Expression-based intrinsic glioma subtypes are prognostic in low-grade gliomas of the EORTC22033-26033 clinical trial.

INTRODUCTION: The European Organisation for Research and Treatment of Cancer (EORTC) 22033-26033 clinical trial (NCT00182819) investigated whether initial temozolomide (TMZ) chemotherapy confers survival advantage compared with radiotherapy (RT) in low-grade glioma (LGG) patients. In this study, we performed gene expression profiling on tissues from this trial to identify markers associated with progression-free survival (PFS) and treatment response. METHODS: Gene expression profiling, performed on 195 samples, was used to assign tumours to one of six intrinsic glioma subtypes (IGSs; molecularly similar tumours as previously defined using unsupervised expression analysis) and to determine the composition of immune infiltrate. DNA copy number changes were determined using OncoScan arrays. RESULTS: We confirm that IGSs are prognostic in the EORTC22033-26033 clinical trial. Specific genetic changes segregate in distinct IGSs: most samples assigned to IGS-9 have IDH-mutations and 1p19q codeletion, samples assigned to IGS-17 have IDH-mutations without 1p19q codeletion and samples assigned to other intrinsic subtypes often are IDH-wildtype. A trend towards benefit from RT was observed for samples assigned to IGS-9 (hazard ratio [HR] for TMZ is 1.90, P = 0.065) but not for samples assigned to IGS-17 (HR 0.87, P = 0.62). We did not identify genes significantly associated with PFS within intrinsic subtypes, although follow-up time is limited. We also show that LGGs and glioblastomas differ in their immune infiltrate, which suggests that LGGs are less amenable to checkpoint inhibitor-type immune therapies. Gene expression analysis also allows identification of relatively rare subtypes. Indeed, one patient with a pilocytic astrocytoma was identified. CONCLUSION: IGSs are prognostic for PFS in EORTC22033-26033 clinical trial samples.

SPECT ventilation perfusion scanning with the addition of low-dose CT for the investigation of suspected pulmonary embolism.

Single-photon emission computed tomography (SPECT) ventilation perfusion (V/Q) scanning with low-dose computed tomography (LDCT) is an emerging imaging technique for investigation of suspected pulmonary embolism (PE). We aimed to estimate diagnostic utility of the combined technique using results from all patients referred in 2009 compared with final diagnosis and 6-month follow-up status. PE was diagnosed in 28 of 106 patients (26%), including in 2 of 80 (2%) with negative SPECT V/Q and LDCT. The estimated negative predictive value of SPECT V/Q for PE was 97%. LDCT was abnormal in 43 (41%) patients, including 41 patients who had negative SPECT V/Q. In 29 (27%) patients, LDCT provided information on alternative pathologies that accounted for presenting symptoms, and the combined technique had a diagnostic yield of 52%.

Respiratory symptoms and lung function in aborigines from tropical Western Australia.

To estimate the prevalence of respiratory symptoms, bronchial hyperresponsiveness, smoking, and atopy in a population of Australians of Aboriginal descent (AAD), to determine the association of these and other factors with lung function, and to compare levels of lung function of AAD with Australians of European descent (AED) according to age and height, and to explore reasons for their differences, we conducted a study of 96 male (41 of whom were under 18 yr of age) and 111 female (48 of whom were under 18 yr of age) AAD living in a single remote tropical community in 1993. This population provided data on age, height, and lung function. A modified British Medical Research Council (MRC) questionnaire on respiratory symptoms and smoking was administered. FEV1, FVC, height, age, and bronchial responsiveness to inhaled methacholine were measured. Atopic status was assessed by skin prick tests for eight common allergens. Age- and sex-adjusted lung function was similar to that of other AAD groups and lower than in AED. For children, lung function increased less with increasing height in AAD than in AED. Lung function was reduced in adult AAD as compared with adult AED, although it was not possible to determine statistically whether lung function started to decline at an earlier age or declined faster with increasing age in AAD. A history of asthma, smoking, dyspnea, cough, or sputum production; atopic status; and increased bronchial responsiveness were all associated with lower levels of lung function. Differences in lung function between AAD and AED appear to be determined by characteristics that may be inherited, as well as by adverse external influences.

A genome-wide search for quantitative trait loci underlying asthma.

Asthma now affects one child in seven in the United Kingdom. Most cases (95%) of childhood asthma are associated with atopy, the immunoglobulin E (IgE)-mediated familial syndrome of allergic asthma, eczema and rhinitis. Segregation analysis has consistently suggested the presence of major genes influencing atopy and IgE levels, with the expectation that these genes may be identified by positional cloning or the examination of candidate genes. Here we report the results of a genome-wide search for linkage to one qualitative and four quantitative traits associated with allergic (atopic) asthma. We have identified six potential linkages (P<0.001), five of which are to quantitative traits. Monte Carlo simulations show that 1.6 false-positive linkages at this level of significance would be expected from the data. One linkage, to chromosome 11q13, has been established previously. Three of the new loci show evidence of linkage to a second panel of families, in which maternal effects and pleiotropy of linked phenotypes are seen. The results demonstrate the extent and the complexity of the genetic predisposition to asthma.

Treatment of brain metastases from primary lung cancer.

PURPOSE: A retrospective study of patients treated at the Peter MacCallum Cancer Institute for brain metastases from primary carcinoma of the lung is presented. METHODS AND MATERIALS: The medical records of 416 patients with the diagnosis of primary carcinoma of the lung who presented with, or subsequently developed, brain metastases during the period January 1984 to December 1987 were reviewed. Information on a number of factors of potential prognostic significance (sex, age, histology, performance status and interval between diagnosis of the primary and brain metastases) was collected. Details of surgery, radiation and steroid usage were recorded, and any steroid side effects documented. Survival was calculated from the date of diagnosis of brain metastases. Stepwise regression based on Cox's proportional hazards model was used to determine significant prognostic factors affecting survival. Patients with and without steroid side effects were compared using Yates's corrected chi-square test. RESULTS: The overall estimated median survival was only 3.3 months (95% confidence interval 2.9-3.7 months). Only two factors were found to be associated with a significantly improved survival--surgical intervention and good performance status. After taking these two factors into account, the dose of radiation used (< 30 Gy or > or = 30 Gy) did not influence survival. There was a 3% incidence of gastric bleeding or perforation in patients taking steroids, with a 40% fatality rate. Predisposing factors to gastric side effects were a prior history of peptic ulcer and/or aspirin or nonsteroidal anti-inflammatory drug consumption. CONCLUSION: Radiation of brain metastases from primary lung cancer results in modest survival benefit. Radiation dose (< 30 Gy or > or = 30 Gy) is not a significant determinant of survival. Other treatment modifications, such as concurrent radiation and chemotherapy, should be explored. Steroids should be used with caution as fatal side effects can occur.

Pulmonary toxicity following MOPP chemotherapy.

Pulmonary toxicity is a well recognised side effect of anticancer agents particularly bleomycin, cyclophosphamide, methotrexate, and busulphan. In contrast this problem has been infrequently reported following MOPP (nitrogen mustard, vincristine, prednisolone, procarbazine) chemotherapy for Hodgkin's disease and has been attributed principally to the procarbazine. We report a further instance of MOPP associated pulmonary toxicity. This case and a review of previously published cases indicate that MOPP chemotherapy may be associated with the development of permanent lung damage as well as an acute reversible hypersensitivity lung disease.

Mortality from asthma in Western Australia.

From a cohort of all 5760 male and 4979 female patients who were admitted to WA hospitals and were discharged with a diagnosis of asthma between 1976 and 1980, 265 deaths in men and 189 deaths in women were identified by the end of 1982. The standardized mortality ratio (SMR) for all causes of death for this cohort was 1.6 for men (P less than 0.001) and 1.7 for women (P less than 0.001). Both sexes showed a significant increase in deaths that were attributable to asthma (SMR, 57.9), chronic airflow obstruction (SMR, 9.3) and ischaemic heart disease (SMR, 1.3). The excess death rates for asthma were observed in all age groups, but those for chronic airflow obstruction and ischaemic heart disease were present in older age groups only. These findings indicate that asthma remains a potentially fatal disease in the Australian community. The excess mortality ratios for chronic airflow obstruction that were observed in patients who were admitted to hospital with asthma also suggest that asthma may result in irreversible airflow obstruction.

Hypoxemia from right to left shunting through patent foramen ovale.

We report a patient with severe hypoxemia from a large (41%) right to left shunt through a patent foramen ovale after right ventricular myocardial infarction, and review 18 previous descriptions of patients with right to left shunting through patent foramen ovale. These shunts occur when right atrial pressure is elevated above left atrial pressure, or when the anatomic relationship of the interatrial septum to the inferior vena cava is altered. Since 15-35% of the population have a potentially patent foramen ovale, interatrial right to left shunting may occur more frequently than had previously been recognized, and should be considered in a differential diagnosis of hypoxemia.

A murine model for multiple laparoscopies: I. Early lymphoid response to intraperitoneal insufflation of CO2.

In a model for multiple laparoscopies proliferation of T-lymphocytes was an early, but transitory, immunologic reaction in the spleen to intraperitoneal CO2 insufflation. Intraperitoneal insufflations of approximately 3.5 ml of CO2 were given daily to three groups of BALB/c mice for 11, 20, and 32 consecutive days, respectively. Air insufflation was given to experimental controls. The observations in the insufflation model are summarized as follows: 1) Multiple CO2 insufflation approximately doubled the number of splenic T lymphocytes. 2) The percentage value was highest on the day of the last insufflation. The difference between this value in each of the three groups was statistically not significant; ie, there was no dose-response relationship in the range of 11-32 insufflations. 3) There was a dose-response effect in the range of 3-9 insufflations. 4) The number of splenic T lymphocytes decreased with each day after the end of treatment. Untreated control values were reached in 12-16 days. 5) Air insufflation had only a minimal effect on the proliferation of T lymphocytes in the spleen. In this model there is correlation between early proliferation of T lymphocytes in the spleen and the late occurrence of a high incidence of malignant lymphoma (approximately 60%). The long-term survivors of CO2 insufflation also developed a wide spectrum of intraabdominal malignancies. It was speculated that CO2 insufflation provided an abnormal internal environment that affected a variety of target tissues. Prolonged CO2 accumulation might have modified nucleic acid structure via chronic intracellular acidosis. Could the neoplastic sequelae in this model be a clue to a similar sequel in humans after multiple laparoscopies?

Post-transplantation development of malignant lymphoma, an experimental model: syngeneic lymph node transplants.

Previously, malignant lymphomas in mice have been found to be the late sequelae of the autologous transplantation of skin grafts pretreated with CO(2); these did not occur with grafts cultured in air alone. The clinical result in this autologous system reflects environmental differences in vitro (Goldsmith & Narvaez 1975). In the present study the syngeneic transplantation in BALB/c mice of lymph node tissue resulted in the late appearance of malignant lymphomas (48-69%), irrespective of the pretransplantation treatment of the grafts. Lymph node grafts were exposed to three different environments before transplantation into syngeneic hosts: (1) to culture in air (24 hours); (2) to culture in an atmosphere of 45% CO(2) in air (24 hours); (3) direct transplantation without in vitro exposure. Transplantation of these three groups of differently treated grafts was followed by the same clinical results in their recipients. These were: (1) The development of lymphoma whereas the spontaneous incidence was zero. (2) The proliferation of T-lymphocytes in the spleen; the incidence of this abnormality correlates with the lymphoma incidence. (3) A higher than normal occurence of immune-associated lesions (amyloidosis, interstitial nephritis and myocarditis). Both syngeneic and autologous transplantations may serve as animal models for the study of clinical malignant lymphoma.

Metabolic carcinogenesis--induction of murine lymphoma by CO2-treatment in vivo and in vitro.

Metabolic carcinogenesis may be viewed as a process in which a chronic disturbance of metabolic homeostasis leads to malignancy. Fluctuation in the CO2 tension in tissues is accompanied by changes in the intracellular pH. This prompted investigations into the long-term clinical effects of high CO2 tensions on various normal tissues in mice by two different methods. The first consisted of exposing different tissues in vitro to a high CO2% in air before transplantation into syngeneic or autologous hosts. The second method consisted of exposing intraperitoneal tissues in vivo to CO2-infusion, thus avoiding graft-host interactions. This is a report of the most significant findings in the series of investigations analyzed, 1. High incidences of malignant lymphoma in strains of mice with a low or zero spontaneous incidence followed: (a) syngeneic transplantation, (b) autologous transplantation, (c) in vivo exposure to CO2-infusion. 2. Syngeneic graft recipients developed similar high lymphoma incidences, irrespective of the tissue grafted or the pretransplantation treatment of the graft. 3. In the autologous system, however, the clinical results reflect the differences in the pretransplantation treatment, in contrast to those in the syngeneic system. 4. Whereas intraperitoneal CO2-infusion induced lymphoma, air-infusion did not. 5. Non-lymphoid grafts exposed in vitro to elevated CO2 induced only lymphoid malignancies. But non-lymphoid tissues exposed in vivo to elevated CO2 developed tumors of other tissues, such as lung tumor, in addition to lymphoid malignancies. 6. The same morphological lymphoid abnormalities occurred in all lymphoma-developing animals in these three experimental models. Hyperplasia in the splenic T-cell areas appeared most frequently. 7. The presence of immune-associated lesions in experimental animals (amyloidosis, interstitial nephritis and myocarditis) points to the activation of immune mechanisms in this lymphoma development. The evidence as a whole suggests the possibility that chronic immunological stimulation of host lymphoid tissue may be involved in the development of lymphoid malignancies in these animal models.

Bilateral congenital coronary artery--pulmonary artery fistulae: report of two unusual cases.

Congenital coronary arteriovenous fistulae involving both coronary arteries are rare. Those terminating in a right heart chamber or the pulmonary artery usually mimic a patent ductus arteriosus because of the presence of a continuous murmur. Since the vascular resistance is much lower in the pulmonary circuit than in myocardial capillaries, a large percentage of coronary blood flow may be directed through the fistula. Such a "steal" can cause myocardial ischemia distal to the origin of the fistula. Angina has been reported to occur. About 20% of coronary A-V fistulae are associated with other congenital cardiac anomalies.

Field accumulation of aflatoxin in cottonseed as influenced by irrigation termination dates and pink bollworm infestation.

Aflatoxin accumulation in Deltapine 16 cottonseed, grown in Yuma, Ariz., in a 3-year study, was significantly influenced by the timing of irrigation terminations and by level of pink bollworm infestations. In 1971 and 1972, termination of irrigations by early August resulted in significantly less aflatoxin than in plots where two additional irrigations were applied. Significantly less aflatoxin also was found in the 1971 and 1973 plots where low levels of pink bollworm infestations were maintained.