(ICORG 05-03): prospective randomized non-inferiority phase III trial comparing two radiation schedules in malignant spinal cord compression (not proceeding with surgical decompression); the quality of life analysis.

BACKGROUND: The optimal primary external beam radiation therapy (EBRT) radiation schedule for malignant epidural spinal cord compression (MSCC) remains to be determined. The ICORG 05-03 trial assessed if a 10 Gy single fraction radiation schedule was not inferior to one with 20 Gray (Gy) in five daily fractions, in terms of functional motor outcome, for the treatment of MSCC in patients not proceeding with surgical decompression. This article reports on two of the secondary endpoints, Quality of life (QoL), assessed according to the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) version 3.0 (EORTC Data Center, Brussels, Belgium) and pain control assessed using a visual analog scale. METHODS: A randomized, parallel group, multicenter phase III trial was conducted by Cancer Trials Ireland (formerly All-Ireland Cooperative Oncology Research Group, ICORG), across five hospital sites in Ireland and Northern Ireland. Patients were randomized to 10 Gy single fraction of EBRT or 20 Gy in five fractions in a 1:1 ratio. Patients with baseline and 5-week follow up QoL data are included in this analysis. FINDINGS: From 2006 to 2014, 112 eligible patients were enrolled for whom 57 were evaluated for this secondary analysis. After adjusting for pre-intervention scores, there was no statistically significant difference in post-treatment Summary scores (excl. FI and QL), or pain scores between the two RT schedules at 5 weeks and 3 months following EBRT. There was a statistically significant relationship between the pretreatment and post-treatment Summary scores (p = .002) but not between the pre-treatment and post-treatment pain scores. INTERPRETATION: Primary radiotherapy for the treatment of MSCC significantly improves QoL in patients not proceeding with surgical decompression. After adjusting for pre-intervention scores, there was no statistically significant difference between a 10 Gy single fraction radiation schedule and one with 20 Gy in five daily fractions on post-treatment QoL Summary scores. For most patients, an effective treatment with low burden would be desirable. A single fraction schedule should be considered for this group of patients.

Prophylactic cranial irradiation in small cell lung cancer: a single institution experience.

BACKGROUND: Prophylactic cranial irradiation (PCI) is used to prevent the development of brain metastases in small cell lung carcinoma. PCI confers an overall survival (OS) benefit in both limited and extensive stage disease. AIMS: We analyze the incidence of symptomatic brain metastases, progression-free survival (PFS) and OS in a cohort of patients who received PCI, in a 5-year period. METHODS: A retrospective review of all patients who had received PCI between 2006 and 2011 at the Whitfield Clinic was completed. Patient- and disease-related characteristics, the number of patients who developed brain metastases, PFS and OS data were collected. RESULTS: 24 patients were identified. 14 (58.3 %) patients were male, 10 (41.7 %) were female, with a mean age of 62.5 years (range 31-78). All patients were smokers. 12 (50 %) patients had limited stage small cell lung cancer (SCLC), 12 (50 %) had extensive stage disease. 2 (8.2 %) patients developed brain metastases post PCI (p = 0.478.) The median PFS for limited stage SCLC was 13 months (range 3-20) and 10 months (range 5-18) for extensive stage SCLC. Median OS was 15 months (range 4-29) in limited stage SCLC, and 11 months (range 5-29) in extensive stage SCLC. CONCLUSIONS: Our study demonstrated a low incidence of symptomatic brain metastases and favourable median PFS and OS in the patients that received PCI, when compared to published phase III data.

Increased in vivo transcription of an IL-8 haplotype associated with respiratory syncytial virus disease-susceptibility.

Interleukin-8 (IL-8) has been implicated in the pathogenesis of RSV-induced bronchiolitis. Previously, we have described an association between bronchiolitis disease severity and a specific IL-8 haplotype comprising six single-nucleotide polymorphisms (SNPs) (-251A/+396G/+781T/+1238delA/+1633T/+2767T, haplotype 2). Here we investigated the functional basis for this association by measuring haplotype-specific transcription in vivo in human primary cells. We found a significant increase in transcript level derived from the IL-8 haplotype 2 relative to the mirror haplotype 1 (-251T/+396T/+781C/+1238insA/+1633C/+2767A) in respiratory epithelial cells but not in lymphocytes. A promoter polymorphism, -251A, present on the high producer haplotype, had no significant affect on the allele-specific level of transcription when analyzed in reporter gene experiments in human respiratory epithelial A549 cells. We proceeded to systematically screen for allele-specific protein-DNA binding in this functional haplotype, which revealed significant differential binding at the +781T/C polymorphism. C/EBP beta was identified as being part of a transcription factor binding complex that preferentially bound in the presence of the +781 T allele. These results suggest that the mechanism for disease susceptibility to RSV-induced bronchiolitis may occur through a haplotype-specific increase in IL-8 transcription, which may be mediated by functional polymorphisms within that haplotype.

Respiratory syncytial virus--viral biology and the host response.

Respiratory syncytial virus (RSV) is the most important cause of respiratory tract infection in infants. We have an incomplete understanding of the reasons why some infants are more severely affected by RSV than others. There is no effective antiviral treatment for the infection. Advances in our understanding of the biology of RSV, particularly in relation to the attachment protein G and the fusion protein F, have revealed potential targets for new antiviral therapies and vaccine development. In response to RSV infection an intense inflammatory response is triggered, mediated initially by the infected airway epithelial cells. Cell mediated responses are important in controlling the extent of infection and in viral clearance. Humoral responses are important in protection. There is early evidence that genetic variation of the host response can influence the outcome of RSV-induced bronchiolitis.

Malignant pleural mesothelioma: a phase II trial with docetaxel.

Current cytotoxic therapy has been of limited benefit to patients with malignant pleural mesothelioma. Single agent chemotherapy has been extensively evaluated in small series of phase II clinical trials, with disappointing responses. Docetaxel, an effective taxane in the treatment of advanced breast cancer and non-small-cell lung cancer, was administered intravenously at a dose of 100 mg/m2 every 3 weeks to 30 chemotherapy naive patients with malignant pleural mesothelioma in a prospective multi-institutional phase II clinical trial. An objective response rate (partial responses) of 10% was documented. Additionally, 21% of the patients had minor responses (intention-to-treat analysis). Three patients died within 2 weeks post-first cycle of therapy, although only one patient's death was directly attributed to the investigational drug, whilst in the majority of the patients, manageable and treatable toxicities were encountered. In this phase II clinical trial, docetaxel proved to be mildly effective in the treatment of patients with malignant pleural mesothelioma.

Respiratory distress syndrome and birth order in premature twins.

OBJECTIVE: To determine the effect of birth order on respiratory distress syndrome (RDS) in the outcome of twins in a large premature population managed in a modern neonatal intensive care unit. METHODS: An historical cohort study design was used to analyse the neonatal outcomes of 301 premature liveborn twin sibling pairs of between 23 and 31 weeks gestation from the Australia and New Zealand Neonatal Network 1995 database. RESULTS: Among the 56 twin sibling pairs who were discordant for RDS, the second twin was affected in 41 cases (odds ratio (OR) 2.7, 95% confidence interval (CI) 1.5 to 5.3). The excess risk of RDS in the second twin increased with gestation and was statistically significant for twins above 29 weeks gestation (OR 4.4, 95% CI 1.6 to 15). CONCLUSIONS: There is a significant increased risk of RDS associated with being the second born of premature twins, which appears to depend on gestation.

Idiopathic pulmonary fibrosis in infants: good prognosis with conservative management.

BACKGROUND: Pulmonary interstitial fibrosis in children is a disease of unknown aetiology, usually associated with a poor prognosis. METHODS: In this case series we describe 11 children presenting over a 10 year period, managed conservatively and associated with a good prognosis. RESULTS: In six, symptoms were present from birth and 10 had symptoms at or before 3 months. Diagnosis was made using chest computed tomography and percutaneous lung biopsy. All patients were treated with oral prednisolone. In five no steroid response was noted. One patient responded to hydroxychloroquine. Home oxygen was required in five patients. At follow up all patients are alive at a median age of 6 years (range 1 to 12 years). The two recently diagnosed children have significant symptoms, seven have dyspnoea on exercise, and two are symptom free. CONCLUSION: The good prognosis seen in these patients is different to previous case reports, indicating a greater than 50% mortality.

5'-[2-(2-Nitrophenyl)-2-methylpropionyl]-2'-deoxy-5-fluorouridine as a potential bioreductively activated prodrug of FUDR: synthesis, stability and reductive activation.

5'-[2-(2-Nitrophenyl)-2-methylpropionyl]-2'-deoxy-5-fluorouridine was synthesized as a potential bioreductively activated prodrug of 5-fluoro-2'-deoxyuridine (FUDR). The target compound was stable in both phosphate buffer and human serum and was found to release quickly the parent drug FUDR in quantitative yield upon mild chemical reduction.

Molecular diagnosis of multiple endocrine neoplasia type 2A.

OBJECTIVE: To identify by means of genetic analyses individuals who are at risk of developing medullary thyroid cancer that is a component of multiple endocrine neoplasia. SUBJECTS: A three-generation kindred with clinically and biochemically diagnosed medullary thyroid cancer. METHOD: Identification of a heterozygote mutation by nucleic acid sequencing and restriction analyses. RESULTS: A heterozygote T-->C (Cys-->Arg) mutation at codon 618 in exon 10 of the RET proto-oncogene was identified in 4 family members who had previously been diagnosed with medullary thyroid cancer. The same mutation was also found in one of the proband's presymptomatic children who subsequently underwent a pre-emptive thyroidectomy. The genetic diagnosis was confirmed by histology. No mutations were detected in any other family members. CONCLUSION: Identification of heterozygote germline mutations in multiple endocrine neoplasia is direct, highly accurate and cost-effective. This study demonstrates that, appropriately used, molecular diagnosis can supersede conventional biochemical methods in the management of patients with inherited cancers.

Weekly gemcitabine and monthly cisplatin for advanced non-small cell lung carcinoma.

Most chemotherapy for non-small cell lung cancer (NSCLC) currently includes combination chemotherapy based on cisplatin. Gemcitabine is a nucleoside analog with demonstrated activity against NSCLC, yet it has low toxicity. This phase II study was designed to examine the efficacy of a combination chemotherapy regimen consisting of gemcitabine followed by cisplatin. The patient population comprised 53 patients with pathologically confirmed locally advanced or metastatic NSCLC. Gemcitabine 1,000 mg/m2 was administered on days 1, 8, and 15 and cisplatin 100 mg/m2 was given on day 15. Chemotherapy was administered every 28 days. Of the 50 patients evaluable for response, there were two complete responses (4%) and 24 partial responses (48%). The median duration of response was 8.5 months, median survival was 13 months, and the 1-year survival rate was 61%. The regimen was generally well tolerated. World Health Organization grade 3 leukopenia occurred in 28.8% of patients, while grade 3 and 4 neutropenia occurred in 38.8% and 19.2% of patients, respectively. Grade 3 and 4 thrombocytopenia was seen in 13.3% and 7.7% of patients, and grade 3 and 4 anemia occurred in 11.5% and 1.9% of patients, respectively. Alopecia and oral toxicity was mild, although most patients experienced mild nausea and vomiting. Relatively few patients required dose modifications for any of the three weekly doses of chemotherapy. We conclude that the combination of gemcitabine and cisplatin is an effective regimen for NSCLC, resulting in high response and survival rates. Additional prospective randomized studies with other cisplatin-based combination chemotherapy regimens are warranted.

Weekly gemcitabine with monthly cisplatin: effective chemotherapy for advanced non-small-cell lung cancer.

PURPOSE: The aim of this study was to examine the efficacy of a regimen of initial gemcitabine followed by cisplatin in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifty-three patients (36 men and 17 women; age range, 35 to 74 years) were enrolled. Patients had bidimensionally measurable disease. Gemcitabine (phase-specific agent) was administered on days 1, 8, and 15 at a dose of 1,000 mg/m2. Cisplatin (cycle-specific agent) was administered on day 15 (100 mg/m2). Chemotherapy was administered in 28-day cycles. RESULTS: Of 53 patients enrolled, 50 were assessable for response. The overall response rate was 52%. There were two complete responses (4%) and 24 partial responses (48%). The median survival duration was 13 months and the 1-year survival rate was 61%. The regimen was generally well tolerated. World Health Organization (WHO) grade 3 and 4 neutropenia occurred in 38.8% and 19.2% of patients, respectively. Grade 3 and 4 thrombocytopenia occurred in 13.3% and 7.7% of patients, respectively. Most patients experienced mild nausea and vomiting. Few patients had hair loss and oral toxicity was mild. Relatively few patients required dose modifications for any of the three weekly doses of chemotherapy. For the first two cycles of chemotherapy, the dose-intensity per infusion was 947 mg/m2 for gemcitabine and 85 mg/m2 for cisplatin. CONCLUSION: This regimen of gemcitabine and cisplatin was effective, with high response and survival rates and few dosage modifications during its administration. Prospective randomized studies with other cisplatin-based combination chemotherapy regimens are indicated.

Efficacy and safety profile of gemcitabine in non-small-cell lung cancer: a phase II study.

PURPOSE: The aim of this study was to evaluate the efficacy and toxicity of gemcitabine at higher doses than had been used previously in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Eighty-four patients (65 men, 19 women; age range, 35 to 75 years; mean age, 59 years) with locally advanced or metastatic pathologically documented NSCLC were enrolled. Patients had bidimensionally measurable disease, as defined by computed tomographic (CT) scan or chest x-ray. A total of 28.6% had previously been surgically treated, while 9.5% had received radiotherapy. Fifty-three patients commenced at a dose of 1,000 mg/m2, and 31 at a dose of 1,250 mg/m2. Patients were to receive two dose escalations of 25%, provided that overall toxicity was no worse than World Health Organization (WHO) grade 1 or WHO grade 0 for platelets. Responding patients were reviewed and validated by a blinded oncology review board (ORB) of experts not involved with the study. Of the original 84 patients enrolled, 76 were assessable. RESULTS: The overall response rate was 20% (95% confidence interval [CI], 11.6% to 30.8%). There were two complete responses (3%) and 13 partial responses (17%). Hematologic toxicity was negligible. WHO grade 3 WBC toxicity occurred in 0.9% of doses and WHO grade 4 in 0.1%. WHO grade 3 and 4 thrombocytopenia occurred in 0.1% and 0.1% of all doses, respectively. Nonhematologic toxicity was minor and easily controlled. Common side effects included peripheral edema, asthenia, and transient malaise. CONCLUSION: The single-agent efficacy of gemcitabine is equivalent to other agents commonly used to treat NSCLC. Gemcitabine has an unusually mild side effect profile for such an active agent. The nausea and vomiting experienced with gemcitabine are mild and generally well controlled with standard antiemetics; 5-HT3 receptor antagonists are typically not required. The use of gemcitabine does not cause significant alopecia, and hematologic toxicity is modest and unlikely to require hospitalization. Gemcitabine may have a role as monotherapy in patients with inoperable NSCLC.

Combined perilymphatic fistulas of the round window and lateral semicircular canal. A report of 2 cases.

Two patients with combined perilymphatic fistulas of both the round window and the lateral semicircular canal are presented. They became asymptomatic only when both fistulas were closed. In both cases the hearing improved concurrently. It is recommended that when a traumatic perilymphatic fistula is not cured by closing window fistulas, the lateral semicircular canal be explored.

Perilymphatic fistulas: are they exclusive to the round and oval windows?

Eleven patients suspected of having perilymphatic fistulas were evaluated. A perilymphatic fistula was demonstrable in ten of these patients. In six patients, fistulas of one of the windows, or both were found. In two patients, combined fistulas of both the round window and lateral semicircular canal were found. In two other patients, fistulas were found only in the lateral semicircular canal. The patients in whom fistulas were found and repaired improved dramatically. The patient without a demonstrable fistula remained symptomatic. We have shown that perilymphatic fistulas can occur in the lateral semicircular canal, and suggest exploring this area when indicated.