Health‐Related Quality of Life With Adjuvant Docetaxel‐ and Trastuzumab‐Based Regimens in Patients with Node‐Positive and High‐Risk Node‐Negative,HER2‐Positive Early Breast Cancer: Results from the BCIRG 006 Study

Background.

This study aims to describe and compare health-related quality of life (HRQL) in patients with node-positive and high-risk node-negative HER2-positive early breast cancer receiving adjuvant docetaxel and trastuzumab-based or docetaxel-based regimens alone.

Methods.

Eligible patients (n = 3,222) were randomly assigned to either four cycles of adjuvant doxorubicin and cyclophosphamide followed by four cycles of docetaxel (AC→T) or one of two trastuzumab-containing regimens: adjuvant doxorubicin and cyclophosphamide followed by docetaxel plus trastuzumab administered for 1 year (AC→TH) or six cycles of docetaxel plus carboplatin combined with trastuzumab administered for 1 year (TCH). The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 and BR-23 were administered at baseline, the start of cycle 4 (mid), and the end of chemotherapy (EOC), as well as at 6, 12, and 24 months after chemotherapy.

Results.

Compliance rates for the EORTC questionnaires were acceptable at 72%–93% of eligible patients out to the 12-month assessment. Systemic side effect (SE) change scores were significantly improved for TCH-treated patients compared with AC→TH and AC→T at EOC, suggesting improved tolerability. Physical functioning (PF) was only slightly worse at midpoint for those receiving TCH, compared with patients who were just starting on taxane in an AC→TH regimen, but was otherwise similar between arms. All treatment arms recovered from the deterioration in SE, PF, and Global Health Scale scores by 1 year and median future perspective change scores continued to improve throughout treatment and follow-up.

Conclusion.

HRQL outcomes for adjuvant docetaxel and trastuzumab-based regimens are favorable and support TCH as a more tolerable treatment option.     

Endometriosis-associated ovarian carcinoma: differential expression of vascular endothelial growth factor and estrogen/progesterone receptors

BACKGROUND: Multiple epidemiologic and histologic studies have suggested that ovarian endometriosis can give rise to malignant ovarian tumors, primarily those of epithelial origin. The progression of endometriosis to endometriosis-associated ovarian carcinoma (EAOC) has not been investigated thoroughly and is poorly understood at best. Using immunohistochemical methods, we compared the differential expression patterns of various cytokines and growth factors in atypical endometriosis (AE) and EAOC. METHODS: Using the Johns Hopkins Pathology Data Bank, tissue blocks from patients diagnosed with EAOC or AE were identified. Tissue blocks were stained for 4 markers: vascular endothelial growth factor (VEGF), Ki-67, estrogen receptor (ER), and progesterone receptor (PR). RESULTS: Seventeen cases of EAOC and 8 cases of AE were identified. Staining for VEGF was documented in 16 of 17 (94%) EAOC tissue blocks and in only 1 of 8 (12.5%) AE tissue blocks (P < 0.0001). Only 4 of the 17 (23%) EAOC tissue blocks exhibited positive staining for ER, compared with 8 of 8 (100%) AE tissue blocks (P = 0.0005). Positive staining for PR was noted in only 6 of 17 (35%) EAOC samples but was present in 8 of 8 (100%) AE samples (P = 0.003). Seventy percent of EAOC samples exhibited positive staining for Ki-67, compared with 37.5% of AE samples (P = 0.19). CONCLUSIONS: EAOC appears to be associated with overexpression of VEGF and reduced expression of both ER and PR. Variations in VEGF expression may be associated with the malignant transformation of endometriosis and may present both diagnostic and therapeutic options for the treatment of ovarian malignancies.     

Postgenomics,uncertain futures,and the familiarization of susceptibility genes

This paper draws on empirical findings from interview studies in the USA and Canada to interrogate the idea that expanding practices of genetic testing are likely to transform kin and family relations in fundamental ways. We argue that in connection with common adult onset disorders in which susceptibility genes with low predictive power are implicated it is unlikely that family relationships will be radically altered as a result of learning about either individual or family genotypes. Rather, pre-existing family dynamics and ideas about family susceptibilities for disease may be reinforced. The case of the ApoE gene and its relationship to Alzheimer’s disease is used as an illustrative example. We found that “postgenomic” thinking, in which complexity of disease causation is emphasized, is readily apparent in informant narratives.     

Clinical significance of Her-2/neu overexpression in uterine serous carcinoma

OBJECTIVE: To evaluate the clinico-pathologic characteristics and survival outcome associated with overexpression of Her-2/neu in patients with uterine serous carcinoma (USC). METHODS: Twenty-five patients with a confirmed pathologic diagnosis of USC and available paraffin embedded tissue samples treated at the Johns Hopkins Medical Institutions from 1/1/1992 through 12/31/2000 were identified retrospectively. Her-2/neu expression was evaluated by immunohistochemistry using HercepTest (DAKO). Clinical data were abstracted from medical records. Clinico-pathologic characteristics associated with Her-2/neu overexpression like staging, histology, lymph-vascular space involvement, and myometrial invasion were evaluated using logistic regression analysis and Fisher's exact test. Analyses of overall survival time were performed using the Kaplan-Meier method and Cox proportional hazards regression models. RESULTS: Twelve (48%) of the 25 USC cases demonstrated Her-2/neu overexpression. There was a significant difference in Her-2/neu overexpression and surgical staging (81.8% vs. 28.6%, P = 0.01). Survival analysis according to primary tumor characteristics revealed that overexpression of Her-2/neu was significantly associated with a worse survival outcome (HR = 6.58, 95%CI: 1.36-31.89, P = 0.02). CONCLUSIONS: Her-2/neu overexpression is associated with advanced surgical stage USC and poor survival outcome. These data may be useful in guiding the clinical management of patients with USC and have potential implications for the development of novel treatment strategies.     

Ketamine for rapid sequence induction in patients with head injury in the emergency department

Objective: To examine the evidence regarding the use of ketamine for induction of anaesthesia in patients with head injury in the ED. Method: A literature review using the key words ketamine, head injury and intracranial pressure. Results: Advice from early literature guiding against the use of ketamine in head injury has been met with widespread acceptance, as reflected by current practice. That evidence is conflicting and inconclusive in regards to the safety of using ketamine in head injury. A review of the literature to date suggests that ketamine could be a safe and useful addition to our available treatment modalities. The key to this argument rests on specific pharmacological properties of ketamine, and their effects on the cerebral haemodynamics and cellular physiology of brain tissue that has been exposed to traumatic injury. Conclusion: In the modern acute management of head‐injured patients, ketamine might be a suitable agent for induction of anaesthesia, particularly in those patients with potential cardiovascular instability.     

Impact of trimethoprim-sulfamethoxazole prophylaxis on falciparum malaria infection and disease

BACKGROUND: Trimethoprim-sulfamethoxazole (TS) prophylaxis is recommended for persons living with human immunodeficiency virus infection and acquired immunodeficiency syndrome in Africa. TS and the antimalarial combination sulfadoxine-pyrimethamine (SP) share mechanisms of action and resistance patterns, and concerns about the impact of TS resistance on SP efficacy have contributed to reluctance to implement TS prophylaxis in Africa. METHODS: To determine whether TS prophylaxis impairs SP efficacy for treatment of uncomplicated falciparum malaria, we conducted a randomized, controlled, open-label study of TS prophylaxis. Two hundred and forty children 5-15 years old were randomized in a 2 : 1 fashion to receive either thrice-weekly TS for 12 weeks or no prophylaxis and were treated with SP for subsequent episodes of malaria. The incidence of malaria, SP efficacy, and the prevalence of parasite mutations that confer antifolate drug resistance were measured. RESULTS. TS prophylaxis had a 99.5% protective efficacy against episodes of clinical malaria, with 97% efficacy against infection. Four SP treatment failures occurred in the control group, and none occurred in the TS group. No evidence was seen for selection by TS of antifolate resistance-conferring mutations in parasite dihydrofolate reductase or dihydropteroate synthase during subclinical infections. CONCLUSIONS. In this setting of low antifolate resistance, TS was highly effective in preventing falciparum malaria infection and disease and did not appear to select for SP-resistant parasites.     

TP53 mutations in serous tubal intraepithelial carcinoma and concurrent pelvic high-grade serous carcinoma--evidence supporting the clonal relationship of the two lesions

Serous tubal intraepithelial carcinomas (STICs) have been proposed to be the most likely precursor of ovarian, tubal and 'primary peritoneal' (pelvic) high-grade serous carcinoma (HGSC). As somatic mutation of TP53 is the most common molecular genetic change of ovarian HGSC, occurring in more than 95% of cases, we undertook a mutational analysis of 29 pelvic HGSCs that had concurrent STICs to demonstrate the clonal relationship of STICs and HGSCs. In addition, we correlated the mutational data with p53 immunostaining to determine the role of p53 immunoreactivity as a surrogate for TP53 mutations in histological diagnosis. Somatic TP53 mutations were detected in all 29 HGSCs analysed and the identical mutations were detected in 27 of 29 pairs of STICs and concurrent HGSCs. Missense mutations were observed in 61% of STICs and frameshift/splicing junction/nonsense mutations in 39%. Interestingly, there were two HGSCs with two distinctly different TP53 mutations each, but only one of the mutations was detected in the concurrent STICs. Missense mutations were associated with intense and diffuse (≥ 60%) p53 nuclear immunoreactivity, while most of the null mutations were associated with complete loss of p53 staining (p < 0.0001). Overall, this p53 staining pattern yielded a sensitivity of 87% and a specificity of 100% in detecting TP53 missense mutations. In conclusion, the above findings support the clonal relationship of STIC and pelvic HGSC and demonstrate the utility of p53 immunostaining as a surrogate for TP53 mutation in the histological diagnosis of STIC. In this regard, it is important to appreciate the significance of different staining patterns. Specifically, strong diffuse staining correlates with a missense mutation, whereas complete absence of staining correlates with null mutations.     

Nicotinic acid therapy in chronic schizophrenia

The clinical changes in male veteran hospitalized chronic schizophrenic patients treated with nicotinic acid were investigated. Twenty-seven patients randomly selected from the available population completed the study; 14 of these were designated as experimental subjects and 13 constituted a control group. Nicotinic acid was given to the experimental subjects in the divided dosage of 3 g daily for 90 days. All subjects were interviewed at the beginning of the study and were seen every 3 weeks thereafter until its completion. A behavior rating scale designed by the authors, consisting of 22 items, was scored twice weekly by the attending nursing personnel. An effort was made to administer MMPI and ICL tests to all subjects before and upon completion of the study. The improvement was rated as worse, none, minimum, moderate, or marked.Two of 14 experimental subjects showed marked improvement in their behavior; 4 others showed minimal to moderate improvement; the remaining subjects either showed no change or mild deterioration of their conditions. In comparison, in the control group, only 1 subject showed marked improvement, 1 moderate, and the others either no change or mild deterioration. The better outcome in the exeprimental group compared to the control group was more apparent than real. This improvement was not considered significant because it was probably due to the unique features in the illness of the patient considered improved. In addition, inadvertent biases introduced in the study favored a better outcome in the experimental subjects. It was concluded that the value of nicotinic acid in the treatment of chronic schizophrenic patients is doubtful.