Showing papers by "Memorial Sloan Kettering Cancer Center published in 1991"
TL;DR: The updated information on tolerance of normal tissues of concern in the protocols of this contract, based on available data, is presented, with a special emphasis on partial volume effects.
Abstract: The importance of knowledge on tolerance of normal tissue organs to irradiation by radiation oncologists cannot be overemphasized. Unfortunately, current knowledge is less than adequate. With the increasing use of 3-D treatment planning and dose delivery, this issue, particularly volumetric information, will become even more critical. As a part of the NCI contract N01 CM-47316, a task force, chaired by the primary author, was formed and an extensive literature search was carried out to address this issue. In this issue. In this manuscript we present the updated information on tolerance of normal tissues of concern in the protocols of this contract, based on available data, with a special emphasis on partial volume effects. Due to a lack of precise and comprehensive data base, opinions and experience of the clinicians from four universities involved in the contract have also been contributory. Obviously, this is not and cannot be a comprehensive work, which is beyond the scope of this contract.
4,133 citations
TL;DR: Because patients with APL can be induced into remission with high dose RA therapy, it is proposed that the nonliganded PML-RAR protein is a new class of dominant negative oncogene product.
1,429 citations
Duke University1, University of North Carolina at Chapel Hill2, University of Pittsburgh3, Vanderbilt University4, University of South Florida5, University of Virginia6, Memorial Sloan Kettering Cancer Center7, St. Elizabeth's Medical Center8, Virginia Mason Medical Center9, Johns Hopkins University10, Medical College of Wisconsin11, University of Chicago12, Stanford University13, Amgen14, University of California, Los Angeles15
TL;DR: A randomized clinical trial to test the hypothesis that recombinant methionyl granulocyte colony-stimulating factor (G-CSF) can reduce chemotherapy-related neutropenia in patients with cancer and the clinical implications.
Abstract: Background. Neutropenia and infection are major dose-limiting side effects of chemotherapy. Previous studies have suggested that recombinant methionyl granulocyte colony-stimulating factor (G-CSF) can reduce chemotherapy-related neutropenia in patients with cancer. We conducted a randomized clinical trial to test this hypothesis and the clinical implications. Methods. Patients with small-cell lung cancer were enrolled in a multicenter, randomized, double-blind, placebo-controlled trial of recombinant methionyl G-CSF to study the incidence of infection as manifested by fever with neutropenia (absolute neutrophil count, <1.0×l09 per liter, with a temperature ≥38.2°C) resulting from up to six cycles of chemotherapy with cyclophosphamide, doxorubicin, and etoposide. The patients were randomly assigned to receive either placebo or G-CSF, with treatment beginning on day 4 and continuing through day 17 of a 21 -day cycle. Results. The safety of the study treatment could be evaluated in 207 of the 211 pa...
1,314 citations
TL;DR: Tretinoin is a safe and highly effective agent for inducing complete remission in patients with acute promyelocytic leukemia and clinical response to this agent is associated with leukemic-cell differentiation and is linked to the expression of an aberrant RAR-alpha nuclear receptor.
Abstract: Background and Methods. Patients with acute promyelocytic leukemia have a characteristic (15;17) translocation, with a breakpoint on chromosome 17 in the region of the retinoic acid receptor—alpha (RAR-α). Since this receptor has been shown to be involved with growth and differentiation of myeloid cells in vitro, and since recent clinical studies have reported that tretinoin (all-trans-retinoic acid) induces complete remission in patients with acute promyelocytic leukemia, we studied the effects of tretinoin on cellular maturation and molecular abnormalities in patients undergoing the induction of remission with this agent. Results. Eleven patients with acute promyelocytic leukemia were treated with tretinoin administered orally at a dose of 45 mg per square meter of body-surface area per day. Nine of the 11 patients entered complete remission. In two patients, complete remission was preceded by striking leukocytosis that then resolved despite continued drug treatment. Serial studies of cellular ...
1,279 citations
TL;DR: A four-parameter empirical model has been applied to a compilation of clinical tolerance data developed by Emami et al. and the four parameters to characterize the tissue response have been determined and graphical representations of the derived probability distributions are presented.
Abstract: During external beam radiotherapy, normal tissues are irradiated along with the tumor. Radiation therapists try to minimize the dose of normal tissues while delivering a high dose to the target volume. Often this is difficult and complications arise due to irradiation of normal tissues. These complications depend not only on the dose but also on volume of the organ irradiated. Lyman has suggested a four-parameter empirical model which can be used to represent normal tissue response under conditions of uniform irradiation to whole and partial volumes as a function of the dose and volume irradiated. In this paper, Lyman's model has been applied to a compilation of clinical tolerance data developed by Emami et al. The four parameters to characterize the tissue response have been determined and graphical representations of the derived probability distributions are presented. The model may, therefore, be used to interpolate clinical data to provide estimated normal tissue complication probabilities for any combination of dose and irradiated volume for the normal tissues and end points considered.
1,186 citations
TL;DR: The 23% incidence of late cardiac abnormalities warrants continued evaluation of patients after anthracyclines to guide patient care and the design of future chemotherapeutic protocols.
Abstract: Objective. —To assess the cardiac status of long-term survivors of pediatric malignancies who received chemotherapy, including anthracyclines. Design and Method. —Patients were evaluated by echocardiogram from 4 to 20 years (median, 7 years) after completion of anthracyclines, with prospective and retrospective analysis. Patients. —The consecutive sample of 201 patients had received a total anthracycline dose of 200 to 1275 mg/m2(median, 450 mg/m2), and 51 patients had mediastinal radiotherapy. Main Outcome Measures. —The overall incidence and severity of abnormal systolic cardiac function were determined for the entire cohort. Risk factors of total anthracycline dose, mediastinal radiotherapy, age during treatment, and length of follow-up were examined. Results. —Twenty-three percent (47/201) of the cohort had abnormal cardiac function on noninvasive testing at long-term follow-up. Correlation between total cumulative dose, length of follow-up, and mediastinal irradiation with incidence of abnormalities was significant. Fifty-six patients were followed up for 10 years or more (median, 12 years), with a median anthracycline dose of 495 mg/m2, Thirty-eight percent (21/56) of these patients, compared with 18% (26/145) of patients evaluated after less than 10 years, had abnormal findings. Sixty-three percent of patients followed up for 10 years or more after receiving 500 mg/m2or more of anthracyclines had abnormal findings. Nine of 201 patients had late symptoms, including cardiac failure and dysrhythmia, and three patients died suddenly. Microscopic examination of the myocardium on biopsy and autopsy revealed fibrosis. Conclusion. —The 23% incidence of late cardiac abnormalities warrants continued evaluation of patients after anthracyclines to guide patient care and the design of future chemotherapeutic protocols. (JAMA. 1991;266:1672-1677)
929 citations
TL;DR: Primary responses to cisplatin/carboplatin-based treatment are common in patients with ovarian cancer who have previously responded to the agents and increase in frequency with greater distance from the initial therapy.
Abstract: In an effort to critically define the incidence and clinical characteristics of secondary responses to cisplatin-based therapy in patients with ovarian cancer previously treated with a cisplatin-based program, a retrospective review was undertaken of patients at the Memorial Sloan-Kettering Cancer Center who received greater than or equal to two cisplatin/carboplatin-based programs. Eighty-two patients were identified who met the entry criteria of having had a cisplatin-free interval (CFI) of more than 4 months between the completion of their first regimen and the institution of a second cisplatin/carboplatin program. Of the 72 assessable patients (10 had no measurable disease, and a laparotomy was not performed to assess response), 31 (43%) responded, including 10 surgically defined complete responses (S-CRs). The overall response rates (and S-CR rate), based on duration of CFI, were 5 to 12 months, 27% (5%); 13 to 24 months, 33% (11%); and more than 24 months, 59% (22%). Twenty-nine patients (35%) received noncisplatin/carboplatin-containing treatments between the cisplatin programs. Patients without any treatment for more than 24 months from the completion of their initial therapy experienced a 77% (17 of 22) response rate and a 32% (seven of 22) S-CR rate. In conclusion, secondary responses to cisplatin/carboplatin-based treatment are common in patients with ovarian cancer who have previously responded to the agents and increase in frequency with greater distance from the initial therapy.
780 citations
TL;DR: The primary structure of rat betaglycan is described, a polymorphic membrane-anchored proteoglycan with high affinity for transforming growth factor-beta (TGF-beta) and its unique features suggest important roles in cell interaction with TGF- beta.
637 citations
602 citations
TL;DR: A neuronal antigen (HuD) recognized by the sera of patients with antibody-associated paraneoplastic encephalomyelitis has been isolated by screening a lambda cerebellar expression library and is likely to play a role in neuron-specific RNA processing.
567 citations
TL;DR: Analysis of the relationship between levels of quinolinic acid in the CSF and serum and integrity of the blood‐brain barrier, as measured by theCSF: serum albumin ratio, it appears that CSF levels are derived predominantly from intracerebral sources and perhaps from the serum.
Abstract: Quinolinic acid is an "excitotoxic" metabolite and an agonist of N-methyl-D-aspartate receptors Of patients infected with human immunodeficiency virus type 1 (HIV-1) who were neurologically normal or exhibited only equivocal and subclinical signs of the acquired immunodeficiency syndrome (AIDS) dementia complex, concentrations of quinolinic acid in cerebrospinal fluid (CSF) were increased twofold in patients in the early stages of disease (Walter Reed stages 1 and 2) and averaged 38 times above normal in later-stage patients (Walter Reed stages 4 through 6) However, in patients with either clinically overt AIDS dementia complex, aseptic meningitis, opportunistic infections, or neoplasms, CSF levels were elevated over 20-fold and generally paralleled the severity of cognitive and motor dysfunction CSF concentrations of quinolinic acid were significantly correlated to the severity of the neuropsychological deficits After treatment of AIDS dementia complex with zidovudine and treatment of the opportunistic infections with specific antimicrobial therapies, CSF levels of quinolinic acid decreased in parallel with clinical neurological improvement By analysis of the relationship between levels of quinolinic acid in the CSF and serum and integrity of the blood-brain barrier, as measured by the CSF:serum albumin ratio, it appears that CSF levels of quinolinic acid may be derived predominantly from intracerebral sources and perhaps from the serum While quinolinic acid may be another "marker" of host- and virus-mediated events in the brain, the established excitotoxic effects of quinolinic acid and the magnitude of the increases in CSF levels of the acid raise the possibility that quinolinic acid plays a direct role in the pathogenesis of brain dysfunction associated with HIV-1 infection
TL;DR: It is reported that day-12 colony-forming-unit spleen (CFU-S12)5 cells and reconstituting haematopoietic stem cells attach to the C-terminal, heparin-binding fragment of fibronectin by recognizing the CS-1 peptide of the alternatively spliced non-type III connecting segment (IIICS) of human plasma fibronECTin.
Abstract: THE self-renewal and differentiation of haematopoietic stem cells occurs in vivo and in vitro in direct contact with cells making up the haematopoietic microenvironment1–4. In this study we used adhesive ligands and blocking antibodies to identify stromal cell-derived extracellular matrix proteins involved in promoting attachment of murine haematopoietic stem cells. Here we report that day-12 colony-forming-unit spleen (CFU-S12)5 cells and reconstituting haematopoietic stem cells attach to the C-terminal, heparin-binding fragment of fibronectin by recognizing the CS-1 peptide of the alternatively spliced non-type III connecting segment (IIICS) of human plasma fibronectin. Furthermore, CFU-S12 stem cells express the α4 subunit of the VLA-4 integrin receptor, which is known to be a receptor for the CS-1 sequence, and monoclonal antibodies against the integrin α4 subunit of VLA-4 block adhesion of CFU-S12 stem cells to plates coated with the C-terminal fibronectin fragment. Finally, polyclonal antibodies against the integrin β1 subunit of VLA-4 inhibit the formation of CFU-S12-derived spleen colonies and medullary haematopoiesis in vivo following intravenous infusion of antibody-treated bone marrow cells.
TL;DR: A method of calculating complication probabilities for inhomogeneously irradiated normal tissues is presented, using examples from an NCI 3-D treatment planning contract.
Abstract: New tools are needed to help in evaluating 3-D treatment plans because of the large volume of data. One technique which may prove useful is the application of complication probability calculations. A method of calculating complication probabilities for inhomogeneously irradiated normal tissues is presented in this paper. The method uses clinical estimates of tolerance doses for a few discreet conditions of uniform partial organ irradiation, an empirical fit of a continuous function to these data, and a technique (the effective volume method) for transforming nonuniform dose-volume histograms into equivalent uniform histograms. The behavior of the effective volume histogram reduction method for various boundary conditions is reviewed. The use of complication probabilities in evaluating treatment plans is presented, using examples from an NCI 3-D treatment planning contract.
TL;DR: There was no significant difference between the accuracies of CT and MR imaging in detecting mediastinal node metastases (N2 or N3); the sensitivities were 52% and 48%, respectively, and specificities were 69% and 64%.
Abstract: The accuracies of magnetic resonance (MR) imaging and computed tomography (CT) in determining tumor classification and assessing mediastinal node metastases were compared in a prospective cooperative study of 170 patients with non-small cell bronchogenic carcinoma. The sensitivity of CT in distinguishing T3-T4 tumors from T0-T2 tumors was 63%; specificity was 84%. These values for MR imaging were not significantly different (56% and 80%). With receiver operating characteristic (ROC) analysis, no difference existed between the accuracies of CT and MR imaging in diagnosis of bronchial involvement or chest wall invasion, but MR imaging was significantly more accurate than CT (P = .047) in diagnosis of mediastinal invasion. Lymph node sampling was performed in 155 patients (642 node stations). Cancerous nodes were found in 14% of stations in 21% of patients. There was no significant difference between the accuracies of CT and MR imaging in detecting mediastinal node metastases (N2 or N3); the sensitivities were 52% and 48%, respectively, and specificities were 69% and 64%. ROC analysis also showed no difference between CT and MR imaging.
TL;DR: The author’s views are based on personal experience, research, and interviews conducted at the 2016 USGS workshop on “Biology of infectious disease: Foundations of Natural Selection and Response to infectious disease .”
Abstract: AND PERSPECTIVE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 827 ORGANIZATION OF HISTONE GENES-STRUCTURE OF HISTONE mRNAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 828 OVERVIEW OF HIS TONE SYNTHESIS IN THE CELL CyCLE . . . . . . . . . . . . . . . . . . . . . . . . 829 TRANSCRIPTIONAL REGULATION . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 832 Higher Eukaryotes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . ... . . . . . . . . 832 Lower Eukaryotes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..... . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . 841 POSTTRANSCRIPTIONAL REGULATION . . . . . .. . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . .. . . . . . . . .... 847 Higher Eukaryotes. . . . . .. . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....... . . . . . . . . . . . . . . . .. . . . . . . . 847 Lower Eukaryotes . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...... . . . . . . . . . . . . . . . . . . 853 MULTIPLE FORMS OF REGULATION MODULATE HISTONE mRNA LEVELS IN THE CELL CyCLE . . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . !l55 FUTURE PROSPECTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..... . . .. . . . . . . . . . . . . . . . . . ... .. . . . . .. . . . . . . . . . 856
TL;DR: It appears that this gene family, the DNA-binding portion of which is unlike that of any previously recognized DNA- binding proteins, may contribute to differentiation of cells in internal organs in both vertebrates and invertebrates.
Abstract: By analysis of cDNA clones that cross-hybridized with a portion of the cDNA encoding the recently described rat protein hepatocyte nuclear factor 3 alpha (HNF-3 alpha, previously called HNF-3A), we now describe two additional members, HNF-3 beta and HNF-3 gamma, of this gene family. A 110-amino-acid region in the DNA-binding domain of this family is not only very highly conserved in rodents (HNF-3 alpha, -3 beta, and -3 gamma are identical in 93 of 110 amino acids in this region) but also in Drosophila where the homeotic gene fork head has 88 of the 93 residues that are identical in the three rat genes. The HNF-3 family in rodents is expressed in cells that derive from the lining of the primitive gut; some of the embryonic Drosophila cells in which fork head is expressed also give rise to gut and salivary glands. Thus, it appears that this gene family, the DNA-binding portion of which is unlike that of any previously recognized DNA-binding proteins, may contribute to differentiation of cells in internal organs in both vertebrates and invertebrates.
TL;DR: The examination of bone marrow for micrometastases remains an experimental procedure; the clinical usefulness of the test will be established through larger studies with long-term follow-up, and evaluation for BMM might be used to stratify patients for adjuvant treatment programs.
Abstract: We used monoclonal antibodies to identify occult micrometastases in the bone marrow of 49 patients with operable (stage I and II) breast carcinoma. Follow-up (mean, 29 months; median, 30 months) revealed that 12 patients recurred. The presence of bone marrow micrometastases (BMM) was significantly associated with early recurrence (P less than .04). The estimated 2-year recurrence rate for patients with no BMM detected (BMM-) was 3%; in patients with BMM, the 2-year recurrence rate was 33%. When BMM and axillary lymph node (LN) status were combined, groups of patients at low risk (LN-, BMM-; 2-year recurrence rate, 0%) and high risk (LN+, BMM+; 2-year recurrence rate, 42%) for early recurrence were identified. Bone marrow tumor burden was related to early recurrence. Among patients with BMM, those who did not recur had on average fewer extrinsic cells in their marrow than those who recurred (15 v 43 cells, respectively). Multivariate analysis comparing BMM, LN+ versus LN-, and tumor size (less than or equal to 2 cm v greater than 2 cm) revealed no factor independently associated with early recurrence. Peripheral tumor burden of BMM (0 or less than 10 extrinsic cells v greater than or equal to 10 extrinsic cells) was the only independent predictor of early recurrence (P less than .003). In conjunction with conventional prognostic factors, particularly axillary LN status, evaluation for BMM might be used to stratify patients for adjuvant treatment programs. Because this pilot study involved few patients with short-term follow-up, the results should be interpreted with caution. The examination of bone marrow for micrometastases remains an experimental procedure; the clinical usefulness of the test will be established through larger studies with long-term follow-up.
TL;DR: This behavior successfully forecast the ability of both flavonoids to suppress tumor multiplicity and ultimately tumor development.
Abstract: Dietary quercetin (QU) and rutin (RU), phenolic flavonoids commonly found in many fruits and vegetables, were provided to CF1 female mice for 50 weeks to assess the ability of these compounds to inhibit azoxymethanol (AOM)-induced colonic neoplasia. In addition to a control group fed an AIN 76A diet, five other groups received that diet to which was added either 0.1, 0.5 or 2.0% QU and 1.0 or 4.0% RU. Acute studies revealed that, among saline controls, no alteration of any proliferative parameters of colonic epithelial cells was observed among those groups receiving any dose of QU or RU. However, among the AOM-treated mice, both 2% QU and 4% RU significantly reduced hyperproliferation and inhibited the shift of S-phase cells to the middle and upper portion of crypts. Moreover, mice fed these concentrations of QU and RU had significantly fewer AOM-induced focal areas of dysplasia (FADs) than those fed the control diet (0.2 +/- 0.4 and 0.4 +/- 0.5 versus 3.6 +/- 2.3 respectively). Tumors occurred more frequently in the distal half of the colon, regardless of treatment. Compared with controls, mice fed 2% QU had a significantly reduced tumor incidence (25.0% versus 5.9%, P = 0.03). Those fed 4% RU showed only a trend toward inhibition (25% versus 9.7%, P = 0.11). Nevertheless, both 2% QU and 4% RU suppressed tumor multiplicity, i.e. fewer tumors/animal arose in these groups than in the AOM-treated control mice (1.2 versus 2.3, P = 0.005; 1.1 versus 2.3, P = 0.003 respectively). Clearly, QU and RU exhibit significant activity in reducing AOM-induced hyperproliferation of colonic epithelial cells and FAD incidence. This behavior successfully forecast the ability of both flavonoids to suppress tumor multiplicity and ultimately tumor development.
TL;DR: The existence and re-growth of local residual disease in localized prostatic carcinoma promotes an enhanced spread of metastatic disease, and that early and complete eradication of the primary tumor is required if a long term cure is to be achieved, although the clinical expression of secondary metastases may not become apparent for 6.5 years or more in one-half of the patients.
Abstract: The study evaluates the effect of the locally recurring tumor on the incidence of metastatic disease in early stage carcinoma of the prostate. The probability of distant metastases was studied in 679 patients with Stage B-C/NO carcinoma of the prostate treated at MSKCC between 1970 and 1985 (median follow-up of 97 months). Patients were staged with pelvic lymph node dissection and treated with retropubic 125I implantation. The actuarial distant metastases free survival (DMFS) for patients at risk at 15 years after initial therapy was 37%. Cox proportional hazard regression analysis of covariates affecting the metastatic outcome showed that local failure, used in the model as a time dependent variable, was the most significant covariate, although stage, grade, and implant volume were also found to be independent variables. The relative risk of metastatic spread subsequent to local failure was 4-fold increased compared to the risk without evidence of local relapse. The 15-year actuarial DMFS in 351 patients with local control was 77% compared to 24% in 328 patients who developed local relapses (p < 0.00001). The relation of distant spread to the local outcome was observed regardless of stage, grade, or implant dose. Even stage BI/NO-Grade I patient with local control showed a 15-year actuarial DMFS of 82%, compared to 22% in patients with local relapse; p < 0.00001). The median local relapse-free survival (LRFS) in the 268 patients with local recurrences who did not receive hormonal therapy before distant metastases were detected was 51 months, compared to a median of 71 months for DMFS in the same patients (p < 0.001), consistent with the possibility that distant dissemination may develop secondary to local failure. Furthermore, distant metastases in patients with local control, apparently already existing as micrometastases before treatment, were detected earlier (median DMFS of 37 months) than in patients with local relapse (median DMFS of 54 months; p = 0.009). These data suggest that the existence and re-growth of local residual disease in localized prostatic carcinoma promotes an enhanced spread of metastatic disease, and that early and complete eradication of the primary tumor is required if a long term cure is to be achieved, although the clinical expression of secondary metastases may not become apparent for 6.5 years or more in one-half of the patients.
TL;DR: It is concluded that IDR/Ara-C can effectively replace standard therapy with DNR/ARA-C in adult patients less than age 60 with newly diagnosed AML.
TL;DR: The presence of anti‐Ri antibody identifies a subset of patients with paraneoplastic ataxia and eye movement disorders (opsoclonus) who usually suffer from breast or other gynecological cancer; the antibody when present is a useful marker for an underlying malignancy.
Abstract: The serum and cerebrospinal fluid (CSF) of 8 women with ataxia, 6 of whom also had eye movement abnormalities believed to be opsoclonus, were found to contain a highly specific antineuronal antibody we call anti-Ri. Seven of the 8 women also had or developed cancer: carcinoma of the breast in 5, adenocarcinoma in an axillary lymph node in 1, and carcinoma of the fallopian tube in 1. Four patients presented with the neurological disorder; the cancer was diagnosed first in the other 4. Immunohistochemical studies using serum or CSF from all 8 patients revealed a highly specific antibody interaction with central nervous system neuronal nuclei but not with glial or other cells; the titer ranged from 1:5,000 to 1:320,000 in serum and from 1:2,000 to 1:16,000 in CSF. Biotinylated IgG from the patients' serum reacted with the tumors of 3 of 4 patients with anti-Ri antibody but not with breast cancers from patients without anti-Ri antibody. Immunoblots against cerebral cortex neuronal extracts identified protein antigens of 55-kd and 80-kd relative molecular mass. Serum titers by immunoblot ranged from 1:500 to more than 1:40,000 and CSF titers, from 1:10 to 1:2,000. The relative amount of anti-Ri was always higher in CSF than in serum. The antibody was not present in sera from normal individuals; patients with breast cancer without opsoclonus; other patients with opsoclonus; or patients with other paraneoplastic syndromes related to breast, ovarian, or small-cell lung cancer. We conclude that the presence of anti-Ri antibody identifies a subset of patients with paraneoplastic ataxia and eye movement disorders (opsoclonus) who usually suffer from breast or other gynecological cancer; the antibody when present is a useful marker for an underlying malignancy.
TL;DR: The lyt -10 gene defines a new subfamily (rel/poly-G/ankyrin) of NF-κB-rel transcription factors with potential for oncogenic activation in human cancer.
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TL;DR: The present studies demonstrate the existence of an unusual Mg(2+)-dependent ceramide-activated protein kinase that may mediate some aspects of TNF-alpha function.
Abstract: Recent investigations have identified a signal-transduction system involving sphingomyelin and derivatives. In this paradigm, sphingomyelin hydrolysis by a sphingomyelinase generates ceramide, which may be converted to the protein kinase C inhibitor sphingosine or to ceramide 1-phosphate. Ceramide may have second-messenger function because it induces epidermal growth factor receptor phosphorylation, presumably on Thr-669 in A-431 cells. The present studies describe a kinase that may mediate ceramide action. With a 19-amino acid epidermal growth factor receptor peptide containing Thr-669, a membrane-bound activity that phosphorylated the peptide was detected in A-431 cells. Activity was linearly related to ATP (0.3-300 microM) and peptide concentration (0.02-1 mg/ml), possessed a physiologic pH optimum (pH 7.0-7.4), and was Mg(2+)-dependent. Other cations--Ca2+, Mn2+, and Zn(2+)--were ineffective. Natural and synthetic ceramide induced time- and concentration-dependent enhancement of kinase activity. Ceramide (0.5 microM) increased kinase activity 2-fold by 30 s, and activity remained elevated for at least 15 min. As little as 0.001 microM ceramide was effective, and 1 microM ceramide induced maximal phosphorylation. Sphingosine was similarly effective. Because tumor necrosis factor (TNF) alpha rapidly induces sphingomyelin hydrolysis to ceramide during monocytic differentiation of HL-60 cells, its effects on kinase activity were assessed. Kinase activity was increased 1.5-fold at 5 min and 2-fold at 2 hr in membranes derived from TNF-stimulated cells. The effective concentration range was 3 pM-30 nM TNF. Exogenous ceramide induced a similar effect. In sum, these studies demonstrate the existence of an unusual Mg(2+)-dependent ceramide-activated protein kinase that may mediate some aspects of TNF-alpha function.
TL;DR: Recommendations for treatment include a wide excision of the primary tumor and either elective or early therapeutic regional node dissection, which suggests an orderly "cascade" pattern of spread for this tumor.
Abstract: • Seventy patients with Merkel cell carcinoma were treated at Memorial Sloan-Kettering Cancer Center between 1969 and 1989. The overall estimated 5-year survival rate was 64%. Factors predictive of improved survival included head and neck site and negative lymph nodes at presentation. Local recurrence was seen in 18 patients (26%) and did not correlate with patient-, tumor-, or treatment-related variables. Nine patients with local recurrence (50%) were free of disease following aggressive reoperation. Regional nodes were involved at some point during the course of the disease in forty-six patients (66%). Regional lymph node involvement was apparent within 2 years of diagnosis in 40 (87%) of 46 patients in whom it occurred. Systemic disease was nearly uniformly preceded by the appearance of nodal metastases and was uniformly fatal regardless of subsequent therapy. This suggests an orderly "cascade" pattern of spread for this tumor, in which elective regional lymph node dissection may be justified. Our recommendations for treatment include a wide excision of the primary tumor and either elective or early therapeutic regional node dissection. The role of adjuvant radiotherapy or chemotherapy remains unproven. ( Arch Surg . 1991;126:1514-1519)
TL;DR: DVHs show promise as tools for comparing rival treatment plans for a specific patient by clearly presenting the uniformity of dose in the target volume and any hot spots in adjacent normal organs or tissues, but because of the loss of positional information in the volume under consideration, it should not be the sole criterion for plan evaluation.
Abstract: A plot of a cumulative dose-volume frequency distribution, commonly known as a dose-volume histogram (DVH), graphically summarizes the simulated radiation distribution within a volume of interest of a patient which would result from a proposed radiation treatment plan. DVHs show promise as tools for comparing rival treatment plans for a specific patient by clearly presenting the uniformity of dose in the target volume and any hot spots in adjacent normal organs or tissues. However, because of the loss of positional information in the volume(s) under consideration, it should not be the sole criterion for plan evaluation. DVHs can also be used as input data to estimate tumor control probability (TCP) and normal tissue complication probability (NTCP). The sensitivity of TCP and NTCP calculations to small changes in the DVH shape points to the need for an accurate method for computing DVHs. We present a discussion of the methodology for generating and plotting the DVHs, some caveats, limitations on their use and the general experience of four hospitals using DVHs.
TL;DR: Fifty patients with esophageal cancer proved by means of biopsy underwent preoperative staging with endoscopic ultrasonography (US); in 42 of the patients, dynamic CT of the chest and abdomen was also performed.
Abstract: Fifty patients with esophageal cancer proved by means of biopsy underwent preoperative staging with endoscopic ultrasonography (US); in 42 of the patients, dynamic CT of the chest and abdomen was also performed. All results were compared with the findings at pathologic examination of resected specimens. In staging the depth of tumor growth, endoscopic US was significantly more accurate (46 of 50 tumors [92%]) than CT (25 of 42 tumors [60%]) (P less than .0003). In staging regional lymph nodes, it was more accurate (44 of 50 patients [88%]) than CT (31 of 42 patients [74%]), but this was not statistically significant. In staging distant metastases, however, CT was more accurate (38 of 42 patients [90%]) than endoscopic US (35 of 50 patients [70%]) (P less than .016). The highest concordance with surgical and pathologic findings in overall stage (36 of 42 tumors [86%]) occurred with the combined use of CT and endoscopic US, which was significantly more accurate than use of CT alone (27 of 42 tumors [64%]) (P less than .008).
TL;DR: It is concluded that treatment with an MAb that inhibits EGF receptor function is safe at the doses and schedule studied and further studies are warranted to explore the potential therapeutic efficacy of anti-EGF receptor MAbs.
Abstract: Murine monoclonal antibody (MAb) 225 (IgG1) against the epidermal growth factor (EGF) receptor competitively blocks EGF binding and inhibits EGF-induced activation of receptor tyrosine kinase and cell proliferation. The effect of MAb 225 was studied in a phase I trial in patients with inoperable squamous cell carcinoma of the lung, which invariably expresses high levels of EGF receptors. Groups of three patients received total doses of MAb 225 ranging from 1 mg to 300 mg. Except at the lowest dose, each infusion included 4 mg of indium 111 (111In)-labeled MAb 225. No toxicity was observed. Tumors were imaged in all patients who received doses of 20 mg or greater. Presumed metastases greater than or equal to 1 cm in diameter were imaged with doses of 40 mg or greater. Single-photon-emission-computed tomography could be carried out at the 120-mg and 300-mg doses and significantly improved tumor visualization. All patients produced anti-murine antibodies. We conclude that treatment with an MAb that inhibits EGF receptor function is safe at the doses and schedule studied. 111In-labeled MAb images squamous cell lung carcinoma; tumor uptake of the labeled MAb is dose dependent. Further studies are warranted to explore the potential therapeutic efficacy of anti-EGF receptor MAbs and other agents that act in a comparable manner.
TL;DR: The interrelationships of depression and suicide with adolescent drug use, delinquency, eating disorders, and the risk factors for these different problems were investigated among 597 9th and 11th graders in an urban high school.
Abstract: The interrelationships of depression and suicide with adolescent drug use, delinquency, eating disorders, and the risk factors for these different problems were investigated among 597 9th and 11th graders in an urban high school. There is a strong association of drug use with suicidal ideation among girls, and a stronger relationship with attempts among girls and boys. Suicidal youths are ill-adjusted and display a lack of attachment and commitment to family and school. Causal models indicate that poor interpersonal interactions with parents, absence of peer interactions, and life events lead to depression, which in turn leads to suicidal ideation. Depressive symptoms are the strongest predictors of suicidal ideation. Among females, depression predicts drug involvement, and in turn, drug use increases suicidal ideation. Drug use is only one class of problem behaviors that constitutes a risk factor for suicidal behavior in adolescence. Delinquency and eating disorders also have direct effects on suicidal ideation beyond those of depressive affect. As for drug involvement, these problem behaviors are more predictive of suicidal behavior among girls than boys. Similarity and specificity of the predictors for problem behaviors within and between the sexes are discussed. Although young women use drugs to handle feelings of depression, drug use appears ineffective in the long run in relieving these depressive feelings. Understanding the dynamics of suicidal ideation in adolescence has important public health implications, since ideation is a strong predictor of attempts, especially among females.