Determinants of improved outcome in small-cell lung cancer: an analysis of the 2,580-patient Southwest Oncology Group data base

We analyzed the 2,580-patient Southwest Oncology Group (SWOG) small-cell lung cancer data base from 1976 to 1988 in order to (1) determine the prognostic value of favorable demographic and tumor-related factors and therapy programs using Cox multivariate analyses in limited- and extensive-stage disease (LD, ED), and (2) define patient subgroups with significantly different survivals using recursive partitioning and amalgamation (RPA) analysis to refine the current two-stage system. Cox multivariate models were applied to 1,363 patients in six LD trials: good performance status, female sex, age less than 70 years, white race, and normal lactate dehydrogenase (LDH) were significant favorable independent predictors. Concurrent chemoradiotherapy was also a strong independent predictor of survival. For 1,217 patients in four ED trials, a normal LDH, treatment with an intensive multidrug regimen, and a single metastatic lesion were favorable independent variables in the Cox model. RPA analysis of 1,137 patients in recent LD and ED trials resulted in a regression tree in which the most important prognostic split was LD versus ED. Normal or abnormal LDH, absence or presence of a pleural effusion, and age less than 70 or greater than or equal to 70 years were important in LD, but only LDH was significant in ED. The terminal nodes of the regression tree were amalgamated to form four distinct prognostic subgroups with median survivals of 19.0, 12.5, 10.5, and 6.3 months (P less than .0001). The best survival occurred for younger patients with "true" LD: no effusion and normal LDH. The two intermediate patient subgroups had either LD or ED but still lived significantly longer than those patients with true ED (elevated LDH). This analysis suggests that although several factors were independent prognostic variables in LD in the Cox models, a smaller number of variables can be used to form important prognostic subgroups through RPA. The LDH emerged as a highly significant factor, but performance status and sex did not. A refinement of the current staging system should be made if our results can be confirmed with a combined-group data base analysis.     

Antibodies to CD18 influence neutrophil migration through extracellular matrix

Mac-1 (CD11b/CD18) is known to be involved in neutrophil (PMN) adhesion to endothelial cells and extracellular matrix. Although antibodies to CD 18 are being tested for therapy in humans, their role in PMN migration through the extracellular matrix is unknown. We used direct visualization to quantify PMN motility through reconstituted, three-dimensional gels of collagen type I. Gels were prepared with different concentrations of collagen (ranging from 0.1 to 1.0 mg/mL) and PMN migration was examined in the presence and absence of antibodies to CD18 (anti-CD18), with and without stimulation by N-formyl peptides. In low-concentration gels (<0.6 mg/mL), anti-CD18 had a significant influence on PMN migration, increasing motility in unstimulated PMN by 90% at 0.3 mg/mL collagen, and decreasing motility in N-formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated PMN by 70% at 0.4 mg/mL collagen. But antiCD18 had no effect on the rate of cell migration through high-concentration collagen gels (>0.6 mg/mL). PMN migration through collagen gels is CD18-dependent but only under conditions of high hydration, suggesting that CD18-mediated effects (e.g., adhesion to gel fibers) are only important when the fiber density is relatively low. Anti-CD18 inhibited, but did not eliminate, the adhesion of fMLP-stimulated PMN to the surface of collagen gels, suggesting that cells use multiple mechanisms for gaining traction within the gel. Because of the multiple modes of interaction between motile cells and the deformable fiber matrix, blockade of one component, such as CD18, can enhance the rate of cell migration under one set of conditions, and inhibit under another.     

Priming of neutrophil [Ca2+]i signaling and oxidative burst by human fracture fluids

BACKGROUND: Patients with major fracture/soft-tissue injuries are at risk for adult respiratory distress syndrome after secondary infection. Fracture fluids (FF) are rich in neutrophil (PMN) -specific chemokines such as interleukin-8. PMN respond to both interleukin-8 and bacterial stimuli with calcium ([Ca2+]i) fluxes, which can initiate respiratory burst (RB). We hypothesize that small amounts of FF entering the circulation could exaggerate PMN [Ca2+]i and RB responses, potentially increasing the risk of adult respiratory distress syndrome. METHODS: FF were obtained from 10 patients at open fixation of the femur 2 to 5 days postinjury. Volunteer PMN were isolated and loaded with fura dye. PMN were preincubated either in 30% autologous plasma (AP)/70% buffer, or in 5% FF/25% AP/70% buffer. Cells were resuspended in buffer with 1,2,3-dihydrorhodamine and stimulated with low-dose n-formyl-methionyl-leucyl-phenylalanine (fMLP). [Ca2+]i was assayed by fura fluorescence at 505 nm after excitation at 340/380 nm. RB was assessed by 1,2,3-dihydrorhodamine fluorescence at 530 nm after 488 nm excitation. RESULTS: PMN basal [Ca2+]i was higher after FF incubation than AP incubation (94+/-12 vs. 61+/-9 nmol/L, p = 0.0002). Peak [Ca2+]i response to fMLP was 475+/-47 nmol/L after FF but only 356+/-22 nmol/L after AP (p = 0.01). Two hundred seconds after fMLP, [Ca2+]i remained higher after FF (172+/-17 vs. 145+/-9 nmol/L, p = 0.04). Basal RB was slightly higher after FF than AP (13.4+/-0.3 vs. 11.3+/-0.3 units, p = 0.051) as was the maximal rate of extracellular oxidant release (1.10+/-0.17 vs. 0.76+/-0.16 units/s, p = 0.004) and total oxidant production (42.5+/-0.8 vs. 31.7+/-0.8 units, p = 0.006). CONCLUSION: Small amounts of FF in plasma can exaggerate PMN [Ca2+]i flux and RB responses to subsequent bacterial stimuli. These findings are consistent with the hypothesis that release of FF into the circulation primes PMN and, thus, may predispose to adult respiratory distress syndrome. Such PMN priming events might have important implications for both the operative and medical management of patients with major fractures.     

Patterns of response and relapse in chemotherapy of extensive squamous carcinoma of the lung

Summary In a large study of combination chemotherapy for patients with extensive squamous carcinoma of the lung, 44 of 247 patients (18%) achieved>50% regression of tumor mass. The likelihood of response was significantly (and independently) higher for females and for fully ambulatory patients. Bone and liver were the most commonly involved metastatic sites, with documented involvement pretreatment in 32 and 16% of patients, respectively. Recurrence in the ipsilateral hemithorax after radiation therapy was the only clinical evidence of disease in 24% of the patients. There were no significant differences in response rate by individual metastatic sites, or for single compared to multiple sites. The median time to response was 4 weeks, with response noted by 8 weeks in 74%.Clinically evident relapse has occurred in 39. Among these, the primary site was the only clinical site of failure in 14, of whom 7 never received radiation therapy. The brain was the only site of initial failure in 6, only 1 of whom had preexisting evidence of brain involvement. Failure in a single area of previously evident disease or the brain accounted for 74% of recurrences in the responding group. These observations suggest that sequential, planned radiation therapy to sites of previous clinical involvement, together with prophylactic whole-brain radiation, may be of benefit in the drug-responsive subpopulation of patients with extensive disease.     

Characterization of a unique cell line (LAZ 221) from human acute lymphocytic ("null" cell) leukemia.

A unique human cell line designated LAZ 221 has been established from the peripheral blood of a patient with acute lymphocytic leukemia of the "null" cell type. The cell line does not possess the Epstein-Barr virus nuclear antigen and has a karyotype of 45,XX,-9,-12,+(9q12q). Both the established cell line and the patient's uncultured blast cells share the same phenotypic markers. They both lack T-cell markers. They fail to form sheep erythrocyte rosettes and do not react with T-cell-specific antisera (TH1-, HTL-), nor do they possess B-cell markers. They do not form rosettes with erythrocytes sensitized with complement, and they are surface immunoglobulin negative. However, they do possess an HLA-D-related glycoprotein complex of 23,000 to 30,000 daltons, an la-like antigen. Thus, LAZ 221 shares the phenotype of the patient's uncultured blasts and is a cell line representative of about 75% of all human acute lymphocytic leukemias. In this respect it differs from previously described human hematopoietic cell lines.     

Minimal head injury: is admission necessary?

The records of 138 patients admitted a Glasgow Coma Score (GCS) of 14 or 15 following head injury were reviewed to assess the need for hospital observation and to determine whether obtaining a normal computerized tomography (CT) scan in the emergency department could have avoided admission. GCS was 15 in 103 patients (74%) and 14 in 35 (26%). Eighty-three patients were admitted for their head injury alone, and 55 had other injuries but would have required admission for their head injury. Loss of consciousness was documented in 51 per cent and suspected in another 29 per cent and was distributed equally regardless of GCS. Seven per cent (5/71) of skull x rays were positive and were associated with CNS pathology in three patients. Skull x rays in an additional four patients with positive CT findings were negative including a patient with an epidural hematoma (EDH). Seventeen per cent (13/75) of CT scans were positive (contusions 5, subdural hematoma 3, subarachnoid hemorrhage 2, edema 2, EDH 1). Only the patient with the EDH required operative treatment. No patient with a normal CT scan went on to develop any neurosurgical problems, and 78 per cent of the patients admitted with isolated head injuries were discharged within 48 hours. Significant CNS pathology does occur following "minimal" head injuries. Skull x rays are not helpful. The use of CT scanning appears to triage those patients requiring admission and in hospital observation.     

Diffuse cortical dysplasia, or the 'double cortex' syndrome: the clinical and epileptic spectrum in 10 patients

Diffuse neuronal migration disorders associated with epilepsy can now be recognized by modern neuroimaging techniques, particularly high-resolution MRI. We report 10 patients with a recently described MRI picture of continuous or generalized band heterotopia underlying the cortical mantle, giving the appearance of a "double cortex." They have epilepsy, and almost all have mental retardation. The epileptic disorder varies in nature and degree of severity. Patients may present with infantile spasms, a Lennox-Gastaut syndrome, or other forms of secondary generalized or multifocal epilepsy. Response to medical treatment is variable. Callosotomy may lead to considerable reduction of drop attacks, present in 60%. Mental retardation is usually mild or moderate, and only rarely severe. It correlates with the type of epileptic syndrome, and is greater in patients with more disorganized cortex overlying the heterotopia. Recognition of this entity by MRI is important for appropriate diagnosis of the epileptic disorder, planning of therapeutic strategy, and prognosis.     

BMI distribution changes in adolescent British girls.

Body mass index (BMI) distribution changes were assessed in 2547 relatively affluent English girls, aged 12-16 years, during the UK childhood obesity epidemic (1986-96). An increase in BMI variability was observed only in 12-14 year olds, suggesting that BMI changes for population subgroups were complex, and inconsistent with a generalised increase in BMI.