Long-term outcomes to neoadjuvant pembrolizumab based on pathological response for patients with resectable stage III/IV cutaneous melanoma.

BACKGROUND: While neoadjuvant immunotherapy for melanoma has shown promising results, the data have been limited by a relatively short follow-up time, with most studies reporting 2-year outcomes. The goal of this study was to determine long-term outcomes for stage III/IV melanoma patients treated with neoadjuvant and adjuvant programmed cell death receptor 1 (PD-1) inhibition. PATIENTS AND METHODS: This is a follow-up study of a previously published phase Ib clinical trial of 30 patients with resectable stage III/IV cutaneous melanoma who received one dose of 200 mg IV neoadjuvant pembrolizumab 3 weeks before surgical resection, followed by 1 year of adjuvant pembrolizumab. The primary outcomes were 5-year overall survival (OS), 5-year recurrence-free survival (RFS), and recurrence patterns. RESULTS: We report updated results at 5 years of follow-up with a median follow-up of 61.9 months. No deaths occurred in patients with a major pathological response (MPR, <10% viable tumor) or complete pathological response (pCR, no viable tumor) (n = 8), compared to a 5-year OS of 72.8% for the remainder of the cohort (P = 0.12). Two of eight patients with a pCR or MPR had a recurrence. Of the patients with >10% viable tumor remaining, 8 of 22 patients (36%) had a recurrence. Additionally, the median time to recurrence was 3.9 years for patients with ≤10% viable tumor and 0.6 years for patients with >10% viable tumor (P = 0.044). CONCLUSIONS: The 5-year results from this trial represent the longest follow-up of a single-agent neoadjuvant PD-1 trial to date. Response to neoadjuvant therapy continues to be an important prognosticator with regard to OS and RFS. Additionally, recurrences in patients with pCR occur later and are salvageable, with a 5-year OS of 100%. These results demonstrate the long-term efficacy of single-agent neoadjuvant/adjuvant PD-1 blockade in patients with a pCR and the importance of long-term follow-up for these patients. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02434354.

Prevalence of and risk factors for cerebral microbleeds among adult patients with haemophilia A or B.

INTRODUCTION: Cerebral microbleeds (CMBs) represent clinically silent haemorrhagic events. Cerebral microbleeds (CMBs) portend negative neurovascular and cognitive outcomes in the general population and are associated with cognitive impairment in persons with haemophilia (PWH). Prevalence, patterns, and risk factors for CMBs in PWH have not been directly compared to persons without coagulopathy. AIM: To examine prevalence, patterns, and risk factors for CMBs in PWH vs normal controls. METHODS: Adults with haemophilia A or B and haemostatically normal controls were recruited. Subjects were excluded if taking an antithrombotic agent other than low-dose aspirin (<100 mg). All subjects underwent T2*MRI of the brain; scans were reviewed independently by two neuroradiologists blinded to subject group to determine the presence of CMBs. RESULTS: We recruited 31 PWH and 32 controls. Human immunodeficiency virus (HIV) and history of hepatitis C virus (HCV) infection were more prevalent in PWH; smoking was more common among controls. Cardiovascular (CV) risk factors were similar between groups. Prevalence of CMBs was 35% in PWH and 25% in controls (P = .42). Among PWH, advanced age, history of HCV infection, and CV risk factors were associated with CMBs. Multiple and large (>5 mm) CMBs were seen only in PWH. CONCLUSIONS: Cerebral microbleeds (CMBs) are common in adults with haemophilia, but not clearly more prevalent than in haemostatically normal controls. In PWH, older age, HCV infection, CV risk factors, and the presence of an inhibitor were associated with CMBs. Large CMBs and multiple CMBs may be more prevalent in PWH than in the general population. The clinical impact of CMBs in PWH requires further study.

Diagnostic accuracy of IgG-specific versus polyspecific enzyme-linked immunoassays in heparin-induced thrombocytopenia: a systematic review and meta-analysis.

Essentials Immunoassay specificity varies in heparin-induced thrombocytopenia (HIT) testing. This meta-analysis examined 9 studies that tested samples by both IgG and polyspecific methods. IgG-specific assays confer superior diagnostic accuracy compared with polyspecific assays. These results further support recommendations in favor of IgG-specific testing. SUMMARY: Background There are conflicting data on whether the IgG-specific or polyspecific antiplatelet factor 4/heparin (PF4/H) enzyme-linked immunosorbent assay (ELISA) is preferred for the laboratory diagnosis of heparin-induced thrombocytopenia (HIT). Objectives To directly compare diagnostic accuracy of IgG-specific versus polyspecific ELISA in HIT. Patients/Methods A systematic search yielded nine studies comprising 1948 patients with suspected HIT tested by both IgG-specific and polyspecific ELISAs and a reference standard against which the diagnostic accuracy of the ELISAs could be measured. Study quality was assessed by QUADAS-2 criteria. Results There was identical sensitivity for IgG-specific and polyspecific ELISAs (0.97; 95% confidence interval (CI), 0.95-0.99) and superior specificity of IgG-specific compared with polyspecific ELISA (0.87 [0.85-0.88] vs. 0.82 [0.80-0.84], respectively). Performance was similar in subgroups using the serotonin release assay and a single commercial ELISA manufacturer. The negative predictive values of IgG-specific and polyspecific ELISA were similarly high (0.99, [0.99-1.00], but the positive predictive value was superior with IgG-specific compared with polyspecific ELISA (0.56 [0.52-0.61] vs. 0.32 [0.28-0.35], respectively). The positive likelihood ratio (LR) was higher in IgG-specific than polyspecific ELISA, although negative LRs were similar. There was high risk of quality concerns in domains of index test and reference standard. Conclusions The superior diagnostic accuracy of IgG-specific ELISA reinforces the ISTH-SSC recommendation for standardization of laboratory testing for HIT. Likelihood ratios of individual assays may be used in combination with clinical scoring systems as part of an integrated diagnostic algorithm for HIT.

Interventional therapies and in-hospital outcomes in acute coronary syndromes complicated by von Willebrand disease.

INTRODUCTION: von Willebrand disease (VWD) is one of the most common inherited bleeding disorders. AIM: Investigate the impact of the VWD bleeding tendency on in-hospital management of acute coronary syndromes (ACS). METHODS: Using discharge data from the National Inpatient Sample (NIS), the features of presentation and in-hospital treatment among ACS hospital discharges with and without a VWD diagnosis were investigated. A total of 264 case discharges and 705 860 control discharges were identified. RESULTS AND CONCLUSIONS: There was a significantly higher percentage of women among the case discharges compared to the control discharges (59.5% and 39.4%, respectively; P < 0.001). The rate of medical therapy alone [i.e. avoidance of percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG)] was significantly higher among unstable angina cases than controls (55.0% vs. 46.4%; P = 0.01), and among cases undergoing PCI, bare-metal stents (BMS) were utilized in preference to drug-eluting stents (DES) (adjusted OR = 3.5); P < 0.001). No difference in in-hospital death was identified, but reported bleeding among discharges that underwent CABG was higher in cases compared to controls (12.9% vs. 5.2%; P = 0.047). Although medical and interventional management of ACS appears to be well tolerated in the majority of hospitalized patients with VWD, the gender ratio is reversed, interventions and DES are utilized less frequently and procedure-related bleeding may be increased, calling for further study.

Correction of human hemophilia A whole blood abnormalities with a novel bypass agent: zymogen-like FXa(I16L).

BACKGROUND: Approximately 30% of hemophilia A (HA) and 5% of hemophilia B patients develop inhibitors to protein replacement therapy, and this is the major cause of disease-related morbidity in the developed world. We previously developed zymogen-like factor Xa (FXa) molecules with impaired active site maturation, enabling a greater half-life than wild-type FXa while maintaining full procoagulant function in the prothrombinase complex. Here we evaluated the ability of zymogen-like FXa(I16L) to correct whole blood thromboelastometry abnormalities of severe HA subjects with and without inhibitors. METHODS: Fourteen severe HA subjects without and five with inhibitors were enrolled at baseline ( FVIII: C < 1%) > 5 half-lives from factor or bypass therapy. The subjects' whole blood was evaluated by thromboelastography (ROTEM(®) ) using INTEM analysis with two concentrations of FXa(I16L) or recombinant factor VIIa (rFVIIa). RESULTS: With 0.1 nm FXa(I16L) , clot time (CT, in minutes [min]) among HA subjects without and with inhibitors (mean = 2.87 min, 95% CI = 2.58-3.15 min, and mean = 2.9 min, 95% CI = 2.07-3.73 min, respectively) did not significantly differ from control CT (mean = 2.73 min, 95% CI = 2.62-2.85 min). Addition of 20 nm rFVIIa, simulating a 90-µg/kg dose, resulted in significantly prolonged CTs for HA subjects without and with inhibitors (mean = 5.43 min, 95% CI = 4.53-6.35 min, and mean = 4.25 min, 95% CI = 3.32-5.17 min, respectively) relative to controls. CONCLUSIONS: FXa(I16L) restored thromboelastometry CT to control values in severe HA subjects with and without inhibitors. The findings corroborate previous animal data and demonstrate the first evidence of zymogen-like FXa(I16L) correcting human HA subjects' whole-blood abnormalities and support the use of FXa(I16L) as a novel hemostatic agent.

Cellular senescence checkpoint function determines differential Notch1-dependent oncogenic and tumor-suppressor activities.

Notch activity regulates tumor biology in a context-dependent and complex manner. Notch may act as an oncogene or a tumor-suppressor gene even within the same tumor type. Recently, Notch signaling has been implicated in cellular senescence. Yet, it remains unclear as to how cellular senescence checkpoint functions may interact with Notch-mediated oncogenic and tumor-suppressor activities. Herein, we used genetically engineered human esophageal keratinocytes and esophageal squamous cell carcinoma cells to delineate the functional consequences of Notch activation and inhibition along with pharmacological intervention and RNA interference experiments. When expressed in a tetracycline-inducible manner, the ectopically expressed activated form of Notch1 (ICN1) displayed oncogene-like characteristics inducing cellular senescence corroborated by the induction of G0/G1 cell-cycle arrest, Rb dephosphorylation, flat and enlarged cell morphology and senescence-associated ß-galactosidase activity. Notch-induced senescence involves canonical CSL/RBPJ-dependent transcriptional activity and the p16(INK4A)-Rb pathway. Loss of p16(INK4A) or the presence of human papilloma virus (HPV) E6/E7 oncogene products not only prevented ICN1 from inducing senescence but permitted ICN1 to facilitate anchorage-independent colony formation and xenograft tumor growth with increased cell proliferation and reduced squamous-cell differentiation. Moreover, Notch1 appears to mediate replicative senescence as well as transforming growth factor-ß-induced cellular senescence in non-transformed cells and that HPV E6/E7 targets Notch1 for inactivation to prevent senescence, revealing a tumor-suppressor attribute of endogenous Notch1. In aggregate, cellular senescence checkpoint functions may influence dichotomous Notch activities in the neoplastic context.

MEK inhibition affects STAT3 signaling and invasion in human melanoma cell lines.

Elevated activity of the mitogen-activated protein kinase (MAPK) signaling cascade is found in the majority of human melanomas and is known to regulate proliferation, survival and invasion. Current targeted therapies focus on decreasing the activity of this pathway; however, we do not fully understand how these therapies impact tumor biology, especially given that melanoma is a heterogeneous disease. Using a three-dimensional (3D), collagen-embedded spheroid melanoma model, we observed that MEK and BRAF inhibitors can increase the invasive potential of ∼20% of human melanoma cell lines. The invasive cell lines displayed increased receptor tyrosine kinase (RTK) activity and activation of the Src/FAK/signal transducers and activators of transcription-3 (STAT3) signaling axis, also associated with increased cell-to-cell adhesion and cadherin engagement following MEK inhibition. Targeting various RTKs, Src, FAK and STAT3 with small molecule inhibitors in combination with a MEK inhibitor prevented the invasive phenotype, but only STAT3 inhibition caused cell death in the 3D context. We further show that STAT3 signaling is induced in BRAF-inhibitor-resistant cells. Our findings suggest that MEK and BRAF inhibitors can induce STAT3 signaling, causing potential adverse effects such as increased invasion. We also provide the rationale for the combined targeting of the MAPK pathway along with inhibitors of RTKs, SRC or STAT3 to counteract STAT3-mediated resistance phenotypes.

Periostin cooperates with mutant p53 to mediate invasion through the induction of STAT1 signaling in the esophageal tumor microenvironment.

Periostin (POSTN), a matricellular protein, has been reported to be important in supporting tumor cell dissemination. However, the molecular mechanisms underlying POSTN function within the tumor microenvironment are poorly understood. In this study, we observe that the inducible knockdown of POSTN decreases esophageal squamous cell carcinoma (ESCC) tumor growth in vivo and demonstrate that POSTN cooperates with a conformational missense p53 mutation to enhance invasion. Pathway analyses reveal that invasive esophageal cells expressing POSTN and p53(R175H) mutation display activation of signal transducer and activator of transcription 1 (STAT1) target genes, suggesting that the induction of STAT1 and STAT1-related genes could foster a permissive microenvironment that facilitates invasion of esophageal epithelial cells into the extracellular matrix. Genetic knockdown of STAT1 in transformed esophageal epithelial cells underscores the importance of STAT1 in promoting invasion. Furthermore, we find that STAT1 is activated in ESCC xenograft tumors, but this activation is attenuated with inducible knockdown of POSTN in ESCC tumors. Overall, these results highlight the novel molecular mechanisms supporting the capacity of POSTN in mediating tumor invasion during ESCC development and have implications of therapeutic strategies targeting the tumor microenvironment.

Acquired cancer stem cell phenotypes through Oct4-mediated dedifferentiation.

There is enormous interest to target cancer stem cells (CSCs) for clinical treatment because these cells are highly tumorigenic and resistant to chemotherapy. Oct4 is expressed by CSC-like cells in different types of cancer. However, function of Oct4 in tumor cells is unclear. In this study, we showed that expression of Oct4 gene or transmembrane delivery of Oct4 protein promoted dedifferentiation of melanoma cells to CSC-like cells. The dedifferentiated melanoma cells showed significantly decreased expression of melanocytic markers and acquired the ability to form tumor spheroids. They showed markedly increased resistance to chemotherapeutic agents and hypoxic injury. In the subcutaneous xenograft and tail vein injection assays, these cells had significantly increased tumorigenic capacity. The dedifferentiated melanoma cells acquired features associated with CSCs such as multipotent differentiation capacity and expression of melanoma CSC markers such as ABCB5 and CD271. Mechanistically, Oct4-induced dedifferentiation was associated with increased expression of endogenous Oct4, Nanog and Klf4, and global gene expression changes that enriched for transcription factors. RNAi-mediated knockdown of Oct4 in dedifferentiated cells led to diminished CSC phenotypes. Oct4 expression in melanoma was regulated by hypoxia and its expression was detected in a sub-population of melanoma cells in clinical samples. Our data indicate that Oct4 is a positive regulator of tumor dedifferentiation. The results suggest that CSC phenotype is dynamic and may be acquired through dedifferentiation. Oct4-mediated tumor cell dedifferentiation may have an important role during tumor progression.

Melanoma progression exhibits a significant impact on connexin expression patterns in the epidermal tumor microenvironment.

Melanoma depends on, interacts with and reacts to the stroma in which it is embedded, including fibroblasts, extracellular matrix, endothelial cells and immune cells. However, the impact of melanoma on the epidermal tumor microenvironment-the multilayered epithelium of the skin-is poorly understood. Gap junctions are essential for intercellular communication and involved in proliferation, differentiation and homeostasis of keratinocytes. We have shown previously that the gap junction proteins connexin 26 and 30 (Cx26 and Cx30) are induced in the epidermal tumor microenvironment of skin cancers including melanoma. This study compares the extent of Cx26, Cx30 and Cx43 expression in the epidermal microenvironment of melanocytic nevi and melanomas and its association with melanoma thickness, proliferative index of the tumor and its microenvironment, and with 5-year metastasis and survival. We found that induction of Cx26 and Cx30 cell-cell border expression in the epidermal tumor microenvironment correlates to malignancy. Importantly, there was a significant correlation of tumor thickness with the vertical epidermal Cx26 and Cx30 expression pattern and the horizontal Cx26 dissemination. Furthermore, horizontal Cx26 expression correlated with metastasis. Vertical epidermal expression patterns of Cx26 and Cx30 significantly correlated with the proliferative index in the epidermal tumor microenvironment but not with the proliferative index in the tumor. In contrast, Cx43 did not correlate with malignancy, thickness or proliferative index. In summary, here we show for the first time a significant association between the progression of melanoma and alterations in its epithelial tumor microenvironment.

Multi-gene epigenetic silencing of tumor suppressor genes in T-cell lymphoma cells; delayed expression of the p16 protein upon reversal of the silencing.

To understand better T-cell lymphomagenesis, we examined promoter CpG methylation and mRNA expression of closely related genes encoding p16, p15, and p14 tumor suppressor genes in cultured malignant T-cells that were derived from cutaneous, adult type, and anaplastic lymphoma kinase (ALK)-expressing T-cell lymphomas. p16 gene was epigenetically silenced in all but one of the 10 malignant T-cell lines examined, p15 gene silenced in roughly half of the lines, and p14 was the least frequently affected. Extensive methylation of the p16 promoter was seen in six out of 10 cutaneous T-cell lymphoma patient samples and corresponded with lack of p16 protein expression in the cases examined. Treatment of cultured T-cells with the DNA methyltransferase inhibitor, 5-aza-2-deoxy-cytidine, resulted in reversal of the p16 gene silencing. However, expression of p16 protein was delayed in relationship to p16 promoter demethylation and required up to 3 weeks to occur, seemingly reflecting late activation of the p16 gene. These findings indicate that epigenetic silencing affects in T-cell malignancies, often simultaneously, several tumor suppressor genes that impact on key cell functions. The observed differential silencing of p16 and p14, and to a lesser degree p15 gene, indicates that the silencing is governed by precise, promoter region-specific mechanisms. The study provides also further rationale for treatment of at least some types of T-cell lymphomas with DNA methyltransferase inhibitors to target the epigenetically silenced tumor suppressor genes.

Long-term event-free survivors after high-dose therapy and autologous stem-cell transplantation for low-grade follicular lymphoma.

Although follicular lymphoma (FL) is generally responsive to conventional-dose chemotherapy, improved survival in patients with this disease has been difficult to demonstrate. High-dose chemo/radiotherapy followed by autologous stem-cell transplantation (ASCT) can improve response rates, although its effects on survival remain controversial. Between 1990 and 2003, we transplanted 49 patients with low-grade FL at our institution. Twenty-two patients (45%) had undergone histologic transformation at the time of ASCT. In all, 44 patients (90%) had relapsed disease and five patients (10%) were resistant to chemotherapy at the time of transplantation. After ASCT, 30 patients (61%) were in complete remission (CR). The median overall survival (OS) has not been reached, while the median event-free survival (EFS) is 2.4 years. At a median follow-up of 5.5 years (longest 12.4 years), a plateau has been reached with 56% of patients remaining alive, and 35% event-free. ASCT was well tolerated except for two (4%) treatment-related deaths. In multivariable analysis, CR after ASCT and age less than 60 years are the best predictors of EFS and OS. ASCT is thus a safe therapeutic approach in FL, resulting in long-term EFS and OS for some patients, even with transformed disease.

The effect of patient reminders on the use of screening mammography in an urban health department primary care setting.

Mammography screening continues to be under-utilized, especially among women from lower socioeconomic groups. In order to determine whether having direct access to health care services has an effect on mammography use among low income women, we conducted a randomized trial of two alternative letter reminders among 1,717 women who were enrolled at two locations of a multi-site inner city health department in Detroit. All participants were 39(1/2) years of age and older and were due for a screening mammogram at randomization. A physician-directed reminder form was placed in each of the participant's medical records at the beginning of the study. In addition participants were randomized to receive either a letter directing them to visit their primary care physician, a letter directing them to contact the clinic directly to schedule a mammogram, or no letter. Study participants were predominantly African-American, two-thirds of whom were over age 50, and who had minimal health insurance coverage. During the intervention year, mammograms were completed by 179 out of 967 study women at site one (18.5%), and 90 out of 750 study women at site two (12%). A multivariate model controlling for the simultaneous effect of age, insurance type, visit history and past mammography use, showed no significant independent effect of either type of letter reminder on mammography completion during the study year. In conclusion, letters targeted at women due for screening mammograms did not have a beneficial effect on mammography utilization above and beyond that of a physician medical record reminder.

Developmental role of the SNF1-related kinase Hunk in pregnancy-induced changes in the mammary gland.

The steroid hormones 17 beta-estradiol and progesterone play a central role in the pathogenesis of breast cancer and regulate key phases of mammary gland development. This suggests that developmental regulatory molecules whose activity is influenced by ovarian hormones may also contribute to mammary carcinogenesis. In a screen designed to identify protein kinases expressed in the mammary gland, we previously identified a novel SNF1-related serine/threonine kinase, Hunk (hormonally upregulated Neu-associated kinase). During postnatal mammary development, Hunk mRNA expression is restricted to a subset of mammary epithelial cells and is temporally regulated with highest levels of expression occurring during early pregnancy. In addition, treatment of mice with 17 beta-estradiol and progesterone results in the rapid and synergistic upregulation of Hunk expression in a subset of mammary epithelial cells, suggesting that the expression of this kinase may be regulated by ovarian hormones. Consistent with the tightly regulated pattern of Hunk expression during pregnancy, mammary glands from transgenic mice engineered to misexpress Hunk in the mammary epithelium manifest temporally distinct defects in epithelial proliferation and differentiation during pregnancy, and fail to undergo normal lobuloalveolar development. Together, these observations suggest that Hunk may contribute to changes in the mammary gland that occur during pregnancy in response to ovarian hormones.

A randomized design for repeated binary outcomes used to evaluate continued effectiveness of a breast cancer control intervention strategy.

The literature has not discussed in detail design and evaluation strategies for the assessment of continued effectiveness of intervention strategies. In this article we present an approach to evaluating continued effectiveness with two repeated binary outcomes that are related to the use of preventive services. We present a two-stage design with independent randomization procedures for each of two successive controlled trials and discuss the implications of the randomization plan for the statistical evaluation. Intervention effectiveness for each year is determined by an adjusted odds ratio that compares the odds of procedure use for those who received the intervention to those who did not. Changes in the two adjusted odds ratios between successive years are assessed within the context of a regressive logistic model. We demonstrate these methods by applying them to the Metropolitan Detroit Project to Reduce Avoidable Mortality from Breast Cancer. In this project, computer-generated physician mammography reminders placed prominently in medical records were used to promote mammography referrals among women visiting primary care clinics during a 2-year intervention period. An assessment of the change in intervention effectiveness as well as an adjusted estimate of the overall intervention effectiveness for the 2 years were obtained from a multivariate regressive logistic model. The advantage of this approach was its potential for reducing bias and producing a balanced comparison between intervention groups during the second year of intervention. This issue was important because previous work indicated that having had a mammogram had a significant impact on subsequent mammography use. An important component in the implementation of this design was an information management system that facilitated doing two randomization procedures efficiently. As information and computer technology advance, and as more sophisticated information systems are used for data management, designs such as these become reasonable alternatives to consider.

How reminders given to patients and physicians affected pap smear use in a health maintenance organization: results of a randomized controlled trial.

BACKGROUND: Despite its effectiveness as a method of controlling cervical carcinoma, the use of Pap smear testing remains incomplete, and its promotion in the primary care setting provides an important opportunity for intervention. METHODS: The authors conducted a randomized controlled trial that involved three sites of a health maintenance organization (HMO) serving an urban minority population. Their aim was to evaluate the impact of reminders given to patients and physicians on site visitation by patients and Pap smear use. Eligible women (n=5801) were randomly assigned to 1 of 4 intervention combinations (in which reminders were given to either the patient or the physician, to both, or to neither). If they were ineligible for patient reminder intervention, patients were randomized only to physician reminder intervention (the presence or absence of it). The letter of reminder mailed to the patient invited women due for Pap smears to visit the HMO site, and the reminder for physicians was a medical record notice that a Pap smear was due. Logistic and survival analyses were used to investigate the correlation of intervention status with visitation, interval of time to a visit, and Pap smear use. RESULTS: In the primary intent-to-treat analysis, there was no significant effect of either patient or physician reminder interventions on rates of visitation or Pap smear completion. The secondary efficacy analyses demonstrated no overall effect of either patient or physician reminders, but effects among subgroups of women at individual HMO sites were noted. At Site 3, there was an apparent increase in time to the next visit among the subgroup of women with a chronic illness (16 weeks with intervention vs. 9 weeks without). With the physician reminder, the odds that a Pap smear would be given during the study year were increased among women without a previous Pap smear at Site 1 (adjusted odds ratio=1.39) and those with a chronic illness at Site 2 (adjusted odds ratio=3.38). CONCLUSIONS: Reminders given to patients and physicians had a limited impact on visitation by patients to the HMO sites or Pap smear completion. Although some subgroups of women may benefit, the authors also observed a possibly unfavorable impact among other subgroups. These results emphasize the importance of identifying more effective interventions, targeting them to women most likely to benefit, and not overlooking the possibility that preventive intervention will have an unanticipated adverse effect.

Factors affecting participation in a mammography screening program among members of an urban Detroit health maintenance organization.

Breast cancer mortality rates remain disproportionately high among black women despite recent improvements in mammography screening utilization. We conducted a telephone survey among a sample of women (N = 202) participating in a randomized controlled trial investigating the effectiveness of a mammography reminder letter that was one component of a breast cancer control intervention strategy. The objectives of the survey were to ascertain the extent to which the letter reminder was received and acted upon, and to determine attitudes and breast cancer control practices in the target population. The study was conducted among members of a large health maintenance organization serving predominantly black women in Detroit, Michigan. Forty-eight percent of the participants completed a mammogram during the year after the letter was sent. While 72% of the women remembered receiving the letter reminder, only 5% responded to the recommendations in the letter. Important predictors of mammography completion included past mammogram utilization (OR: 2.49; 95% CI: 1.05-5.93), a prior physician recommendation for a mammogram (OR: 1.99; 95% CI: 1.00-3.95) and subject's knowledge of her primary physician's name (OR: 2.05; 95% CI: 0.91-4.60). Letter reminders promoting primary care visits were relatively ineffective since few women reported being prompted by the letter recommendation. Strategies which target physician mammography referral behavior may have an important impact on mammography utilization among inner-city women.

Promoting screening mammography in inner-city settings. The sustained effectiveness of computerized reminders in a randomized controlled trial.

OBJECTIVES: The authors conducted a randomized controlled trial to evaluate the sustained effectiveness of a computerized reminder system in promoting mammography during a second year of continuing intervention at three primary care practices of a Health Department and a health maintenance organization in Detroit, Michigan. METHODS: Out-of-pocket mammography cost was eliminated for all participants (limited intervention). Computer-generated reminders promoting physician referral for mammography were placed in the medical records of women due for mammography 1 month in advance of their due date (full intervention). RESULTS: Among 1,225 year 2 visitors, mammography rates were 44% for full intervention versus 28% for limited intervention at the health department (adjusted odds ratio [OR] for effect of full intervention 1.84; 95% confidence interval [CI]: 1.40-2.40) and 45% for full versus 46% for limited at the health maintenance organization (adjusted OR 1.06; 95% CI 0.80-1.42). These second year results contrasted with those observed for year 1, during which a significant effect of full intervention was demonstrated for both organizations. After controlling for patient characteristics and site, the effect sizes of full intervention were reduced significantly in the second year compared with the first year (P = 0.05). CONCLUSIONS: The effect of computerized mammography reminders can be sustained in a second year of continued intervention, but individual practice sites and organizations vary in their responsiveness to the intervention. Strategies to promote periodic and repetitive procedure use must identify and address time-varying barriers to their effectiveness.