast breast cancer tissue. They also provide a prognostic system for classifying breast cancer patients on the basis of the microscopic characteristics of the primary tumor and surrounding breast tissue. The latter system should be of value in comparing the therapeutic benefits of various treatments.


Carcinoembryonic antigen in 228 patients with carcinoma of the lung.

Two hundred and twenty-eight patients who were treated for carcinoma of the lung were followed and their plasma CEA levels assessed at intervals during the course of the disease. In addition, plasma samples were taken from 487 healthy blood  donors for comparison as a control. CEA assay is not selective or specific enough, at this time, to be used for screening purposes even though 68% of the patients who have lung cancer will have an elevated concentration of CEA regardless of the histological cell type. In patients with plasma levels of CEA above 15 ng/ml the prognosis is uniformly poor. CEA in the author's view does have value as a prognostic marker capable of suggesting the successful resection of a tumor and to a lesser degree confirming the clinical objective response to the radiotherapy or chemotherapy. It was found that the presence of CEA was not necessarily related to the volume of the tumor or the site of organ metastasis, but reflects the metabolic properties and characteristics of the individual tumor as it occurs in the patient.


Hodgkin's disease in the bone marrow.

Tumor involvement of the bone marrow in patients with Hodgkin's disease may be suspected in the presence of other manifestations of advanced disease such as fever, lymphopenia, hypoalbuminemia, mixed cellular histologic type, or Stage III or IV disease by other clinical parameters. It occurs more frequently in the older age groups. When anemia, leucopenia, and/or thrombocytopenia are present and are unrelated to recent bone marrow suppressant chemotherapy, marrow involvement is likely to be present. Bone marrow examination, done by multiple trephine biopsies, provides an adequate sampling of tissue and results in a high incidence of detection of involvement by Hodgkin's disease. This manifestation of Hodgkin's disease is associated with a relatively short survival. Aggressive combination chemotherapy is necessary to produce a significant remission.


Hodgkin's disease in childhood.

A retrospective study of 116 children with Hodgkin's disease diagnosed in the period 1935-1970 was undertaken to assess the prognostic role of histopathologic classiciation and clinical extent of the disease. The ages of the 80 boys and 36 girls ranged from 2.5 years to 15.0 years (mean, 10.0 years). The histopathologic diagnosis by lymph node biopsy revealed lymphocyte predominance in 22, nodular sclerosis in 67, mixed cellularity in 24, and lymphocyte depletion in 3. Within the subgroup of nodular sclerosis, 47 biopsies had classic well-developed collagenous bands, whereas 20 were in the cellular phase (10 without collagenous bands and 10 with minimal collagen). The clinical extent of disease was determined. There were 33 patients with Stage I disease, 38 with Stage IIA, 12 with Stage IIB, 24 with Stage III, and 9 with Stage IV. Survival correlated with histopathologic type and clinical stage, but not with age or sex. Survival was not dependent on the degree of collagenization in nodular sclerosis. There were 28 patients who survived for more than 10 years. Four of these 29 subsequently died owing to acute myelomonocytic leukemia, carcinoma of the breast, sepsis, and progression of Hodgkin's disease, respectively. Neoplasms developed in two other long-term survivors (thyroid carcinoma in one, and multiple basal cell carcinomas in the other).


Disseminated melanoma with unique unilateral distribution.

This is a case report of extensive metastases of dermal and subcutaneous malignant melanomas limited to the right side of the body, with the left side remaining singularly free of any evidence of tumor. The primary melanoma, which had been excised 7 years before the development of metastases, existed on the posterior aspect of the chest, slightly to the right of the midline. This is the only case of its kind noted.


Features of prognostic significance in solid ovarian teratoma.

The morphology of 20 ovarian tumors reported as solid teratomas is reviewed and correlated with their clinical behavior, in an attempt to select histologic features of prognostic significance. Utilizing a grading system quantitating immature tissue of embryonic origin a tendency was shown for fully mature tumors to follow a benign course, and for those composed predominantly of immature tissues to prove fatal. This method, however, was prognostically unreliable in 16 tumors. An additional but far more important prognostic guide in this series was provided by extra-embryonic tissue of yolk sac origin, which was present in variable amounts and diverse histologic patterns; all teratomas including this component were fatal, frequently with evidence of extra-abdominal metastases. In certain circumstances, immature embryonic teratomas were associated with widespread peritoneal implants, causing death from intestinal obstruction and recurrent ascites. It is important when considering prognosis and therapy to realize the metastatic potential of extra-embryonic elements in teratomas, as distinct from the tendency of immature embryonic components to implant locally and mature into noninvasive deposits, which may be amenable to surgery.


Excess occurrence of cancer of the oral cavity, lung, and bladder following cancer of the cervix.

The risk of developing a second cancer among white and black females with an initial cancer of the uterine cervix or corpus has been estimated based on the experience of the Charity Hospital of Louisiana Tumor Registry, a participant of the End Results Program of the National Cancer Institute. Observed second primary cancers were compared to expected numbers in order to obtain a direct estimate of risk. White females having an initial cancer of the cervix had a 5-to-6-fold excess risk of developing a subsequent cancer of the oral pharynx, lung or bladder during the first 5 years following their initial cancer with no excess risk for developing subsequent cancer of the breast or large intestine, but a slight excess risk for developing subsequent cancer of the ano-rectum. There was a 7% excess risk among both whites and blacks with initial cancer of the corpus uteri of subsequently developing another cancer.


Mesenchymal tumors of the uterus. V. Intravenous leiomyomatosis. A clinical and pathologic study of 14 cases.

Fourteen examples of intravenous leiomyomatosis in the FIP files were studied. Growth beyond the uterus occurred in 10 of the 14 examples, largely in vessels in the broad ligament and in uterine and iliac veins. Metastasis to the heart occurred in 1 example. The study provides evidence that is consistent with both theories of origin of intravenous leiomyomatosis; namely, that it may arise either from the wall of veins within the myometrium or be a result of unusually extensive vascular invasion from a leiomyoma of the myometrium. Intravenous leiomyomatosis should be distinguished from a leiomyoma with vascular invasion by arbitrarily limiting the designation of leiomyoma with vascular invasion to neoplasms in which the vascular growth is a microscopic finding and confined within the leiomyoma. Criteria are given for distinguishing intravenous leiomyomatosis from endometrial stromal sarcoma, leiomyosarcoma, leiomyoma with vascular invasion, and leiomyomatosis peritonealis disseminata.


Benign metastasizing uterine leiomyoma. Multiple lymph nodal metastases.

A case of histologically benign lymph nodal metastases from a uterine leiomyoma in a 27-year-old woman is reported. It is postulated that fragments of a leiomyoma, detached at the time of endometrial curettage, entered dilated lymphatic channels in or adjacent to a large projecting submucous leiomyoma, and seeded several pelvic and para-aortic lymph nodes. During an interval of 8 years, these grew slowly and did not infiltrate the perinodal tissues or give rise to secondary metastases.


Unusual intracardiac tumor in a child. Inflammatory pseudotumor or "granulomatous" variant of myxoma?

An intracardiac tumor arising in the right atrium of a young child is reported. Morphologically, the lesion was reminiscent of "plasma cell granulomas," but unprecedented in this location. Based on clinical manifestations, laboratory findings, histologic and ultrastructural characteristics of the mass, the speculation is put forth that this lesion may represent a cardiac myxoma with atypical structural features. An extension of this proposal is a pathogenetic sequence that would try to reconcile the complex clinical course of some myxomas with the described structural observations. Alternative choices for classification of the lesion are also given consideration.


Incidence, mortality or prevalence as indicators of the cancer problem.

The magnitude of the cancer problem, as conveyed by the incidence, mortality and prevalence figures, was studied by analysis of the material of the Finnish Cancer Registry from 1953-1970. The prevalence was defined as the number of persons who had cancer, or had ever had cancer, and were living on December 31, 1970. The incidence and mortality of cancer in males exceeded those in respect of females, whereas the prevalence with females was clearly higher than that with males. According to all 3 indices, the commonest site of cancer was in the lungs in males. In females, cancer of the breast was the commonest malignant neoplasm measured by incidence and prevalence, where as in mortality statistics it was second to cancer of the stomach. Cancers with poor prognosis such as cancer of the lung, stomach, pancreas and esophagus, and leukemia, exhibited relatively low prevalence figures, whereas cancers with good prognosis, such as cancer of the breast, uterus, larynx and lip, showed relatively large numbers of prevalent cases. In females, cancer of the genitals, including the breasts, constituted nearly as may prevalent cases as did the total figure in males. As the 3 cancer indices measure different things, the nature of the index used should be taken into account in evaluation of the magnitude of the cancer problem.


Hemangiopericytoma. A clinicopathologic study and long-term followup of 60 patients.

The clinical courses of 60 patients with hemangiopericytoma of the somatic soft tissues are summarized in this retrospective study. The tumors were subjected to a comparative histologic review and classified as benign (12 lesions), borderline malignant (16 lesions), and malignant (32 lesions). Tumors with 1 mitotic figure per 10 high-power field and moderate cellular anaplasia or 1 mitotic figure per 20 high-power fields and moderate cellular anaplasia may be expected to follow a malignant clinical course. Six of the 16 tumors with these microscopic features (borederline lesions) metastasized (37.5%), and 6 exhibited local recurrences after excision. Of the 32 malignant tumors, 25 (78%) metastasized. Twenty-three patients with malignant tumors were followed for more than 5 years or until death from tumor, and only one patient was alive and free of disease. Fifteen of the 23 patients experienced one of more local recurrences. None of the benign tumors metastasized. Surgical ablation of hemangiopericytioma is, in our experience, the only satisfactory method of treatment. Amputation of an extremity need be done only when the location of the lesion precludes a wide local excision. Local recurrent tumor was experienced by 22 patients after an inadequate local excision. Long-term follow-up is recommended because metastasis became apparent in 11% of patients with malignant tumors and 7% with borderline tumors after 5 "disease-free" years.


Breast cancer screening. Preliminary report of 207 biopsies performed in 4, 128 volunteer screenees.

Thirty-six carcinomas of the breast were pathologically verified in the first 207 biopsies performed to date on women attending the Breast Cancer Detection Center at The University of Cincinnati. Fifty-three percent of these have been minimal breast cancer, 14 being totally in situ. This is compared with a similar number of breast biopsies performed prior to the opening of the Breast Cancer Project. In the latter group of cases there were 45 carcinomas  proven, only 1 of which was in situ, 24 of which were invasive Stage I and 20 Stage II or higher. In addition, 65 biopsies demonstrated proliferative disease of varying degrees of severity as compared to a total of 13 in the non screened population.


The evolution of cancer of the colon and rectum.

The malignant potential of adenomas of the colon and rectum varies with size, histological type and grade of epithelial atypia. The adenomatous polyp is usually small and has a low malignant potential, whereas tumors with a villous structure are usually larger and have a much higher cancer rate. Severe atypia is more common in villous adenomas than in adenomatous polyps. Evidence is presented which suggests that most cancers of the colon and rectum have evolved through the polyp-cancer sequence although the majority of adenomas do not becoma cancerous during a normal adult life span. The slow evolution of the polyp-cancer sequence is stressed. The implications of the polyp-cancer sequence for the design of cancer prevention programmes and the study of the aetiology of large bowel cancer are discussed.


A metastasising ameloblastoma associated with renal calculi and hypercalcaemia.

A young male had an assumed dentigerous cyst marsupialized and later a recurrent ameloblastoma resected. Eleven years later he was admitted with renal stones and hypercalcemia and metastases of the ameloblastoma in the left lung were discovered. Death occurred as a result of spinal and hepatic spread of his tumor and thrombosis of the renal veins. Renal calcification was demonstrated. The possible causes of the hypercalcaemia which was not associated with a raised serum parathormone or affected by parathyroidectomy is discussed.


Survival and phase sensitivity of HeLa cells treated with dianhydrogalactitol (NSC-132313).

The effect of dianhydrogalactitol on survival and phase sensitivity of the cell cycle of HeLa cells was studied. In survival experiments no cells survived when the drug was added and left in contact with the cells at or above a dose of 0.7 mug/ml. Cells synchronized by the mitotic-selection method showed changing sensitivity to the drug during the cell cycle. G, late-S, and M phases were more sensitive to dianhydrogalactitol than the early-S and G phases. The DNA synthetic phase was divided into an early low sensitive and a late highly sensitive stage. The different sensitivity of mid-G and early-S phases was further established in separate survival experiments. Cells treated in G phase entered M phase in a manner similar to untreated control cells, while the progress of cells in S or G phase during treatment was delayed significantly. Lack of phase specificity of this drug is consistent with that of other alkylating agents. Changing sensitivity during some phases of the cell cycle proves that some metabolic events are especially sensitive to this particular drug.


Comparative studies of cyclocytidine (NSC-145668) and cytosine arabinoside (NSC-63878) in mice.

The distribution of cyclocytidine and cytosine arabinoside has been studied in normal BDF mice and in mice bearing 6-day solid L1210 lymphocytic leukemia by whole-body radioautography, bioassay, and radiochemical techniques. Radioactivity was widely distributed throughout the tissues between 15 minutes and 12 hours after a single intravenous dose of either cyclocytidine-2-14C or cytosine arabinoside-2-14C. Whole-body radioautograms demonstrated that for most tissues, cytosine arabinoside-derived 14C was uniformly excreted by 48 hours; cyclocytidine-derived 14C, however, was localized in certain tissues as early as 15 minutes after drug administration and was retained in these sites for 48 hours. Depot loci of 14C included salivary and adrenal glands, fat, cardiac muscle, gastrointestinal tract, and L1210 tumor. The distribution and persistence of cyclocytidine-derived radioactivity is consistent with other reports of toxicity induced by the drug in these tissues. Radiochromatography and bioassay data from BDF mice dosed intraperitoneally with cyclocytidine demonstrated that 65%-95% of the 14C-radioactivity in a number of tissues was the parent compound itself. Thus, cyclocytidine contributed in large measur to the generation of the radioautograms. This study demonstrates that the retention of cyclocytidine in body tissues may serve to effect the sustained release of the deaminase-resistant chemotherapeutic drug from these depot sites and thus prolong cytotoxic levels of drug in tumor tissue.


Microbiologic assay for cytosine arabinoside (NSC-63878): the use of a mutant of streptococcus faecium var. durans resistant to methotrexate (NSC-740) and 6-mercaptopurine (NSC-755).

Cytosine arabinoside has been shown to be effective in the treatment of acute leukemias and lymphomas, especially in combination with other established anticancer agents such as methotrexate, 6-mercaptopurine, and 6-thioguanine. A microbiologic assay capable of detecting cytosine arabinoside in the presence of such anticancer agents in body fluids has been developed using a strain of Streptococcus faecium var. durans resistant to methotrexate and 6-mercaptopurine; the assay can also be used to determine cytosine arabinoside concentrations in the presence of l-thioguanine. In view of the present trend toward drug combinations, including those using tetrahydrouridine, in the chemotherapy for human neoplasms, the proposed assay method will be valuable in cytosine arabinoside distribution studies.


Mutiple myeloma resistant to melphalan (NSC-8806) treated with cyclophosphamide (NSC-26271), prednisone (NSC-10023), and chloroquine (NSC-187208).

A prospective randomized study of the effects of two different therapeutic regimens was conducted in 41 patients with multiple myeloma resistant to therapy with melphalan. The results of treatment with cyclophosphamide plus prednisone were compared with those of cyclophosphamide, prednisone, and chloroquine. Chloroquine, which inhibits the repair process of DNA in animals, has reportedly produced responses to alkylating agents to which the animal had been resistant. No significant differences in response to the doses used with either regimen could be found. Toxocity consisted mainly of leukopenia and thrombocytopenia.


Studies on the antitumor activity of gallium nitrate (NSC-15200) and other group IIIa metal salts.

Several group IIIa metal salts, eg, aluminum nitrate, gallium nitrate, indium nitrate, and thallium chloride, have been evaluated for in vivo toxicity in mice and rats, for cytotoxicity in tumor cells in vitro, and for activity against a broad spectrum of experimental rodent tumors. The position of these agents in the periodical table roughly parallels their toxicity, the LD50s decreasing with increasing atomic weights. This parallel also exists with regard to in vitro cytotoxicity to Walker 256 carcinosarcoma cells. Although all of the metal salts had activity against the ascites Walker 256 carcinosarcoma, they were ineffective in ascites leukemias, plasma cell tumors, or Ehrlich carcinoma. Gallium nitrate was particularly active against solid tumors transplanted subcutaneously, suppressing the growth of six of eight tumors more than 90%. Because of its demonstrated antitumor activity in rodents and its uptake and concentration by various animal and human tumors, gallium nitrate has potential usefulness in the treatment of solid tumors in man and has been entered into a phase I study at the National Cancer Institute.


Coordination complexes of platinum as antitumor agents.

Rosenberg and VanCamp first reported the bacteriostatic and antitumor properties of certain platinum coordination compounds. This pioneering work has led to the synthesis and testing of a large number of related platinum products and the clinical use of cis-dichlorodiammineplatinum (II). This drug has proven very efficacious against a wide variety of mouse tumors when employed as the sole chemotherapeutic agent and has also been combined successfully with other antitumor agents, such as cyclophosphamide and cytosine arabinsoide. Unfortunately, cis-dichlorodiammineplatinum (II) has a low therapeutic index with renal toxicity being the principal limitation of its use. This has prompted the synthesis and testing of many related platinum compounds, of which cis-dichlorobiscyclopentylamine-platinum (II) and the "platinum blues" appear most promising. Experience in the synthesis, purification, and testing of such products will be discussed together with identification of outstanding unsolved problems in this area.


Clinical studies of Platinum Coordination compounds in the treatment of various malignant diseases.

Following the prior work of Rosenberg et al, Rosenberg and VanCamp, and Speer et al, we started clinical trials with cis-dichlorodiammineplatinum(II) in April 1971. Marked tumor regression was noted in several malignant diseases in these initial clinical studies which were reported at the Chemotherapy Congress in Prague, August 1971. At the present time over 178 patients have been treated wihhis durg for a variety of malignant conditions. Approximately half of these patients received the platinum compound alone and the other half received it in combination with four other chemotherapeutic agents...


Inhibition of Deamination of Arabinosylcytosine (NSC-63878) by Rhodium(II) Acetate.

The nobel metal "cage" complex, rhodium(II) acetate, was found to inhibit the deamination of the fraudulent nucleoside, arabinosylcytosine. Potent inhibition of a purified cytidine deaminase from mouse kidney was observed when either cytidine or arabinosylcytosine was used as substrate.


Action of Cis-dichlorodiammineplatinum(II) (NSC-119875) at ehe cellular level.

Asynchronous human lymphoma cells treated for 1 hour with increasing concentrations of cis-dichlorodiammineplatinum(II) revealed a marked decrease in survival as estimated by the colony-forming technique. When the treatmentwas extended for 8 hours at a concentration of 5micrograms/ml, a killing effect (greater than 3 log decades) was observed which was similar to that obtained when 50micrograms/ml is incubated with the cells for 1 hour. This finding suggests that better antitumor effects with fewer toxic effects may be obtained clinically by prolonged infusion of low doses of cis-dichlorodiammineplatinum (II). Synchronized lymphoma cells showed no significant degree of cell-cycle-stage sensitivity to cis-dichlorodiammineplatinum (II). The drug kills cells with similar efficiency in all stages of the cell cycle. No killing effect was elicited after incubation of the cells with spironolactone, a compound said to protect the kidneys from the toxic effects of heavy metals. However, simultaneous incubation of spironolactone and cis-dichlorodiammineplatinum (II) did not prevent the lethal action of the second drug. If spironolactone is proven to be an inhibitor of cis-dichlorodiammineplatinum (II) nephrotoxicity, it will become a valuable addition to the treatment of human neoplasia with this platinum compound. Lymphoma cells given a "priming" dose of 10 micrograms/ml of cis-dichlorodiammineplatinum (II) failed to repair the induced damage. A second exposure to 10 micrograms/ml of the drug at various subsequent intervals elicited greater killing effect than that produced by 20 micrograms/ml given at one time. A clear synergistic effect was noted when cis-dichlorodiammineplatinum (II) was given simultaneously with camptothecin or BCNU. The molecular mechanism by which this effect is accomplished is not presently apparent.


Differential sensitivity of colony-forming cells of hemopoietic tissue, Lewis lung carcinoma, and B16 melanoma to three nitrosoureas.

A comparison has been made of the effects of three nitrosoureas (BCNU, CCNU, and methyl-CCNU) on the cells of Lewis lung carcinoma and B16 melanoma in vivo using a new in vitro method for assaying colony-forming cells. In addition, the effect on early hemopoietic precursors has been studied using the in vivo spleen colony assay and the in vitro agar colony assay. The results show that the three nitrosoureas are selective against Lewis lung carcinoma and B16 melanoma relative to normal hemopoietic precursors. Furthermore, the effect of these nitrosoureas is unchanged when the rate of proliferation of the hemopoietic precursor cells is increased.


Antitumor activity of amygdalin MF (NSC-15780) as a single agent and with beta-glucosidase (NSC-128056) on a spectrum of transplantable rodent tumors.

Experiments are described in which four transplantable rodent tumors (L1210 lymphoid leukemia, P388 lymphocytic leukemia, B16 melanoma, and Walker 256 carcinosarcoma) were used to investigate the antitumor activity of amygdalin MF. Amygdalin MF was given alone and in combination with beta-glucosidase which was administered 1/2 hour prior to amygdalin MF, starting 24 hours after tumor implantation. No antitumor activity was observed in any of the four tumor systems tested with the drug alone or in combined therapy. The combined therapy showed potentiation of toxicity with doses of amygdalin MF greater than or equal to 100 mg/kg.


Inhibition of antilymphoma allograft response in normal and lethally irradiated mice by cyclophosphamide (NSC-26271) and isophosphamide (NSC-109724).

Cyclophosphamide and isophosphamide (an analog) were tested for their effect on the antilymphoma allograft reaction in normal and lethally irradiated mice. Both drugs were effective in abrogating the classic allograft response if given 1 or 3 days before the tumor challenge. While the drugs also inhibited the hemopoietic-histocompatibily response, they were effective when adminstered 7 days before challenge. It is suggested that the activity of various immunosuppressive agents could be compared for their effect on the hemopoietic-histocompatibility system to select the best agent for transplantation of bone marrow or bone marrow or bone marrow-derived cells. Drug toxicity, as well as the effect of the drugs on humoral response and DNA synthesis, was also compared. While isophosphamide was found to be less toxic than cyclophosphamide, the effect of humoral response and DNA synthesis was comparable.


Murine neuroblastoma: further evaluation of the C1300 model with single antitumor agents.

The murine C1300 neuroblastoma model has been evaluated as a possible model for children with widespread metastatic disease. Drug toxicity studies were conducted in adult A/J mice with various doses of antitumor agents. Adriamycin, BCNU, bleomycin, guanazole, acronycine, isophosphamide, DTIC, ICRF-159, cyclophosphamide, vincristine, and vinblastine were adminstered intraperitoneally to random groups of normal mice. After identification of appropriate doses, chemotherapy studies were conducted with varius regimens of drugs. Chemotherapy was administered to adult A/J mice when their subcutaneously implanted tumors measured 1.0-1.7 cm in diameter. Antitumor drugs can be classified into three groups according to drug efficacy. BCNU, cyclophosphamide, and isophosphamide were extremely active. Cytosine arabinoside was reported to be active against this murine tumor in a previous publication. Drugs with minimal activiyt which deserve further evaluation included adriamycin, guanazole, ICRF-159, DTIC, and vinblastine. Inactive drugs were acronycine, bleomycin, 5-fluorouracil, and vincristine. These experiments suggest that children with metastatic neuroblastoma may respond to cyclophosphamide, isophosphamide, and BCNU, while DTIC, adriamycin, ICRF-159, guanazole, and the vinca alkaloids may also be effective. The results suggest that agents selected by the C1300 model should be given adequate clinical trials.


A crystallographic determination of a chemical structure: 6-amino-10-(beta-D-ribofuranosylamino)pyrimido-[5,4-d]pyrimidine, an example of an unusual D-ribose conformation.

The crystal and molecular structure of 6-amino-10-(beta-D-ribofuranosylamino)-pyrimido[5,4-d]pyrimidine has been determined by single crystal X-ray diffraction methods. The crystals are triclinic, of noncentric space group Pl, with cell dimensions a equals 5.434 (5), b equals 12.269 (19), c equals 4.574 (4) A, alpha equals 92.3 (1), beta equals 94.0 (1), gamma equals 95.3 degrees (1) and Z equals 1. The structure has been refined to an R value of 0.049 (Rw equals 0.063), by use of counter measured intensity data for 1063 observed reflections. The pyrimidopyrimidine ring is planar. The sugar moiety is in the envelope conformation with O-1'-endo (0E), and there is an intramolecular hydrogen bond (2.58 A) (O-3'-H-O3'...O-2'). All oxygen atoms except O-1' ring oxygen-atom are involved in hydrogen bonding. The pyrimidopyrimidine rings lie in planes 3.4 A apart.


A preparative synthesis of 3-amino-2,3,6-trideoxy-L-lyxo-hexose (daunosamine) hydrochloride from D-mannose.

A simple, preparative route in nine steps from methyl alpha-D-mannopyranoside (1) is described that affords, in 40% overall yield, the title amino sugar 11, the sugar constituent of the antitumor antibiotics adriamycin and daunorubicin. The 2,3:4,5-dibenzylidene acetal (2) of 1 is converted by butyllithium into the 2-deoxy-3-ketone 3, whose oxime 4 is reduced with high stereoselectivity to the D-ribo amine, isolated as its N-acetyl derivative 5 and converted by action of N-bromosuccinimide into the 4-O-benzoyl-6-bromide 7. Dehydrohalogenation of  gives the 5,6-unsaturated glycoside 8, which, after O-debenzoylation to 9, undergoes stereospecific reduction by hydrogen with net C-5 inversion to give the crystalline, N-acetylated methyl beta-glycoside (10) of daunosamine, readily converted into daunosamine hydrochloride (11) and into the crystalline N-benzoyl (14) and N-acetyl(15) derivatives. No chromatographic procedures for isolation are required in any of the steps.


Preparation and properties of fluorescein-labelled hyaluronate.

Hyaluronate has been labelled with fluorescein groups by two procedures. Products with degrees of substitution ((d.s.) between 0.05 and 0.001 were obtained. Physico-chemical analysis (viscometry, gel chromatography, and measurements of sedimentation and diffusion coefficients) of the parent compound and the products showed that the labelling procedures caused only a limited degradation of the polysaccharide.


Effects of titanium compounds on a D-glucose-D-glucose oxidase assay system.

Titanium compounds affect the measurement of D-glucose oxidase (and therefore D-glucose) by the D-glucose-D-glucose oxidase-peroxidase-2,2'-azinobis-(3-ethylbenzothiazoline-6-sulphonic acid) assay system. The validity of measurement of the activity of D-glucose oxidase immobilised on supports based on titanium oxides is affected by complexation of the intermediate hydrogen peroxide with the support, and such supports may prove to be unsuitable for the immobilisation of D-glucose oxidase. The formation of titanic peroxides is among the reasons discussed for the various interactions encountered. The use of the assay system for the determination of D-glucose oxidase contaminated with catalase and for the determination of hydrogen peroxide is also described.


Changes in left ventricular internal diameter with increasing pericardial pressure.

Changes in left ventricular internal diameter resulting from increasing intrapericardial pressure induced by increasing the pericardial fluid volume were studied in closed chest, anaesthetized dogs. Left ventricular internal diameters were measured by placing an ultrasonic dimension catheter in the left ventricle at the time of the experiments. With increasing pericardial pressure, significant increases occurred in heart rate and mean left atrial pressure. Left ventricular end-diastolic and end-systolic diameter progressively decreased as the pericardial pressure was elevated. After beta adrenergic blockade with propranolol (1 mg/kg), the decline in end-systolic diameter during pericardial tamponade was significantly reduced. These observations indicate the importance of the systolic reserve and the role of beta adrenergic receptors in the adaptation of the left ventricle to increases in pericardial tamponade.


An evaluation of the pericardial sac as a safety factor during tamponade.

Studies were conducted in vitro to determine the permeability characteristics of the rabbit and dog pericardium. The hydraulic conductance (Lp), which was significantly higher than other tissue, was 1.6 +/- 0.19 X 10(-4) and 1.78 +/- 0.18 X 10(-4) g-cm-2-min-1-cm H2O-1 (mean +/- SEM), respectively, for the rabbit and dog pericardium. For various solutes, the permeability coefficient (P) of the pericardium for the rabbit was: 1.40 +/- 0.10 X 10(-4) cm-s-1 for water, 0.50 +/- 0.03 X 10(-4) cm-s-1 for glucose, and 0.73 +/- 0.005 X 10(-4) cm-s-1 for albumin. The reflection coefficient, sigma, for various solutes was: glucose 8.89 +/- 0.86 X 10(-4), sucrose 15.7 +/- 1.5 X 10(-4), dextran (molecular weight 40 000) 0.39 +/- 0.03, albumin 0.42 +/- 0.05, and for haemoglobin 0.58 +/- 0.06. These results, which indicate that the pericardium offers little resistance to the bulk transfer of liquids and to the passage of large molecules, are discussed as possible safety factors during pericardial effusion.


Quantitative analysis of the acute response to haemorrhage of the renin-angiotensin-vasoconstrictor feedback loop in areflexic dogs.

The importance of the renin-angiotensin-vasoconstrictor system during haemorrhagic hypotension was quantitated in 44 areflexic dogs by determining the ability of the arterial pressure to recover following haemorrhage to 8.8 kPa (66 mm Hg). In 30 animals with intact kidneys, the arterial pressure following haemorrhage rose to a new steady-state level averaging 11.7 kPa (88 mm Hg), which represented 65.3 +/- 1.8 (SE) % compensation. In 18 nephrectomized animals only 24.4 +/- 1.5% compensation occurred. The system exhibited a relatively rapid time course for pressure compensation with the new steady state occurring 19.2 +/- 2.0 min after haemorrhage. Following reinfusion of blood the pressure returned to the pre-haemorrhage in 19.2 +/- 3.0 min. Arterial renin activity was significantly elevated following haemorrhage in the intact kidney group and unchanged in the anephric group. The arterial pressure compensation of two animals with intact kidneys was significantly reduced when the angiotensin-converting enzyme inhibitor (SQ 20881) was infused before the haemorrhage. The results are consistent with a renin-angiotensin-vasoconstrictor mechanism of arterial pressure compensation and indicate that this mechanism possesses sufficient gain and time response characteristics to play a homeostatically significatn role during haemorrhagic hypotension.


Short-term variability of pulse rate and blood pressure in cardiac surgery patients.

The magnitude and mathematical nature of short-term variations of pulse rate and mean arterial blood pressure has been studied in 27 post-operative cardiac surgical patients over a continuous period of 200 min in each case. Similar variability was observed in all patients. Short-term variations were composed predominantly of a series of rhythmic changes ranging from one synchronous with respiration to others between 2 and 5 min in cycle length. There was consistent variance of the beat-by-beat values for both variables about a continuously updating 5 min mean. The average standard deviation was 3.75 beats/min for pulse rate and 0.48 kPa (3.64 mm Hg) for mean arterial blood pressure. For both variables the distribution about the 5-min mean did not differ significantly from a normal distribution in 50 out of the 54 records. These findings have implications for the reproducibility of current methods of estimating mean pulse rate and blood pressure, and the change necessary before two estimates may be regarded as significantly different. The results are applicable both to the interpretation of Ward Charts by medical staff and to automated monitoring systems.


Responses to exercise in experimental hypertension.

Exaggerated cardiovascular responses to stressful stimuli and behavioural hyperexcitability have been observed in spontaneously hypertensive rats (SHR). The present series of experiments examined blood pressure and heart rate responses of SHR and renal hypertensive rats (RHR) to a combined physical and mental stress in the form of treadmill exercise. SHRs exhibited only slight and selective hyper-responsiveness to exercise in regard to increases in heart rate, whereas, RHRs responded normally. The excessive sensitivity of "older" SHRs is related mainly to slightly lower resting heart rates.


Effects of local anaesthetics on calcium transport by canine cardiac microsomes (fragmented sarcoplasmic reticulum).

Local anaesthetics inhibit calcium transport by cardiac sarcoplasmic reticulum. However, the concentrations of lidocaine and procaineamide needed to produce these effects are high. No significant differences were found between these agents that could account for reported differences in their electrophysiological effects.


The effects of isoprenaline on epicardial ST-segment elevation, lactate production, and myocardial blood flow following coronary artery ligation.

Isoprenaline was infused at low and high rates into anaesthetized dogs after ligation of the left anterior descending coronary artery, the resultant changes in epicardial ST-segment elevation being compared with lactate production and myocardial blood flow in the infarcting myocardium. Although ST elevation was increased at both infusion rates, there was no change in the arterial-local coronary venous difference of lactate concentration nor in myocardial blood flow at the centre of the infarct. The results suggest that the relationship between epicardial ST-segment elevation and other indices of ischaemic myocardial injury is complex and requires further evaluation.


Haemodynamic effects of a new anti-arrhythmic agent, mexiletine (Kö 1173) in ischaemic heart disease.

The haemodynamic effects of mexiletine (Kö 1173) were studied in six patients. Heart rate and cardiac output remained unchanged. The systemic arterial pressure was reduced in two patients owing to a fall in the peripheral resistance. Cardiac function, assessed by means of the stroke work and pulmonary capillary wedge pressure, was depressed in three patients, who all had a current or past history of severe heart failure.


Effects of three fat-enriched diets on the arterial pressure of rabbits.

Rabbits were fed diets enriched with proprietary edible fats for 5 weeks, raising the fat content of their diet from 4% to 23%. The diet enriched with animal fat caused a 13.5% rise in arterial pressure. The diet enriched with vegetable oil caused an 8.5% rise in arterial pressure. The diet enriched with butter caused an initial rise of 10% decreasing to 6% by the fifth week. Histological examination of the carotid and renal arteries, and aorta revealed no changes in connective tissue or lipid content as compared with those of control animals. It is concluded that changes in arterial pressure can occur after ingestion of excess dietary lipid, and that these changes are not confined to any class of lipid, or related to its properties as an atherosclerotic agent.


Myocardial oxygen consumption at constant left ventricular workload and varying arterial oxygenation.

The effect of arterial oxygen content (CaO2) changes on myocardial O2 consumption (MVO2) was studied in dogs with controlled heart rate, cardiac output, and arterial pressure. MVO2 did not change significantly as a result of systemic or selective left coronary CaO2 changes ranging randomly from hypoxaemia to hyperoxaemia.


Effect of cortisol on human fetal lung in organ culture: a biochemical, electron-microscopic and autoradiographic study.

Human fetal lung tissue obtained during the second trimester was cultured as organ culture with or without cortisol. The effect of cortisol on the phospholipid metabolism, as related to the appearance of osmiophilic lamellar bodies and the localisation of newly incorporated choline, was studied. In cortisol-treated explants, the concentration of saturated lecithins and the incorporation of (Me-3H)-choline into saturated lecithins increases significantly concomitantly with an increased number of osmiophilic lamellar bodies. The labelled choline is predominantly associated with these bodies. The obtained results indicate that cortisol accelerates the synthesis of pulmonary surfactant in the human fetal lung as early as in the second trimester.


Neuronal migration during the early development of the cerebral cortex: a scanning electron microscopic study.

Fixed cerebral vesicles of mouse foetuses were fractured and examined with the scanning electron microscope. This method provides a study of the three dimensional developmental features of the pseudostratified columnar epithelium up to the formation of the early cortex plate. Matrix cells are a cell population of homogeneous shape, however, mitotic cells are easily identified by their spherical form. The external surface of the brain is formed by the closely packed end feet of these cells covered by a basal membrane. The formation of the cortical plate is the result of a continuous cell migration in columnar arrangement towards the pia. Glioependymal cells extend along the whole brain wall and most likely provide guidance for the migrating cell cords. The formation of the so-called migratory zone is a consequence of the growth of the basal and the horizontal prolongations of emigrating cells. The significance of the cell to cell contacts for the neuronal migration processes is discussed.


Ultrastructure of the presumed ion-transporting cells in the gills of ammocoete lampreys, Lampetra fluviatilis (L.) and Lampetra planeri (Bloch).

Mitochondria-rich cells were located in the interplatelet area of gill filaments from ammocoete Lampetra fluviatilis and L. planeri. The ultrastructure of this cell type differs from typical teleost 'chloride cells' by the  absence of a tubular, smooth endoplasmic reticulum (SER). This difference is discussed in relation to the presumed functions of the cell and to the evolutionary histories of lampreys and teleosts. It is concluded that the mitochondria-rich cell is responsible for the active uptake of ions by the ammocoete gill.


Ultrastructural observaitons of growth hormone (STH) cells of anterior pituitary glands of partially hepatectomized rats.

Ultrastructural changes in pituitary growth-hormone cells were observed in partially hepatectomized rats. The hepatectomies were carried out during the afternoon after 3 p.m. The animals were sacrificed by decapitation at midnight at intervals of 32, 80, and 104 hours after the operation. The principal changes in the growth-hormone cells of anterior pituitary glands of partially hepatectomized rats were: (1) increased numbers of secretory granules in exocytosis, (2) increased numbers of microtubules, and (3) enlargement of endoplasmic reticulum and occurrence of dilated cisternae of the endoplasmic reticula. Many growth-hormone cells contained a reduced number of secretory granules. Exocytosis of growth-hormone granules was more frequently observed in animals sacrificed at 32 hours after the operation than in those killed at 80 or 104 hours after surgery. The above results in which appearance of numerous microtubules and active secretory granule extrusion in the growth-hormone cells were observed after hepatectomy indicate that ultrastructure of growth-hormone cells and growth hormone secretion were markedly stimulated by the operation.


Ultrastructural evidence for a direct connection between the myocardial granules and the sarcoplasmic reticulum in the cardiac ventricle of Myxine glutinosa (L.).

The occurrence of structural connections between myocardial granules and tubular elements of the sarcoplasmic reticulum in the cardiac ventricle of the Atlantic hagfish is described. The core substance of the myocardial granules is shown to be uranophilic and in this respect similar to the granular cores within the lumen of the sarcoplasmic reticulum. After application of CaCl2-containing fixatives, the ultrastructure of the core substance of these organelles resembles that described for calcium-containing structures in vertebrate glial cells. Incidences of uranophilic core substance in the extracellular space suggest a secretory function of the myocardial granules. Possible implications of the sarcoplasmic reticulum and the myocardial granules in storage, intracellular transport, and secretion of bound calcium are discussed.


Exocytosis couples to endocytosis of ferritin in parotid acinar cells from isoprenalin stimulated rats.

Distribution of acid phosphatase as a marker enzyme for lysosomes was investigated in the isoprenalin stimulated rat parotid gland. The enzyme was localized in lipofuscin-like bodies as well as in non-discharged granules. The appearance of these bodies was correlated in time to the appearance of smooth vesicles and reduction of the acinar lumen. Ferritin, used as a tracer and introduced into the stimulated gland via cannulated parotid ducts, was found in smooth vesicles, vacuoles and lipofuscin-like bodies throughout the cytoplasm of the acinar cells. Very often ferritin-containing vesicles were found in the vicinity of the Golgi complex. In most cases the vesicles containing ferritin also showed acid phosphatase reaction product. A possible correlation between the lysosomal system and the process of recycling and degradation of membranes in the stimulated gland is discussed.


Ultrastructure of the integumental melanophores of the coelacanth, Latimeria chalumnae.

The integumental melanophores of Latimeria chalumnae were studied by light and electron microscopy. The epidermal melanophore located in the mid-epidermis consists of a round perikaryon with long slender dendrites extending into epidermal cells and intercellular spaces. The dermal melanophores occur in the loose dermal matrix underlying a relatively thick layer of collagen fibers. The dermal melanophores are usually flattened and their dendrites lie parallel to the collagen layer. Both epidermal and dermal melanophores contain oval, electron-opaque melanosomes, large mitochondria, agranular vacuoles of endoplasmic reticulum and microtubules. Microfilaments and RNP particles are less conspicuous. While the peripheral cytoplasm of both dermal and epidermal melanophores is filled with a large number of melanosomes, the perinuclear cytoplasm of many dermal melanophores is occupied by premelanosomes in various stages of differentiation, and that of the epidermal melanophore contains numerous large vacuoles. Despite the scarcity of epidermal melanophores, the epidermal melanin unit is present in the form of melanosome complexes. In addition, the melanophores of Latimeria possess the basic characteristics common to other vertebrates, but they more closely resemble those of lungfish and other aquatic vertebrates.


Effect of denervation on the mitotic index of the intestinal epithelium of the rat.

The infradiaphragmatic section of vagi nerves at the level of the diaphragm crura causes, on the third day after surgery, a reduction of the mitotic activity in the crypts of the intestinal epithelium of the rat. Moreover there is a drastic reduction in number of the goblet cells that remain concentrated at the lower third of the villi. After the third day after vagotomy there is a tendency to normality. Sympathectomy did not affect significantly the intestinal epithelium of the rat. When both surgeries were performed together, there was no additive effect.


Light and electron microscopy of the hepatopancreas of the isopod Acellus intermedius.

Hepatopancreas from Acellus intermedius, a small freshwater isopod, was examined by light and electron microscopy. Of particular interest are the two cell types present in the hepatopancreas. Their ultrastructural features indicate that the major role of the large alpha cells is to absorb material from the lumen as well as secrete materials into the lumen while the major role of the small beta cells is to store the absorbed materials as well as break down stored materials before transport.


The reality of arthropod cuticular laminae.

Examination of etched pyramids of decapod crustacean cuticles with the scanning electron microscope indicates that laminae are continuous around the angles of the pyramids. This observation is in direct contrast to the result expected on Bouligand's (1965, 1971) hypothesis and suggests that laminae may be real structures.


Rate of protein synthesis in rat salivary gland cells after pilocarpine or feeding. I. Rate of (glyco) protein secretion from cells of mixed salivary glands.

In untreated, fasting animals the cells of the serous demilunes of the sublingual gland incorporate [3H]-leucine at a higher rate than any other of the 5 main cell types of the 3 major salivary glands. The acinar cells of the submandibular and the mucous cells of the sublingual gland show intermediate values, while the cells of the granular ducts of the submandibular and the acini of the parotid gland have a low rate of incorporation. In fasting animals extrusion of newly synthesized protein starts early in the cells of the serous demilunes. It starts between 4 and 7 hrs after [3H]-leucine injection in the acinar cells of the submandibular gland, while the other cell types did not lose substantial amounts of labelled (glyco)protein within 7 hrs. The secretion of protein is stimulated by the cholinergic drug pilocarpine in all but one of the 5 types of salivary gland cells studied. The acinar cells of the submandibular gland react strongly, the granular duct cells less strongly. Still less are the reactions of the acinar cells of the parotid and of the nucous cells of the sublingual gland. The cells of the serous demilunes of the latter appear to be insensible to pilocarpine. The effect of food uptake on secretion does not differ from pilocarpine stimulation, with one exception: the acinar cells of the parotid gland react more strongly on food uptake than on cholenergic stimulation.


Rate of protein synthesis in rat salivary gland cells after pilocarpine or feeding. II. Protein synthesis in vivo in cells of the submandibular and parotid gland after secretion.

The effect of pilocarpine and food uptake on the rate of incorporation of [3H]-leucine in vivo was measured by means of quantitative radioautography in three exocrine cells of the rat: the acinar and the granular duct cells of the submandibular and the acinar cells of the parotid gland. The three cell types react differently. The submandibular acinar cells showed a decrease in incorporation rate after pilocarpine administration but not after feeding. The incorporation rate of the granular duct cells of the submandibular gland remains constant after both stimulations. The acinar cells of the parotid gland show an increase in incorporation rate of [3H]-leucine in response to both. The contrast between the submandibular and the parotid gland could also be demonstrated radiobiochemically, the results reflecting the incorporation rates of the acinar cells of both glands, giving no information on the contribution of other cell types. The decrease in incorporation rate of the submandibular gland acinar cells is accompained by a shift of polyribosomes towards monomers.


Rate of protein synthesis in rat salivary gland cells after pilocarpine or feeding. III. Protein synthesis in vitro in the submandibular and parotid gland after stimulation of secretion in vivo.

After stimulation of the protein secretion by pilocarpine or feeding the rate of incorporation of [3H]-leucine increases in the acinar cells of the parotid gland of the rat while the secretory cells of the submandibular gland show a moderate decrease (Kuijper et al., 1975b). Since the rate of labelled amino acid incorporation depends on the specific radioactivity of the amino acid used, which is not easy to determine in vivo, experiments in vitro were performed to get an idea of the influence of this factor on the measured changes in [3H]-leucine incorporation. In vitro both cell types showed a more pronounced but essentially identical reaction as in vivo. Since in these experiments the specific radioactivity of the extracellular leucine is the same whether fragments of stimulated or unstimulated glands incorporate the radioactive amino acid, the increase of incorporation in the parotid and the decrease in the submandibular cells cannot be ascribed to differences in specific radioactivity of leucine, unless the intracellular leucine pool should show great differences between secreting and non-secreting cells. However, in vitro the submandibular gland cells under both conditions appear to use the extracellular leucine for their protein synthesis (or a small compartmentalized pool in rapid exchange with the extracellular pool). In the parotid cells the whole intracellular pool showed such a rapid exchange with the extracellular one that for practical reasons one may say that these cells, too, rely on the extracellular specific radioactivity of leucine in their protein synthesis. We conclude that the rat parotid gland cells show a rapid and substantial increase of protein synthesis after stimulation of their enzyme secretion, while the submandibular gland cells do not.


Subsurface cisterns in the vertebrate retina.

Structures identified as subsurface cisterns (SSC's) were found in retinal neurons and their processes in the Western grey squirrel, the California and 13-line ground squirrels, the South African clawed toad, and the domestic cat. The SSC's are located in amacrine, bipolar, and ganglion cells; they are connected with the rough endoplasmic reticulum and are associated with specific membrane specializations. SSC's were not seen in the Müller cells, an observation which agrees with earlier reports that these organelles do not exist in glial cells.


Development and cytodifferentiation of the rabbit pars intermedia. I. Fetal and perinatal stages.

The developing pars intermedia (PI) of rabbits of between 14 days post coitum (PC) and one day post partum (PP) have been studied by light and electron microscopy. Cell division is marked until 4th week PC, after which it is reduced. The (PI) loses its homogeneity by the 5th week PC due to localisation both intrinsic and invading cells and blood vessels. Four groups of parenchyma cells are recognisable: PI-glandular cells, interstitial cells, ACT-type cells and a heterogeneous group of dark cells. The ultrastructure of the ACT-type cells in the rabbit PI are here described for the first time. The differentiation of these cell types has been traced from 14 days PC to 32 days PC, in particular ACT-type cells are shown to develop in situ and the significance of this is discussed. In the PI-glandular cells dense cored granules appear first on the 15th day PC which is one day before any nerve connection is made with the primitive neural lobe and more than a week before vascularisation. Thereafter granularity increases until parturition when there is a phase of degranulation. Relatively electron lucent, larger vesicles are not found until 4th week PC.


Time- and dose-dependent influence of ouabain on the ultrastructure of optic neurones.

The cardiac glycoside ouabain was injected into the eye-bulb of the teleost fish, Carassius carassius. Three doses of ouabain were used: 10(-4) M, 10(-5) M, 10(-6) M. The final concentrations in the vitreous body of the eye were approximately 3-10(-5) M, 3-10-6 M and 3-10-7 M, respectively. After 8 hrs, 1, 2, 4, 6 and 8 days the ultrastructural alterations of retinal ganglion cells, the optic axons near the bulb and the terminal segments in the optic tectum were studied. The high doses of ouabain induced an early necrobiosis of the cell bodies in the retina followed by degeneration in the nerve. This is characterized as a protracted form of Wallerian degeneration. The significance of the inhibition of Na+ -K+-activated ATPase at the perikaryal level for both the integrity of axonal morphology and the axonal flow is discussed.


Cellular contacts in the synovial membrane of the cat and the rabbit: an ultrastructural study.

Regularly, four different types of cellular contacts are found in synovial folds and villi of the cobital joint of the cat (interdigitations, desmosomes, intermediate junctions, gap junctions). The same types of contact--with the exception of intermediate junctions--occur sporadically also in synovial fat folds of the knee joint of the rabbit. In both species, hemidesmosomes and discontinuous basement membranes are seen in the synovial lining layer. Cellular contacts predominate between A-cells and cells of the intermediate type, hemidesmosomes and incomplete basement membranes predominate in intermediate cells and B-cells. The latter are rare in A-cells. The importance of such contacts for mechanical, metabolic and electrical interactions of cellular elements in the synovial membrane is discussed. No unanimous concept as to their function can be advanced at present.


Ontogeny of the pig hypothalamic neurosecretory system with particular reference to the distribution of neurophysin.

The immunoperoxidase cytochemical reaction was applied to the localization of neurophysin-containing elements in the fetal and adult pig hypothalamus. In the 60 day fetal pig, cells of the supraoptic nucleus (SON) were the only structues in the hypothalamus in which neurophysin was detected. However, by 87 days the cell bodies in both the SON and paraventricular nucleus (PVN) contained neurophysin-like material. The distribution of immunoreactive material in the 111 day fetal animal was similar to that found in the adult pig. In transverse section of the mature pig the SON exists in two discrete components; an antero-lateral group of cells connected by scattered cells to a smaller postero-medial group. Anteriorly, the PVN appears as a line of cells bordering the third ventricle but as we proceed posteriorly the dorsal aspect expands laterally to give a wedge-shaped group of cells. In mid-sagittal sections, the cells of the PVN are distributed over a wide area of the anterior hypothalamus in a triangular profile. The borders between the SON and PVN became more difficult to define in medial sections than in lateral sections. Continuous gradient polyacrylamide gel electrophoresis was carried out on the neural lobe extracts from fetal, newborn and adult pigs. Proteins with an electrophoretic mobility similar to that of porcine neurophysins-I, -II and -III were present in the newborn and 98 day fetal pig. It is concluded that material immunoreactive with anti-neurophysin serum is present in the hypothalamus of the 60 day fetal pig. Furthermore, at late fetal development and during the postnatal period it is tentatively suggested that the neurophysin present in the pituitaries of these animals is chemically identical with that of adult neurophysin.


Electron microscopic studies on the pineal organ of the antarctic penguin, (Pygoscelis papua).

The pineal organ of the migratory antarctic penguin, Pygoscelis papua, has a lobular structure. Clusters formed by different types of parenchymal cells are separated by connective tissue septa containing blood vessels. The predominant cell type displays a well-developed Golgi complex, free ribosomes, clear and granular vesicles (secretory granules), and lysosomes. Other cell types found in the gland are supporting and ependymal-like cells. The former contain dense bodies and filament bundles, the latter possess abundant cilia and clusters of ribosomes. Typical photoreceptor elements are lacking. Blood vessels are located within a perivascular space bordered by basal laminae. This perivascular space extends between the basal protrusions of the parenchymal cells. The presence of pinocytotic vesicles, secretory granules and cytoplasmic processes in the vicinity of these spaces suggests active sites of transport and exchange of substances. Intercellular conaliculi-like spaces are surrounded by parenchymal cells rich in microvilli. These cancliculi are continuous with the cavities (invaginations) of secretory and other parenchymal cells.


The first optic ganglion of the bee. I. Correlation between visual cell types and their terminals in the lamina and medulla.

Each visual unit (ommatidium) of the compound eye of the honey bee contains nine retinula cells, six of which end as axons in the first synaptic ganglion, the lamina, and three in the second optic ganglion, the medulla. A technique allowing light- and electron microscopy to be performed on the same silver-impregnated sections has made it possible to follow all types of retinula axons of one ommatidium to their terminals in order to study the shape of the terminal branches with their position in the cartridge. 1. The axons of retinula cells 1-6 (numbered according to Menzel and Snyder, 1974) end as three different types of short visual fibres (svf) in the lamina; the axons of retinula cells 7-9 run through the lamina to terminate in the medulla and are known as long visual fibres (lvf). Retinula cells of each type are identified by the location of their cell bodies and by the direction of their microvilli. The retinula cells 1 and 4 (group I according to Gribakin, 1967) end as svf type 1 with three tassel-like branches in stratum B of the first synaptic region. The pair of cells 3, 6 and the pair 2, 5 (group II) end in the first synaptic region in stratum A. Cells 3 and 6 have forked endings, svf type 2, whereas cells 2 and 5 have tapered endings, svf type 3. The remaining retinula cells 7, 8 and 9 have long fibres. Nos. 7 and 8 (group III) have tapered endings and are termed lvf types 1 and 2, respectively. The 9th cell is the lvf type 3 with a highly branched ending. 2. The nine axons in the bundle from one ommatidium have relative positions which do not change from the proximal retina to the monopolar cell body layer. 3. By following silver-stained retinula cells and their corresponding axons, it is possible to describe mirror-image arrangements of fibres in the axon bundles in different parts of the eye. This correlation of numbered retinula cells with specific axon types, together with the highly organized pattern in an axon bundle, allows the correlation between histological and physiological findings on polarization and colour perception.


Ultrastructure of the milk fat globule membrane with and without triglyceride.

The primary milk fat globule membrane (MFGM) around freshly secreted milk fat globules consists of a unit membrane separated from the triglyceride core by a dense material. This dense material may widen to include cytoplasmic organelles or may form small blebs. Preincubation and fixation of the globules at temperatures between 4 degrees C and 60 degrees C has no effect on the width or appearance of the dense material. Isolated MFGM profiles show structures identical to those found on intact globules. The dense material on the isolated MFGM profiles is unaffected by extractions which remove essentially all the triglyceride present in the pellets of MFGM. The structure of the primary MFGM is therefore independent of any triglyceride content and the earlier suggestions that the dark material represented a triglyceride layer of high melting point adsorped during cooling of the globules after milking are not supported by the work described in this paper.


Neurosecretion in the sinus gland of the fiddler crab, Uca pugnax.

The ultrastructure of the sinus gland of the fiddler crab, Uca pugnax, was investigated and found to be similar to that in other crustaceans. Five types of neurosecretory axon terminals were tentatively identified on the basis of the size, shape, and electron density of granules within the axons. Release of neuro-secretory material appears to be by exocytosis.


Stimulation of the adrenal gland of the Mongolian gerbil after ovariectomy.

The effect of ovariectomy on the adrenal gland was studied in the Mongolian gerbil. Castration stimulated cells in the zona fasciculata as well as those in the region between the zona fasciculata and zona reticularis. No alterations occurred in the zona reticularis. The width of the intermediate region was enlarged, the cells were hypertrophic and contained an increased number of concentric whorls of rough endoplasmic reticulum. Smooth endoplasmic reticulum was hypertropic in cells of the zona fasciculata and intermediate region. Many mitochondria in cells of the intermediate region were larger than those in controls. Stimulation of cellular ultrastructure is directly correlated with a significant elevation in plasma cortisol in ovariectomized gerbils.


Ultrastructure of the compound eye of the diploid female beetle, Xyleborus ferrugineus.

The compound eye of female (diploid) Xyleborus ferrugineus beetles was examined with scanning and transmission electron microscopy. The eye is emarginate, and externally consists of roughly 70-100 facets. Each ommatidium is composed of a thickly biconvex lenslet with about 50 electron dense and rare layers. The lens facet overlies a crystalline cone of the acone type which is roughly hourglass-shaped. Pigment cells envelop the entire ommatidium, and pigment granules also are abundant throughout the cytoplasm of the 8 retinular cells. The rhabdomeres of 2 centrally situated photoreceptor cells effectively fuse into a rhabdom that extends from the base of the crystalline cone deeply into the ommatidium. Six distal peripheral retinular cells encircle the 2 central cells, and their rhabdomeres join laterally to form a rhabdomeric ring around the central rhabdom. The rhabdom and rhabdomeric ring are effectively separated by the cytoplasm of the two central retinular cells which contains the usual organelles and an abundance of shielding pigment granules. Eight axons per ommatidium gather in a tracheae-less fascicle before exiting the eye through the fenestrate basement membrane. No tracheation was observed among the retinular cells. Each Semper cell of each observed crystalline cone contained an abundance of virus-like particles near the cell nucleus. The insect is laboratory reared, and the visual system seems very amenable to photoreceptor investigations.


The cryptonephridial system in the mealworm Tenebrio molitor: transport of radioactive potassium, thallium and sodium; a functional and structural study.

Larvae of the mealworm Tenebrio molitor were injected with radioactive potassium, sodium or thallium solution. It was found that the rectal complex of the animal was labelled with potassium and thallium, but not with sodium. Potassium and thallium labelled the complex to the same level as if the two ions were tracers for each other. Ramsay has found that potassium is actively transported to the complex from the hemocoel and there are reasons to believe that T1+ follows the same pathway. Therefore animals injected with thallium were investigated both by light and electron microscopy. The results suggest that thallium spreads from the hemocoel through the leptophragma to the neighbouring ordinary tubular cells, and in moist mealworms thallium is further found in the perirectal space. Due to diffusion and washing out of thallium during fixation it can not be determined whether T1+ and K+ follow identical pathways, but it is possible to determine how far thallium has penetrated during the experiments.


The microfiber texture in a specialized plastic cuticle area within a sensillum field on the cockroach maxillary palp as revealed by freeze fracturing.

A field of sensilla extends across the ventral surface of the terminal segment of the maxillary palps of Periplaneta americana. The sensilla project from a sheet of pliable cuticle. Ultrathin sections of the cuticle in this area reveal a clear-cut parabolic microfiber pattern. Microfibers can also be seen from freeze fracture faces running parallel to the cuticular surface. These microfibers have a diameter of 80 A and may consist of chitin crystallites surrounded by a matrix coat. The number of straight parallel microfibers visible in a fracture face increases the more closely parallel to the surface the fracture runs. This result suggests a helicoidal texture, as the model of Bouligand would demand. The layer-to-layer rotational displacement of the microfibers is about 12 degrees. This texture can be regarded as typical for flexible cuticles in general. Other structural properties such as the continuation of the epicuticular dense layer into deeper cuticular layers around the enveloping cells of sensilla can be interpreted as specializations connected with the function of the sensillum field.