Taking account of quality. Discussion.

Another report from the Institute of Medicine in March 2001 has joined a large body of literature documenting serious quality and safety problems. Eight health care leaders discuss ways in which organizations can reduce medical errors and improve patient outcomes.

Low proliferative rate of invasive node-negative breast cancer predicts for a favorable outcome: a prospective evaluation of 669 patients.

This study was designed to compare outcome in terms of disease-free survival (DFS) in women with histologically negative axillary lymph nodes and documented low proliferative rate cancer to other well-defined prognostic factors including type of adjuvant treatment. Between 1988 and 1998, we studied 669 patients with invasive node-negative breast cancer up to 5 cm in size and low proliferative rate measured by flow cytometry to determine S-phase fraction (SPF) or by histochemistry (Ki67/MIB1). At a median follow-up of 53 months, 5-year DFS for the entire group was 94% and did not differ significantly by type of systemic adjuvant treatment: none (133 patients, 95% DFS), tamoxifen (441 patients, 94% DFS), or chemotherapy with doxorubicin and cyclophosphamide (95 patients, 92% DFS). In a multivariate prognostic factor analysis, only tumor size was significant; 5-year DFS was 96% for T1N0 cancer versus 89% for T2N0 cancer (P = 0.01). We have prospectively confirmed that a low rate of proliferation as measured by SPF or MIB1 determination confers an excellent prognosis in invasive node-negative breast cancer up to 5 cm in size, regardless of adjuvant treatment.

All that glitters is not glaucoma

The twentieth century has witnessed great strides in the understanding and management of the major ophthalmic conditions. For example, the surgical treatment of cataract is being honed to perfection with only the goal of accommodative restoration remaining to complement visual clarity. Understanding of the mode of transmission of Chlamydia trachomaitis, plus the new macrolide antimicrobial, azithromycin, which can cure 80 percent of acute trachoma, offers hope in managing this infection. Similarly, the control of the vector Simulium and the microfilariacidal, Ivermectin, promise to eradicate onchocerciasis volvolus. Increasing understanding of the pathogenesis of the microangiopathy of diabetic retinopathy and the recent trials - Diabetic Control and Complication Trial and the European Prospective Study - have paved the way for the control of this condition. However, our understanding and management of chronic open angle glaucoma remains frustratingly elusive. Problems related to the early detection and monitoring progression remain imprecise and sometimes non-specific and misleading. Two cases are presented to illustrate the limitations of the visual field test and underline the fact that it should never be viewed in isolation. Further treatment modalities will dictate more precise objective tests for monitoring optic nerve function, focusing on early diagnosis and small degrees of progression.(AU)

Longitudinal changes in IOP and incident glaucoma in the Barbados Eye Studies

PURPOSE: There are a few longitudinal population studies describing the progression of intraocular pressure (IOP) or the risk of developing incident open-angle glaucoma (OAG). This report examines changes in IOP and measures the incidence of IOG over a 4-year period in the population of the Barbados Eye Studies. METHODS: The Barbados Incidence Study of Eye Disease (BISED) re-examined members of the Barbados Eye Study (BES) cohort, the original sample being based on a simple random sample of the country's population aged 40 - 84 years. At both visits patients had applanation tonometry, automated Humphrey perimetry, a comprehensive opthalmological examination, colour stereo fundus photography, blood pressure and anthropometric measurements and a detailed interview. RESULTS: A total of 3427 participants or 85 percent of the eligible cohort were re-examined in BISED. The IOP analyses were based on the subset of 2640 Black participants without glaucoma (OAG, or other type) or history of IOP lowering treatment at either visit. The mean age at follow-up was 55 years and 60 percent were women. Mean IOP was 17.3 mmHg (SDñ3.0, median 17.0) at baseline and increased by 2.6 mmHg (SDñ3.6 mmHg, median 2.3)(p<0.001by paired 1 test) in 4 years. Factors positively associated with longitudinal increases in IOP include age (p=0.001) and baseline hypertension (p=0.014) or high systolic blood pressure(p=0.005), while there was an inverse association with baseline IOP. Among the 2989 Black participants without OAG at baseline,the 4-year incidence of OAG was 2.2 percent (95 percent CI: 1.7 percent, 2.8 percent). Incidence was highest among persons classified as suspect OAG at baseline (26.1 percent) followed by ocular hypertensives with IOP >21 mmHg (4.9 percent) and lowest in persons with normal / other diagnoses and with IOP ó21 mmHg (0.8 percent). However, 32 of the 67 new cases of OAG (48 percent) had IOP ó21 at baseline. CONCLUSION: Significant increases in IOP were seen at 4-year follow-up in persons without glaucoma or IOP-lowering treatment history. While high IOP increases the risk of OAG, almost half of the incident cases had IOPó21mmHg at baseline. These results highlight the importance of prognostic factors, other than IOP, in determining the development of OAG.(AU)

The outcome of Trabeculectomy with Mitomycin C at the Queen Elizabeth Hospital, Barbados

AIM: To evaluate the efficacy of trabeculectomy with mitomycin-c in a predominantly black population. METHOD: The records of 43 eyes with 34 patients (males 15, females 19; age range 22-87 years), who underwent trabeculectomies with mitomycin-c for uncontrolled glaucoma at the Queen Elizabeth Hospital were reviewed. Forty-three eyes (rt eyes 22, Lt eyes 21, unilateral 25, bilateral 9, combined procedure 4) had trabeculectomies. All surgeries were performed by six surgeons between July 1995 and October 1998. The concentration of mitomycin-c varied from 0.2 to 0.5 mg/ml and was applied over 2 to 5 minutes. RESULTS: We evaluated treatment outcome based on the following categories of surgical results for patients with a pre-operative IOP>21mmHg. 1. The operation was considered successful when the IOP was <21mmHg without any anti-glaucoma medications. 2. The operation was a failure when the IOP was raised >21mmHg and required anti-glaucoma medications to control the IOP. The mean preoperative IOP was 26mmHg and the mean postoperative IOP was reduced to 14mmHG. There was failure in 19 eyes where the IOP was raised over >21mmHg and required anti-glaucoma medications or control. Twenty-four eyes were still functional at 18 months with IOPs less than 21mmHg without any anti-glaucoma medications. Visual acuity (VA) in the functional 24 eyes: the VA remained the same in 9 patients and the VA progressively deteriorated in the remaining 15 patients in spite of reduced IOP after mitomycin trabeculectomies. CONCLUSION: The most common cause of failure after trabeculectomy is scarring at the filtration site due to fibrosis or more appropriately normal healing by fibrosis - mitomycin simply delayed the normal healing. Eyes with pseudopakia are at higher risk for failure. Most of the studies in the past were done in the predominantly white population with a short follow-up period. In contrast, all the patients in this study were of African origin and had at least 18 months follow-up, with mean follow-up of 39 months. To our knowledge, this is one of the longest follow-up studies in a predominantly Black population and is the first in the Caribbean. (AU)

Interferon and ribavirin versus interferon and amantadine in interferon nonresponders with chronic hepatitis C.

OBJECTIVE: The aim of this study was to compare the potential efficacy and safety of a combination of interferon and ribavirin with that of interferon and amantadine in patients who had previously failed to respond to interferon monotherapy. METHODS: A total of 29 patients were randomized to 3 million units of alpha-interferon three times weekly with 1000 mg of ribavirin daily (group A, n = 14) or an identical dose of alpha-interferon and amantadine hydrochloride given in a dose of 200 mg daily (group B, n = 15). Patients were treated for 24 wk and observed for 24 wk posttreatment. RESULTS: The treatment groups were evenly matched with respect to gender, frequency of genotype 1, presence of fibrosis, as well as baseline alanine aminotransferase (ALT) and HCV RNA levels. At the end of therapy, five of 14 or 36% of patients in group A versus 0 of 15 in group B had both normal serum ALT and nondetectable HCV RNA by polymerase chain reaction (p = 0.017). A complete response was sustained, however, in only two of 13 patients (15%) in group A who completed 24 wk of observation posttreatment. CONCLUSIONS: A substantial proportion of interferon nonresponders have an end-of-treatment biochemical and virological response to a combination of interferon and ribavirin, and sustained responses are possible. The addition of amantadine to interferon, in contrast, does not seem to enhance the antiviral effectiveness of interferon in patients who have previously failed to respond.

Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer.

PURPOSE: The Hoosier Oncology Group has previously reported the results of its phase II trial of the combination of cisplatin plus gemcitabine. In that study of 27 assessable patients with advanced or metastatic non-small-cell lung cancer (NSCLC), the response rate was 33%, with a median survival of 8.4 months. Based on such favorable results, the Hoosier Oncology Group designed this randomized phase III study of gemcitabine plus cisplatin compared with cisplatin alone in chemotherapy-naive patients with advanced NSCLC. PATIENTS AND METHODS: Patients were randomized to receive either cisplatin (100 mg/m(2) intravenously on day 1 of a 28-day cycle) or the combination of cisplatin (100 mg/m(2) intravenously on day 1) plus gemcitabine (1,000 mg/m(2) administered intravenously on days 1, 8, and 15 of a 28-day cycle). RESULTS: From August 1995 to February 1997, 522 assessable chemotherapy-naive patients were randomized. Toxicity was predominantly hematologic and was more pronounced in the combination arm, with grade 4 neutropenia occurring in 35.3% of patients compared with 1.2% of patients on the cisplatin monotherapy arm. The incidence of neutropenic fevers was less than 5% in both arms. Grade 4 thrombocytopenia occurred in 25. 4% of patients on the combination arm compared with 0.8% of patients on the cisplatin monotherapy arm. No serious hemorrhagic events related to thrombocytopenia were reported for either arm. The combination of gemcitabine plus cisplatin demonstrated a significant improvement over single-agent cisplatin with regard to response rate (30.4% compared with 11.1%, respectively; P <.0001), median time to progressive disease (5.6 months compared with 3.7 months, respectively; P =.0013), and overall survival (9.1 months compared with 7.6 months, respectively; P =.004). CONCLUSIONS: For the first-line treatment of NSCLC, the regimen of gemcitabine plus cisplatin is superior to cisplatin alone in terms of response rate, time to disease progression, and overall survival.

Masquerade? A case of central retinal vein occlusion

Central retinal vein occlusion is one of the most common retinal diseases seen in clinical practice, ranking second only to diabetes as a cause of catastrophic retinal vascular disease. Recognition of the risk factors for this disease is of particular importance because the complications are a cause of significant visual morbidity. Systemic hypertension and open angle glaucoma are well known associated conditions. Several biochemical factors have been implicated as risk factors, including elevated lipid and cholesterol concentrations, and the presence of antiphospholipid antibodies. Systemic diseases resulting in hyperviscosity such as polycythaemia and Waldenstrom's macroglobulinaemia can cause central retinal vein occlusion. A case study of a 48 year old female who developed prethrombotic central vein occlusion, present on waking on at least three occasions, was investigated. Full cardiovascular investigations and exhaustive haematological screening were negative. However, the patient had a well documented history of snoring and sleep apnea. This was confirmed by polysomnography. Anticoagulation with coumadin led to resolution of the condition on two occasions, but the patient discontinued therapy and suffered a full-blown vein occlusion. This case suggests that obstructive sleep apnea may be one of the predisposing factors for occlusive retinal vein disease. Further improved understanding of the medical conditions associated with this disease may have implications for the patient's general well being (AU)

Differences in urban and rural Britain.

Almost 90 per cent of people in Britain live in urban areas and just over half the population are resident in 66 urban areas with populations of 100,000 or more. These and a wide range of key results from the 1991 Census have been published for all urban areas in Great Britain, updating information that was prepared for the first time after the 1981 Census. This article summarises the socio-demographic characteristics and distributions of urban and rural populations in Great Britain and describes how the distribution of urban population has changed in the decade 1981-91.

Randomized double-blind prospective trial to evaluate the effects of sargramostim versus placebo in a moderate-dose fluorouracil, doxorubicin, and cyclophosphamide adjuvant chemotherapy program for stage II and III breast cancer.

PURPOSE: To determine the effects of sargramostim (recombinant human granulocyte-macrophage colony-stimulating factor [rhu GM-CSF]) on the incidence, duration, and complications of myelosuppression after moderate-dose fluorouracil, doxorubicin, cyclophosphamide (FAC) adjuvant chemotherapy in patients with node-positive breast cancer. PATIENTS AND METHODS: In this randomized, double-blind, placebo-controlled study, 142 women with stage II and III breast cancer were to receive four 21-day cycles of chemotherapy that consisted of fluorouracil 600 mg/ m2 intravenously (IV), doxorubicin 60 mg/m2 IV, and cyclophosphamide 750 mg/m2 IV on day 1, followed by placebo or GM-CSF 250 micrograms/m2/d daily subcutaneously (SC) on days 3 through 15. All patients received prophylactic ciprofloxacin by mouth when the absolute neutrophil count (ANC) was less than 1,000/microL. RESULTS: Eighty-six percent of GM-CSF patients (n = 62) and 96% of placebo patients (n = 69) completed four assessable cycles of treatment on study. Overall, the median duration of severe neutropenia (ANC < 500/microL) was 2.8 days with GM-CSF and 6.8 days with placebo (P < .001); the duration of ANC less than 1,000/microL was 6.0 versus 9.1 days, respectively (P < .001). Hospitalizations for febrile neutropenia were uncommon in either group: GM-CSF, six; placebo, eight. The only other difference in hematologic toxicity was grade 3/4 thrombocytopenia observed with greater frequency in GM-CSF patients than placebo patients in cycles 3 and 4. GM-CSF increased mean the FAC dose-intensity among patients who completed two or more cycles (P < .001). GM-CSF was generally well tolerated and associated with more injection-site reactions, but less mucositis than placebo. There were no deaths on study. CONCLUSION: GM-CSF significantly enhanced ANC recovery after FAC chemotherapy; it decreased the incidence and duration of associated neutropenia and moderately increased the dose-intensity of adjuvant chemotherapy. Whether these effects will ultimately translate into improved long-term outcome remains to be determined.

Low-dose, titratable interferon alfa in decompensated liver disease caused by chronic infection with hepatitis B virus.

BACKGROUND & AIMS: Interferon therapy has been associated with a number of severe side effects when administered to patients with decompensated cirrhosis caused by chronic hepatitis B. The safety and potential efficacy of a low-dose, titratable regimen of interferon alfa-2b in patients with decompensated liver disease caused by chronic hepatitis B virus infection were studied. METHODS: Twenty-six patients were treated at five medical centers. Five patients had Child's class A status, 15 had Child's B status, and 6 had Child's C status. Treatment was continued for 24 weeks whenever possible. Dose adjustments were made according to predefined safety criteria. RESULTS: All patients with Child's A status responded with a sustained loss of serum hepatitis B virus DNA, reduction in aminotransferase activity, and clinical stabilization. Only 5 patients with Child's B (33%) and no patients with Child's C status reached similar end points. The probability of survival was greater in responders than in nonresponders (P = 0.017). Three patients each developed serious infections or greater than twofold increases in serum aminotransferase levels during therapy. CONCLUSIONS: Low-dose, titratable interferon therapy is safer than previously reported regimens. Nonetheless, serious infections were observed relatively frequently, and this therapy should be reserved for individuals with mild to moderate hepatic decompensation, preferably patients with Child's A status.

The new OPCS area classifications.

This article introduces the OPCS area classifications based on the 1991 Census. It illustrates the methodology and results in terms of local authority districts. It follows earlier articles in Population Trends that described the production of similar classifications after the 1971 and 1981 Censuses. Each district in Great Britain is classified as both the centre of a small cluster of districts which correspond closely to it and as a member of a cluster within a division of all districts. The list of corresponding districts is set out in full. Information is also given on how to obtain further details of the classification.

A phase I trial of trimetrexate (NSC352122) on a daily x 5 schedule in patients with refractory adult leukemia.

Seven adult patients with refractory acute leukemia were administered trimetrexate (TMTX), a non-classical folate antagonist, in a phase I trial. TMTX was administered as an intravenous bolus for five consecutive days at doses of 9-12 mg/m2 based on marrow response. The maximum tolerated dose was 12 mg/m2. Hepatotoxicity was the dose-limiting toxicity. Initial dosage reductions in patients with liver disease and/or low protein concentrations may be necessary since TMTX is significantly protein bound and cleared primarily by hepatic metabolism. The recommended phase II dose on this dosing schedule is 9 mg/m2.

Transcriptional regulation of transferrin receptor expression by cultured lymphoblastoid T cells treated with phorbol diesters.

Expression of transferrin receptors (TFR) is required for lymphocyte proliferation. Treatment of lymphoblastic leukemia cell lines with phorbol diester tumor promoters decreases proliferation and induces differentiation. Among changes induced by phorbol diesters is decreased cell surface expression of TFR. To elucidate effects of phorbols on lymphocyte growth and differentiation, we examined TFR expression by measuring 125I-transferrin binding, levels of TFR mRNA by Northern analysis and dot-blot hybridization, and rates of TFR gene transcription by nuclear run-on experiments in CCRF-CEM lymphoblastoid T cells treated with PMA or phorbol dibutyrate. Cell surface expression of TFR was decreased 60 to 85% within 2 min of exposing cells to phorbols and remained decreased for 96 h. Steady state levels of TFR mRNA decreased to less than 30% of control after 48 h. After treating cells with actinomycin D, estimated TFR mRNA t 1/2 was 2.7 h and was unaltered in phorbol-treated cells. Levels of TFR mRNA were not affected by treatment of cells with cycloheximide in either control or phorbol-treated cells. Therefore, post transcriptional mRNA processing by protein factors did not account for decreased TFR mRNA in phorbol-treated cells. Compared to baseline levels, rates of TFR gene transcription in PMA-treated cells increased up to two-fold during the initial 6 h of culture, then decreased over the ensuing 12 h to less than 10% of baseline values. This pattern was not seen in control cultures. Therefore, regulation of TFR gene transcription is a consequence of treating CEM cells with phorbol diesters. Cell surface expression of TFR in phorbol-treated lymphoblastoid T cells may be mediated in part at the level of gene transcription.

A self-heated thermistor technique to measure effective thermal properties from the tissue surface.

A microcomputer based instrument to measure effective thermal conductivity and diffusivity at the surface of a tissue has been developed. Self-heated spherical thermistors, partially embedded in an insulator, are used to simultaneously heat tissue and measure the resulting temperature rise. The temperature increase of the thermistor for a given applied power is a function of the combined thermal properties of the insulator, the thermistor, and the tissue. Once the probe is calibrated, the instrument accurately measures the thermal properties of tissue. Conductivity measurements are accurate to 2 percent and diffusivity measurements are accurate to 4 percent. A simplified bioheat equation is used which assumes the effective tissue thermal conductivity is a linear function of perfusion. Since tissue blood flow strongly affects heat transfer, the surface thermistor probe is quite sensitive to perfusion.