Small cell lung cancer.
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Carcinoma, Small Cell↗
Biomedical subjects
N Murray
Publications and source records attributed to N Murray.
Treatment of small cell lung cancer: the state of the art.
Many innovations have been tested to improve the power of chemotherapy for SCLC including: drug diversity enhancement, dose and dose-intensity escalation, incorporation of new agents, and resistance modification. Although superiority of combination chemotherapy over monotherapy has been shown, clinical trials have failed to demonstrate a clearly superior multiagent regimen. When dose and dose-intensity are diminished from standard levels, the effect is detrimental for both limited and extensive stage SCLC. Trials of dose and dose-intensity above standard levels have not yet shown advantages for patients with extensive stage SCLC. However, the only two randomized trials of chemotherapy dose escalation for limited SCLC show statistically significant survival benefits. The optimal intensity of chemotherapy for limited SCLC has not been defined. State-of-the-art chemotherapy for extensive SCLC could be CAV, EP, or CAV/EP but EP has generally been favored because it is associated with less myelotoxicity and four cycles are considered adequate rather than 6 cycles of the others. EP is widely regarded as state-of-the-art chemotherapy for limited SCLC particularly because this regimen can be integrated with concurrent thoracic irradiation with acceptable toxicity. Early thoracic irradiation with concurrent EP chemotherapy is state-of-the-art treatment for limited SCLC, however, it must be conceded that EP has never been shown to be superior to any other chemotherapy regimen in a phase III trial of either limited or extensive SCLC. Current state-of-the-art treatment for limited SCLC can result in actual 5-year survival rates of at least 20%; declaration of a statistically significant improvement will require sample sizes than most clinical trials performed to date.
Antineoplastic Combined Chemotherapy Protocols↗
Gemcitabine: a promising new agent in the treatment of advanced urothelial cancer.
PURPOSE: To evaluate the efficacy and toxicity of gemcitabine (2',2'-difluorodeoxycytidine) in previously untreated patients with advanced transitional cell carcinoma. PATIENTS AND METHODS: Forty-one patients with measurable advanced transitional cell carcinoma who had received no prior chemotherapy for metastatic disease were scheduled to receive gemcitabine 1,200 mg/m2 intravenously over 30 minutes on days 1, 8, and 15 of a 28-day cycle. Prior adjuvant or neoadjuvant therapy for locally advanced disease was allowed if this was completed greater than 1 year prior to study entry. All patients were treated on an outpatient basis. RESULTS: There were three complete responses and six partial responses seen in 37 assessable patients, for an overall response rate of nine of 37 (24.3%; 95% confidence interval, 12 to 41). Four patients remain in remission at 14, 23, 24, and 31 months. The median survival was 8 months with 17% of patients alive at 2 years. Treatment generally was well-tolerated with three patients having > or = grade 3 nonhematologic toxicity, five having grade 3 neutropenia, two having grade 3 thrombocytopenia, and two episodes of febrile neutropenia. Most patients were able to receive the drug as scheduled with the primary reason for dose reduction or dose delay being neutropenia. CONCLUSION: Gemcitabine has promising single-agent activity against urothelial cancer with a favorable toxicity profile. Further studies in combination with other active agents are warranted.
Aged↗
New drugs for small-cell lung cancer.
Better efficacy of chemotherapy for small-cell lung cancer (SCLC) has not been convincingly demonstrated despite many investigations examining increased drug delivery and enhancement of drug diversity. Improvements in the median- and long-term survival of patients with limited SCLC have been shown, but this change is more closely associated with better integration of chemoradiation than with more effective chemotherapy or radiotherapy components. Recently, a number of new active drugs have been identified for treating patients with SCLC. These drugs include the taxanes, the camptothecins, and gemcitabine. Determining the role of each new agent will require carefully designed and conducted trials like those now in progress.
Antineoplastic Combined Chemotherapy Protocols↗
Teratoma in primary testis tumor reduces complete response rates in the retroperitoneum after primary chemotherapy. The case for primary retroperitoneal lymph node dissection of stage IIb germ cell tumors with teratomatous elements.
BACKGROUND: Recent advances in the therapy of advanced testicular nonseminomatous germ cell tumors (NSGCT) have resulted in increased attention to avoiding double therapy in cases where single modality therapy will suffice. METHODS: Over an 8-year period, 104 patients with Stage II and III testicular NSGCT received primary chemotherapy. Seventy-nine patients had retroperitoneal lymph nodal metastases, 33 of whom had a radiologic complete response, 43 a radiologic incomplete response, and 3 were not re-evaluated after induction chemotherapy. Thirty-nine patients underwent retroperitoneal lymph node dissection (RPLND). The radiologic and pathologic response of the nodes to primary chemotherapy was correlated with tumor burden (lymph node metastasis size < or = 2 cm, 2.1-5 cm, 5.1-10 cm, and >10 cm), primary tumor pathology, and prechemotherapy marker levels. RESULTS: Larger initial lymph node size, metastases size, the presence of teratoma in the primary tumor, and prechemotherapy alpha-fetoprotein (alpha-FP) > 80 mg/L and beta-HCG (bHCG) 10000 IU/L were found to correlate significantly with an incomplete radiologic response. Lymph node metastases size was the only independent prognostic factor on multivariable logistic regression analysis. Prechemotherapy alpha-FP > 80 mg/L and beta-HCG > 10000 IU/L were associated with the presence of teratoma or carcinoma in the retroperitoneal nodes. The presence of teratoma in the primary tumor is associated with a higher incomplete response rate and residual teratoma in the retroperitoneal lymph nodes after primary chemotherapy. CONCLUSIONS: Predictors of need for postchemotherapy RPLND include large lymph node metastasis size and presence of teratomatous elements in the primary tumor. To reduce the need for and morbidity of double therapy, patients with low volume clinical Stage II, NSGCT and teratomatous elements in the primary tumor are arguably better served by primary RPLND.
Adolescent↗
Antitumor effects of granulocyte-macrophage colony-stimulating factor production by melanoma cells.
The use of immunomodulating gene therapy in the treatment of malignant disease is under intensive investigation. In this study, we examined the potential of melanoma-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) to inhibit melanoma progression in a murine model. The HGH18 murine melanoma cell line was transfected with the murine GM-CSF gene in a SV40 expression vector that resulted in melanoma clones that produced varying amounts of GM-CSF. Syngeneic mice inoculated s.c. with HFH18 parental melanoma cells or HFH18 cells transfected with the GM-CSF gene n the noncoding 3'-5' orientation [HFH18/GM-CSF(-) cells] develop large tumors that reach a mean tumor volume of 3300 mm3 by day 30. In contrast, animals inoculated with two melanoma clones producing high levels of GM-CSF [HFH18/GM-CSF(++) and HFH18/GM-CSF(+ + +)] either completely reject the tumor cells or develop tumors with a mean volume of only 40 mm3. In comparison, animals inoculated with a melanoma clone producing low levels of GM-CSF [HFH18/GM-CSF(+)] develop large tumors averaging 2000 mm3, thus demonstrating a dose-response effect of tumor inhibition by melanoma-derived GM-CSF. Additionally, vaccination with irradiated GM-CSF-producing melanoma cells conferred optimal immunogenicity against a subsequent challenge with HFH18 cells. Tissue sections from excised GM-CSF-producing tumor cell inoculation sites but not from HFH18 parental or HFH18/GM-CSF(-) inoculation sites demonstrate a dense inflammatory infiltrate composed of neutrophils, tissue macrophages, and numerous CD4- and CD8-positive lymphocytes but few melanoma cells. Large numbers of dendritic cells and cells expressing the B7-2 costimulatory molecule are detected only within HFH18/GM-CSF(+ + +) melanoma inoculation sites. Our results lend further support to clinical trials of GM-CSF gene therapy in the treatment of advanced malignant melanoma, possibly by the recruitment of dendritic antigen-presenting cells.
Animals↗
Expression of a single-chain HLA class I molecule in a human cell line: presentation of exogenous peptide and processed antigen to cytotoxic T lymphocytes.
We have synthesized a recombinant gene encoding a single-chain HLA-A2/beta 2-microglobulin (beta 2m) molecule by linking beta 2m through its carboxyl terminus via a short peptide spacer to HLA-A2 (A*0201). This gene has been expressed in the beta 2m-deficient colorectal tumor cell line DLD-1. Transfection of this cell with the single-chain construct was associated with conformationally correct cell surface expression of a class I molecule of appropriate molecular mass. The single-chain HLA class I molecule presented either exogenously added peptide or (after interferon-gamma treatment) endogenously processed antigen to an influenza A matrix-specific, HLA-A2-restricted cytotoxic T-lymphocyte line. The need for interferon gamma for the processing and presentation of endogenous antigen suggests that DLD-1 has an antigen-processing defect that can be up-regulated, a feature that may be found in other carcinomas. Our data indicate that single-chain HLA class I constructs can form functional class I molecules capable of presenting endogenously processed antigens. Such molecules should be of use for functional studies, as well as providing potential anticancer immunotherapeutic agents or vaccines.
Amino Acid Sequence↗
Phrenic nerve maturation in the sudden infant death syndrome.
It has been suggested that delayed development in either the peripheral or central nervous system could underlie the sudden infant death syndrome (SIDS). We studied the phrenic nerve in an attempt to find if maturation in this nerve was delayed in SIDS, and to see if fiber size differences could explain the paucity of type I muscle fibers described in SIDS diaphragms. Samples of phrenic nerves were taken at post mortem from 11 SIDS and 10 control infants. Myelinated fibers were quantitated in 1-micron silver-stained resin sections using a semi-automatic image analysis system. The numbers and sizes of all myelinated fibers in the right phrenic nerve were compared between SIDS and control groups. The proportion of small (less than 6-microns diameter) phrenic nerve fibers was similar in SIDS (53.1%, SD 12.8%) and control (53.6%, SD 14.0%) cases. The proportion of small fibers decreased with increasing age at an equivalent rate in both SIDS and control groups. Total numbers of myelinated fibers were similar in the right phrenic nerves of SIDS (3429, SD 440) and control (3457, SD 507) infants, but varied widely between cases and were not correlated with age. Maturation of the phrenic nerve, as judged by increasing size of myelinated fibers, is therefore similar in SIDS and control infants. This argues against a widespread development delay in SIDS. No changes in phrenic nerve fiber sizes were found to account for the finding of fewer type I fibers in SIDS diaphragms.
Age Distribution↗
Retrospective benzene and total hydrocarbon exposure assessment for a petroleum marketing and distribution worker epidemiology study.
A quantitative exposure-estimating algorithm for benzene and total hydrocarbons was developed for a case control study of petroleum marketing and distribution workers. The algorithm used a multiplicative model to adjust recently measured quantitative exposure data to past scenarios for which representative exposure measurement data did not exist. This was accomplished through the development of exposure modifiers to account for differences in the workplace, the materials handled, the environmental conditions, and the tasks performed. Values for exposure modifiers were obtained empirically and through physical/chemical relationships. Dates for changes that altered exposure potential were obtained from archive records, retired employee interviews, and from current operations personnel. Exposure modifiers were used multiplicatively, adjusting available measured data to represent the relevant exposure scenario and time period. Changes in exposure modifiers translated to step changes in exposure estimates. Though limited by availability of data, a validation exercise suggested that the algorithm provided accurate exposure estimates for benzene (compared with measured data in industrial hygiene survey reports); the estimates generally differed by an average of less than 20% from the measured values. This approach is proposed to quantify exposures retrospectively where there are sufficient data to develop reliable current era estimates and where a historical accounting of key exposure modifiers can be developed, but where there are insufficient historic exposure measurements to directly assess historic exposures.
Algorithms↗
Mechanisms of loss of HLA class I expression on colorectal tumor cells.
For several years this laboratory has studied the expression of HLA class I on established colorectal tumor cell lines and on fresh tumors. We review here the mechanisms by which colorectal tumor cells may lose surface expression of HLA class I molecules. Several independent mechanisms have been identified, including loss or mutations in beta 2-microglobulin genes, loss of HLA heavy chain genes, selective lack of expression of HLA alleles, and regulatory defects in HLA expression including loss of expression of the peptide transporters associated with antigen processing (TAP). The data suggest that colorectal tumor cells may evade tumor specific, HLA restricted immune attack by loss of HLA class I expression through a number of mechanisms.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Vulnerability of the infant brain stem to ischemia: a possible cause of sudden infant death syndrome.
In infants, extreme extension or rotation of the head can occlude one or both vertebral arteries. We sought to determine whether small communicating arteries or asymmetric vertebral arteries could predispose the brain stem to ischemia should such head movements occur. In 68 infants, the carotid, posterior communicating, precommunicator posterior cerebral, basilar and vertebral arteries were fixed in formalin, embedded in resin, the circumferences measured by image analysis, and the relative conductance of blood in each artery per gram of brain calculated. Conductance in the vertebrobasilar and carotid systems lagged behind increases in brain weight during the postnatal growth spurt. In 81% of infants, conductance through the communicating arteries was less than 25% of basilar artery conductance. Conductance in one vertebral artery was less than half that of the contralateral artery in 41% of infants. In conclusion, the lag in available blood flow and small communicating and asymmetric vertebral arteries may predispose the infant brain stem to ischemia if one or both vertebral arteries are occluded by head rotation or extension. Because these head movements are likely to be accentuated in the prone sleeping position (a risk factor for sudden infant death syndrome), we suggest that vertebral artery occlusion may underlie some cases of sudden unexpected infant death.
Age Factors↗
Influence of age on the treatment of limited-stage small-cell lung cancer.
PURPOSE: To evaluate the prognostic importance of age on response rate and survival in patients with limited-stage small-cell lung cancer (SCLC), and to determine the effect of age on chemotherapy dose delivery and toxicity. PATIENTS AND METHODS: We undertook a retrospective analysis of data from two multicenter, randomized trials conducted by the National Cancer Institute of Canada (NCIC) in which 608 SCLC patients who presented with limited disease (LD) all received the same chemotherapy. Treatment consisted of cyclophosphamide, doxorubicin, and vincristine (CAV), and etoposide plus cisplatin (EP) administered in an immediate or delayed alternating fashion, plus cranial and thoracic irradiation. RESULTS: There were 520 patients aged less than 70 years, and 88 > or = 70. No significant differences existed between the two age groups in baseline characteristics, including treatment protocol, performance status, and serum lactate dehydrogenase (LDH) level. There were more men in the older group (P = .05). Overall response rates were comparable (78% v 82%, P = .50), and 5-year survival rates were also similar (P = .14), with 11% alive in the younger group and 8% in the older group. Age was a significant predictor of overall survival when analyzed as a continuous variable in a univariate model (P = .01), but it was no longer an independent prognostic factor in our multivariate regression analysis. An analysis of chemotherapy delivery between the two age groups showed that patients aged > or = 70 years received lower total doses of each drug compared with the intended full protocol dose, primarily as a result of dose omissions, rather than dose reductions. The frequency of dose delays was not different between groups. No significant differences were seen in the incidence of either hematologic or most nonhematologic toxicities. CONCLUSION: Age is not a significant adverse prognostic variable in SCLC patients with LD. Moderately aggressive chemotherapy may be delivered safely to elderly patients with a good performance status, although modest attenuation of therapy through either dose reduction or omission may occur more frequently in this population.
Adolescent↗
Genetic analysis of second primary lung cancers in patients surviving small cell lung cancer.
We performed genetic analysis on 12 second primary non-small cell lung cancers in patients surviving small cell lung cancer to assess the potential contribution of smoking to the development of these tumors. Mutations of TP53 were found in three (25%) tumors, KRAS2 in three (25%) tumors, and CDKN2 in two (18%) tumors. Four (50%) mutations (one each in TP53 and CDKN2 and two in KRAS2) were G:C to T:A transversions on the coding strand, a mutation accounting for approximately one-third of mutations in smoking-related tumors but uncommonly found in lung cancers not associated with smoking. The genetic changes in these second lung cancers are more representative of smoking-associated malignancies than lung cancers arising in patients occupationally exposed to irradiation and atomic bomb survivors.
Carcinoma, Small Cell↗
Class I major histocompatibility complex-restricted cytotoxic T lymphocytes specific for Epstein-Barr virus (EBV)-transformed B lymphoblastoid cell lines against which they were raised.
We have raised CD8+ cytotoxic T lymphocytes (CTL) from three Epstein-Barr virus-seropositive donors by incubating peripheral blood lymphocytes with irradiated autologous B95.8-strain EBV-transformed B lymphoblastoid cells (LCL). However, to detect lysis in a standard 51Cr release assay of the LCL against which these CTL were raised, superinfection with recombinant vaccinia expressing the appropriate EBV protein or incubation with the peptide epitope was necessary. The untreated LCL were not lysed, even though Western blotting demonstrated that they expressed the EBV antigens containing the CTL epitopes. We have found CTL of this phenotype that are restricted by human leukocyte antigen-A2, -A3, -B7, or -B39, and which recognize the EBV latent proteins, EBV nuclear antigen (EBNA)-3A, EBNA-3C, or terminal protein. During these experiments, we identified a new human leukocyte antigen-A3-restricted EBNA-3A epitope, residues 603-611, RLRAEAGVK. We raised a spontaneous LCL, transformed by endogenous EBV, from one donor, but this was also not lysed. For at least one of the epitopes, CTL from another donor lysed the LCL without superinfection or addition of peptides. We conclude that the CTL were unable to achieve a high enough avidity of interaction with untreated LCL to trigger effector function, although the LCL were able to stimulate them to grow in vitro for up to 4 mo. To assess whether a small percentage of the LCL might possess a higher antigen density, we used an assay of tumor necrosis factor release from a CTL clone, which was able to detect antigen-bearing cells representing only 1% of a stimulating LCL population. Nevertheless, the untreated autologous LCL line failed to stimulate tumor necrosis factor release.
Amino Acid Sequence↗
Epitope mapping and functional properties of anti-intercellular adhesion molecule-3 (CD50) monoclonal antibodies.
Intercellular adhesion molecule-3 (ICAM-3, CD50), a member of the immunoglobulin gene superfamily, is a major ligand for the lymphocyte function-associated antigen 1 (LFA-1, CD18/CD11a) in the resting immune system and plays a role as a signaling and costimulatory molecule on T lymphocytes. In this study we have generated a large panel of anti-ICAM-3 monoclonal antibodies (mAb) and show that the biological effects of these antibodies are critically dependent on the epitope recognized. By using an adhesion assay employing COS cells expressing LFA-1 binding to recombinant chimeric ICAM-3-Fc proteins (which overcomes the confounding effects of interleukocyte LFA-1/ICAM binding events), we have been able to examine the effects of these antibodies in blocking LFA-1/ICAM-3 adhesion. Our data suggests that only a small minority of ICAM-3 mAb, recognizing a distinct epitope, are able to mimic the effects of LFA-1 binding to ICAM-3. Moreover these antibodies are functionally distinct as defined by their costimulatory activity and ability to elicit interleukin-2 production and cell proliferation in T lymphocytes.
Animals↗
A single site on the epsilon subunit is responsible for the change in ACh receptor channel conductance during skeletal muscle development.
Four critically positioned amino acids on each of the alpha, beta, delta, and gamma subunits of the Torpedo nicotinic acetylcholine receptor are determinants of channel conductance. Our results show that the gamma and epsilon subunits of Xenopus muscle receptors are identical at all four positions, despite the fact that alpha 2 beta delta epsilon receptors have a 50% greater conductance than alpha 2 beta delta gamma receptors. Instead, the functional difference is conferred by a single charged residue that lies extracellular to all four positions, corresponding to a location in the Torpedo receptor previously shown to have no influence on conductance. Substitution of a positively charged lysine residue in gamma by the neutral methionine in epsilon at this extra-cellular position is responsible for the increased conductance during maturation of the amphibian neuromuscular junction.
Amino Acid Sequence↗
Brain stem nuclei in sudden infant death syndrome (SIDS): volumes, neuronal numbers and positions.
It has been suggested that the defect underlying the sudden infant death syndrome (SIDS) lies in brain stem nuclei involved in cardiac and respiratory function. However, most studies have not used rigorous quantitative techniques to assess brain stem nuclear volumes and neuronal numbers. We have measured the volume, neuronal numbers and position of brain stem nuclei in 11 SIDS and 11 aged-matched control infants. Using serial sagittal sections, nuclei involved in maintaining airway patency (hypoglossal, ambiguus and retroambiguus), heart rate (dorsal vagal) and generation of respiratory rhythm (ambiguus and dorsal vagal) were studied. No significant differences were found in nuclear volume increase with age, total neuronal number or nuclear position between SIDS and control cases. These findings support the hypothesis that the nervous system in SIDS may be normal until the final event that kills these infants.
Age Factors↗
Abortion caused by neosporosis in cattle.
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Abortion, Veterinary↗