Showing papers by "Memorial Sloan Kettering Cancer Center published in 1980"

Relation of mammalian sperm chromatin heterogeneity to fertility.

Abstract: Flow cytometry of heated sperm nuclei revealed a significant decrease in resistance to in situ denaturation of spermatozoal DNA in samples from bulls, mice, and humans of low or questionable fertility when compared with others of high fertility. Since thermal denaturation of DNA in situ depends on chromatin structure, it is assumed that changes in sperm chromatin conformation may be related to the diminished fertility. Flow cytometry of heated sperm nuclei may provide a new and independent determinant of male fertility.

Radation therapy for brain metastases

Abstract: We treated 183 patients who had brain metastases with whole-brain radiation therapy (RT) and adrenocorticosteroids utilizing a new high-dose radiation protocol. Treatment produced neurological improvement in 135 patients (74%); there was no change in 37 (20%), and deterioration occurred in 11 (6%). Of those patients who improved, two-thirds maintained neurological improvement for the remainder of their lives or for at least nine months, and one-third relapsed. One-third of those who relapsed improved again with steroids or further RT. Clinical improvement paralleled tumor regression on CT scan. Despite the clinical response, median survival was only twelve weeks; 24% lived six months and 8% lived one year. Death resulted from progressive brain disease in 16% of the patients. Two-thirds of the patients died of advancing systemic disease in the setting of stable, improved neurological function. These data suggest that the majority of patients with brain metastases benefit from RT and that systemic cancer, not central nervous system disease, limits the length of life.

Epidural spinal cord compression from metastatic tumor: results with a new treatment protocol.

Abstract: Eighty-three patients with epidural spinal cord compression, from metastatic cancer were treated with high-dose adrenocorticosteroids and a new radiation fractionation protocol. Only those patients were included who had complete or almost complete block on myelography and who had not received prior radiation therapy to the area of compression. Patients were given 100 mg of dexamethasone intravenously at the time of diagnosis and 500 rads of radiation on each of the first three days. After a four-day rest, radiation therapy was continued at 300 rads to a total dose of 3,000 rads. The effects of this new protocol on the patient's motor abilities did not differ from those of previous protocols, namely, 47 of 83 patients (57%) were ambulatory after treatment, with no responses in patients totally paraplegic before treatment. However, early administration of high doses of dexamethasone substantially ameliorated pain in the majority of patients, with relief often coming within hours after the drug was given. On the basis of these data, we recommend high doses of adrenocorticosteroids combined with radiation therapy for acute treatment of spinal cord compression. The optimum fractionation schedule for radiation therapy is not established.

The clinical significance of pre-invasive breast carcinoma

Abstract: Improvements in mammography in the past 25 years have made it possible to detect before surgery many lesions with a high probability of being pre-invasive carcinoma. Because these cancers are virtually all cured by mastectomy, there has been considerable interest in alternative types of treatment. Retrospective studies of pre-invasive carcinoma treated by biopsy only revealed subsequent carcinoma in 30 to 40% of patients. Among women with lobular carcinoma in situ (LCIS), the frequency of subsequent carcinoma was nine times the expected rate, and mortality due to the disease was 11 times greater than expected. The risk of later invasive carcinoma appeared to involve both breasts equally when LCIS was present and to be largely limited to the breast that harbored intraductal carcinoma (IDC). When mastectomy was performed for pre-invasive carcinoma, unsuspected invasion was found in 4% of patients with LCIS and 6% with IDC. It remains to be determined whether multicentric preinvasive carcinoma will follow the same course in patients with palpable invasive carcinoma treated by partial mastectomy and some form of adjuvant therapy. At present, it is prudent to treat pre-invasive breast cancer by ipsilateral mastectomy with low axillary dissection and to perform a contralateral breast biopsy. However, prospective, controlled investigations are urgently needed to identify groups of patients with a high or low risk of developing invasive carcinoma and to determine whether non-surgical treatment can alter the course of pre-invasive disease. By pursuing these studies, it may ultimately be possible to measure the success of breast cancer detection by the number of patients cured without mastectomy.

New cell cycle compartments identified by multiparameter flow cytometry

Abstract: Simultaneous measurements of cellular DNA and RNA as well as estimates of the sensitivity of DNA in situ to denaturation by acid (which correlates with the degree of chromatin condensation) and cell ability to incorporate 5-bromodeoxyuridine (BUdR), performed on over 40 different cell systems enabled us to subclassify cells into 12 functionally distinct cell cycle compartments. Quiescent cells had low RNA values, DNA very sensitive to denaturation, and they did not incorporate BUdR. Although in most cell systems they had 2C DNA content (G1Q), quiescent cells with higher DNA values (SQ and G2Q) were also seen. The G1 phase of exponentially growing cells had two distinct compartments, A and B. G1 cells entered S phase only from the B compartment. An increase in RNA and a decrease in the sensitivity of DNA to acid denaturation beyond a specific level characterized the transition of cells from the A to B compartments. Since the G1A to G1B transition was not linear but exponential, it may be assumed that a non-deterministic event triggering cell progression into the cycle resides within G1A. Under adverse growth conditions the probability of a G1A to G1B transition decreased. Cells In G2 had DNA more sensitive to acid denaturation than S or G1 phase cells. Mitotic cells had the most condensed chromatin and their RNA content was twice that of G1A cells. Differentiated cells were characterized by 2C DNA (G1D) but, depending on the cell type, had varying RNA content and different degrees of chromatin condensation. A hitherto undescribed category of cells undergoing transition from quiescence to the cycle (or vice versa) was distinguished based on their intermediate values of RNA, sensitivity of DNA to acid denaturation and inability to incorporate BUdR at the rate characteristic for S cells. Depending on their DNA content (C) at the time of transition these cells could be classified as G1T (2C), ST (4>C>2) or G2T (4C).

Association of Kaposi's sarcoma with second primary malignancies: possible etiopathogenic implications.

Abstract: The association of Kaposi's sarcoma (KS) with second primary cancers, especially of the lymphoreticular system, has been frequently noted. To confirm these reports in a systematic way, data on a series of 92 patients with KS treated at Memorial Sloan-Kettering Cancer Center (MSKCC) 1949–1975 were subjected to extensive statistical analysis. Use was made also of 4517 double primaries including all sites, diagnosed at MSKCC 1949–1974, and 1959 simultaneous double primaries from the Third National Cancer Survey. Some key results: (1) 37% of KS patients had toher primary malignancies; (2) there was a 20-fold increase in the incidence of lymphoreticular malignancies after diagnosis of KS; (3) in the MSKCC series of double primaries, lymphoreticular malignancies were involved in 8% of cases; for KS alone the corresponding figure was 58%. Our findings provide evidence in support of possible etiopathogenic mechanisms that may be involved in the natural course of KS.

Kaposi's sarcoma and its relationship to cytomegalovirus (CMNV). III. CMV DNA and CMV early antigens in Kaposi's sarcoma.

Abstract: DNA-DNA reassociation kinetics, anti-complement immunofluorescence (ACIF) and ACIF-blocking tests were used to search for cytomegalovirus (CMV) gene products in Kaposi's sarcoma (DS) biopsies and early cell cultures deriving from them. Three of eight tumor biopsies were positive for CMV DNA; two of them at 0.35 genome/cell and one at one copy 25% genome/cell. CMV-related antigens, mainly localized in the nucleus, were found in cryostat sections of seven of 31 tumor biopsies and four of 12 KS cell lines at early passage level. It appears that the antigen is present in a high number of tumor cells, like the Epstein-Barr virus nuclear antigen (EBNA) in EBV-transformed cells. Inevitably, the increasing data concerning the oncogenic potential of CMV lead on to consideration of the increasing evidence of its association with Kaposi's sarcoma, a multiple hemorrhagic sarcoma with an epidemiologic distribution in Africa similar to that of Burkitt's lymphoma.

Stimulation of macrophage plasminogen activator activity by colony-stimulating factors

Abstract: Colony-stimulating factors (CSFs) stimulate granulocyte-macrophage praoduction from single hemopoietic progenitor cells. Various preparations of purified CSFs of two different subclasses have been shown here to stimulate a plasminogen-dependent fibrinolytic (plasminogen activator) activity from resident and starch-induced mouse peritoneal macrophages. Lymphocyte supernatants also stimulate macrophage plasminogen activator (PA) activity. Since they contain colony stimulating activity, it is possible that one or more subclasses of CSF in these supernatants is responsible for this effect. Since both colony-stimulating and macrophage growth activities have been detected at inflammatory sites, these findings could reflect a role for CSF in inflammatory processes.

Progress report on controlled trial of fecal occult blood testing for the detection of colorectal neoplasia.

Abstract: Our controlled trial of screening for colorectal cancer has now been in progress for almost five years. Screening is accomplished by rigid sigmoidoscopy in control and study groups and, in addition, by fecal occult blood testing in the study group. Patients screened are men and women age 40 and older, mostly at average risk. Fecal occult blood testing is with Hemoccult slides with patients on a meat-free, high-bulk diet without hydration, and with a four-day storage interval between slide preparation and testing. Patients with positive slides undergo diagnostic investigation that includes both colonoscopy and double-contrast barium enema and, in some, an upper gastrointestinal series. Preliminary results to date include: patient baseline statistics and subgroup comparability, rate of positive slides of 1–4%, predictive value for neoplasia of 44–50%, false-positives of 0.5–2.1%, favorable Dukes' staging of cancers in the study group, and high patient compliance. Considerably more follow-up is needed in our study and control population, and issues such as mortality and cost need to be addressed. Additional time will be necessary to provide firm conclusions.

Radiation-induced malignant and atypical peripheral nerve sheath tumors

Abstract: The reported peripheral nerve complications of therapeutic irradiation in humans include brachial and lumbar plexus fibrosis and cranial and peripheral nerve atrophy. We have encountered 9 patients with malignant (7) and atypical (2) peripheral nerve tumors occurring in an irradiated site suggesting that such tumors represent another delayed effect of radiation treatment on peripheral nerve. In all instances the radio-theray was within an acceptable radiation dosage, yet 3 patients developed local radiation-induced skin and bony abnormalities. The malignant peripheral nerve sheath tumors developed only in the radiation port. Animal studies support the clinical observation that malignant peripheral nerve sheath tumors can occur as a delayed effect of irradiation.

Age and morphine analgesia in cancer patients with postoperative pain.

Abstract: Our objective was to identify age-related differences in analgesia after 8 and 16 mg morphine intramuscularly. Retrospective analyses of controlled relative analgesic potency assays in 947 postoperative cancer patients revealed differences among age groups (18 to 29, 30 to 49, 50 to 69, and 70 to 89 yr) in total pain relief and duration of relief with little differences in peak relief. Weight and initial pain intensity were in the same range among age and dose groups. Aging was associated with enhanced analgesia. The difference in total relief between the extremes of adult age was approximately twice that with twice the dose. While in 50% of the oldest group relief was no longer obtained at 5 hr, in 50% of the youngest group relief was no longer obtained at 3 hr. These observations suggest that age is a factor in morphine analgesia.

Naloxazone, a long-acting opiate antagonist: effects on analgesia in intact animals and on opiate receptor binding in vitro.

Abstract: Administration of naloxazone, a hydrazone derivative of naloxone, to intact mice produces a prolonged inhibition of in vitro [3H]opiate binding lasting up to 3 days. The effect is selective since naloxazone treatment produces no changes in alpha or beta adrenergic, muscarinic or benzodiazepine receptor binding and the effects on opiate binding sites are not reproduced by non-narcotic hydrazines. Scatchard analyses of saturation experiments 24 hr after in vivo naloxazone treatment show an absence of high affinity binding sites of [3H]naloxone, [3H]dihydromorphine and 2-D-[3H]ala-met-enkephalinamide, although low affinity sites are relatively unaffected. Blockade of high affinity sites by naloxazone produces an 11-fold increase in the ED50 value for morphine analgesia at 24 hr with both tailflick and writhing assays. By contrast, naloxazone produces no change in the LD50 value for morphine. As high affinity binding returns to control levels over 3 days, ther ED50 for morphine analgesia in naloxazone-pretreated mice returns to control values. Accordingly, the analgetic, but not lethal, effects of morphine may be mediated by the high affinity subpopulation of opiate receptors.

Prognostic significance of serum lactate dehydrogenase in malignant lymphoma.

Abstract: The pretreatment serum lactate dehydrogenase level (LDH) was the single most important prognostic variable in 30 patients with diffuse histiocytic lymphoma treated between January 1973 and January 1977 with a poly-drug chemotherapy program called the cyclophosphamide L2 protocol at the Memorial Sloan-Kettering Cancer Center. A highly significant difference was found between the survival patterns of patients with LDH levels of 500 U or less and those with LDH levels greater than 500 U. (Two-year survival rates were 67% and 13%, respectively.) A similar trend was observed for 25 patients with diffuse, poorly differentiated lymphocytic lymphoma treated with the same protocol, although this difference was not statistically significant. (Corresponding two-year survival rates were 74% and 33%, respectively.) The association of LDH level with survival was evident even after adjustment for other factors of potential prognostic significance. Pretreatment serum LDH determinations may provide a useful means of stratifying patient populations when comparing treatment programs for advanced stage non-Hodgkin's lymphoma.

Canine hepatic neoplasms: a clinicopathologic study.

Abstract: One hundred ten primary hepatic neoplasms, excluding hematopoietic and vascular tumors, were diagnosed in 12,245 canine necropsies. Included were 55 hepatocellular carcinomas, 24 bile duct carcinomas, 2 combined hepatocellular and cholangiocarcinomas, 15 carcinoids and 14 sarcomas. A majority of the dogs with hepatocellular carcinoma (80%), bile duct carcinoma (65%) and sarcoma (61%) were 10 years old or older; 71% of the dogs with carcinoid were under 10 years old. Hepatocellular carcinoma and sarcoma occurred more often in males, bile duct carcinoma in females, and no sex predisposition was found in dogs with carcinoid. All dogs had hematologic and biochemical abnormalities relating to liver function. The aspartate amino transferase/alanine amino transferase ratio was less than one in cases of hepatocellular carcinoma and bile duct carcinoma, and more than one in cases of carcinoid and sarcoma. A massive lesion in one of the liver lobes was the most common gross morphologic feature in cases of hepatocellular carcinomoa and bile duct carcinoma, with the left lateral lobe affected most often. In cases of carcinoid, most of the lesions were diffuse. The most common sites of metastases were lymph nodes and lungs for hepatocellular carcinoma and bile duct carcinoma, lymph nodes and peritoneum for carcinoid, and spleen for sarcoma.

Both the 7-methyl and the 2'-O-methyl groups in the cap of mRNA strongly influence its ability to act as primer for influenza virus RNA transcription

Abstract: The ability of eukaryotic mRNAs to serve as primers for influenza virus RNA transcription depends on the presence of a 5'-terminal methylated can structure, the absence of which eliminates essentially all priming activity [Plotch, S. J., Bouloy, M. & Krug, R. M. (1979) Proc. Natl. Acad. Sci. USA 76, 1618-1622]. The present study was undertaken to determine the extent to which each of the methyl groups in the cap influences the priming activity of a mRNA. To assess the importance of the 2'-O-methyl group on the penultimate base of the cap, we used several plant viral RNAs containing the monomethylated cap 0 structure, m7GpppG. Brome mosaic virus (BMV) RNA 4 stimulated influenza virus RNA transcription only about 10-15% as effectively as did globin mRNA, which has a cap with a 2'-O-methyl group. When the cap of BMV RNA 4 was enzymatically 2'-O-methylated, its priming activity was increased 14-fold. Qualitatively similar results were obtained with other plant virus RNAs. To assess the importance of the terminal 7-methyl group, BMV RNA 4 containing the cap structure GpppGm was prepared by a series of chemical and enzymatic steps. These molecules were found to be only about 15% as active in priming as BMV RNA 4 molecules containing the fully methylated cap, m7GpppGm, indicating that the terminal 7-methyl group also strongly enhances priming activity. These results indicate that the cap 1 structure (m7GpppXm) found in all mammalian cellular mRNAs is more stringently required for priming influenza virus RNA transcription than for translation in cell-free systems.

Humoral and cell-mediated immune responses in fully allogeneic bone marrow chimera in mice

Abstract: AKR mice were protected from lethal irradiation and established as long-lived chimeras by transplanting allogeneic C57BL/6 (B6) bone marrow that had been treated in vitro with anti-Thy-1 antiserum without complement. In these chimeras, which were designated [B6 {arrow} AKR], virtually all the thymus and spleen cells were shown to be derived from the B6 donor; several immune functions studied in these chimeras were as follows: (a) The chimeric mice were tolerant of histocompatibility antigens of both donor and recipient strain and nearly fully reactive to antigens of third party, as revealed by Simonsen's splenomegaly assay. The tolerance of these chimeras could not be attributed to suppressor cells but was compatible with clonal depletion. (b) Proliferative responses to concanavalin A, phytohemagglutinin, and lipopolysaccharide as well as natural killer and antibody-dependent cell- mediated cytotoxicity activity of the chimeric mice was normal. (c) Plaque- forming cell (PFC) assays of antibody responses to sheep erythrocytes (SRBC) showed gross deficiency in the primary response of the [B6 {arrow} AKR] and [AKR {arrow} B6] chimeras. By contrast, [B6-H-2(k)(E(k)) {arrow} AKR] H-2-compatible chimeras and [AKR {arrow} AKR] syngeneic marrow transplanted mice had normal primary PFC responses. PFC responses after secondary stimulation with SRBC, however, revealed vigorous direct plaque formation and substantial but somewhat smaller indirect plaque formation in the [B6 {arrow} AKR] chimeras. This observation favors operationally the concept of adaptive differentiation proposed by Katz et al. (44). (d) Analysis of ability of the chimeras to develop and express delayed-type hypersensitivity responses to contact sensitizer (2,4-dinitro-l-fluorobenzene [DNFB]) showed no apparent immunodeficiency of either chimeras to this form of immunization. Development of immunologic tolerance to DNFB, however, was grossly deficient in [B6 {arrow} AKR] chimeras but normal in [AKR {arrow} AKR], [B6 {arrow} B6], and [E(k) {arrow} AKR] chimeras. These findings indicate that full chimeras across major histocompatibility complex have considerable immunologic vigor even though primary immune responses that require histocompatibility between interacting cell types are initially defective.

Surgical treatment of single brain metastasis: Factors associated with survival

Abstract: The results of surgical excision of solitary intracerebral metastases followed by whole-brain radiation therapy between 1972 and 1978 in a series of 78 patients were analyzed. The overall median survival of the series was 6 months with a 1-year survival rate of 29%. Statistical analyses of the data revealed that patients who presented with a cerebral metastasis 1 year or more after diagnosis of the primary cancer had a significantly longer survival than those in whom the metastasis was detected within 1 year (P less than .04). Patients with mild or no neurological deficits at time of craniotomy had a longer median survival and a 1-year survival of 44% (P less than .01). The presence of metastases at one or two other sites did not significantly affect overall survival except in those patients in whom the brain metastasis was detected more than 1 year after diagnosis of the primary tumor. Factors found to affect survival in this study may be useful in predicting survival of future patients similarly treated.

Estrogen Receptor Cleavage and Plasminogen Activation by Enzymes in Human Breast Tumor Cytosol

Abstract: Estrogen receptors in cytoplasmic extracts of breast tumors from more than 40 patients were separately analyzed by gel filtration and/or ultracentrifugation under diverse conditions. Resultant patterns are presented for specimens from 11 women with infiltrating duct carcinoma and are representative of results obtained in all samples of sufficient size and receptor content (∼40 fmol/mg cytosol protein) for accurate determination of hydrodynamic parameters. Estradiol-binding components of intracellular origin were distinguished from the serum contaminant, sex hormone-binding globulin, by their high affinity for diethylstilbestrol and negligible affinity for 5α-dihydrotestosterone. The predominant molecular forms of the receptors, but not the steroid specificity, varied dramatically with experimental factors, including the duration of the fractionation procedure, ionic strength, and the presence of protease inhibitors, particularly the bacterial tripeptides N-acetyl- and N-propionyl-l-leucyl-l-leucyl-dl-argi...

Comparison of methods of evaluating nephrotoxicity of cis-platinum.

Abstract: The urinary excretion of leucine aminopeptidase (LAP), N-acetyl-β-glucosaminidase (NAG), and β2-microglobulin was measured in 12 cancer patients receiving cis-platinum to evaluate the sensitivity of these indices for renal tubular damage. NAG and LAP excretion rose markedly in all patients, and β2-microglobutin rose in 11. Seven of the 9 patients who had received cis-platinum 6 wk before the study had prestudy dose elevations of one or more of these indices. We conclude that these urinary proteins are sensitive indicators of proximal renal tubular injury and may provide greater sensitivity for comparison of the nephrotoxic potential of future platinum analogs or for assessing the efficacy of regimens designed to protect the kidney from platinum nephrotoxicity than other measurements. The persistence of high excretion values for these indices 6 wk after a dose demonstrates the persistent renal injury by cis-platinum. Clinical Pharmacology and Therapeutics (1980) 27, 557–562; doi:10.1038/clpt.1980.79

The prevalence of yeasts in clinical specimens from cancer patients.

Abstract: Yeasts recovered from cancer patients during a 15-month period were speciated, and the prevalence of these isolates in various types of clinical specimens was determined. Five species, including Candida albicans, Candida tropicalis, Candida parapsilosis, Candida krusei, and Torulopsis glabrata , accounted for 97.1% of the isolates. Eighteen different species were recovered. Respiratory and urine specimens yielded 75% of the organisms. C. albicans, C. tropicalis, and C. parapsilosis were recovered in about equal frequency from blood cultures. Certain species usually were recovered from one type of specimen: Candida quilliermondii from urine, Trichosporon cutaneum and Candida pseudotropicalis from respiratory sites, and Cryptococcus neoformans from spinal fluid. Pityrosporum orbiculare was isolated only from ear and urine cultures. Most of the yeasts (95.4%) were identified within 48 hours after isolation.