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.

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.

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.

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.

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.

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.

Detroit's avoidable mortality project: breast cancer control for inner-city women.

Mammography remains substantially under-used in low-income minority populations despite its well-established efficacy as a means of breast cancer control. The Metropolitan Detroit Avoidable Mortality Project is a 2-year controlled clinical trial of coordinated interventions which seek to improve the use of early breast cancer detection services at five clinical sites providing primary health care services to inner-city women. Baseline assessment for two of the five participating clinic populations demonstrated that only one-quarter of women who visited these clinics were referred for mammography in 1988, and only half of those who were referred were able to complete the procedure. Patient characteristics including age, marital status, ethnicity, and insurance status were not associated with use of mammography during the baseline period. Each of the project's intervention components is a cue to action: a physician prompt for mammography referral within the medical record of procedure-due women, a reminder postcard for scheduled appointments, and a telephone call to encourage rescheduling of missed appointments. The interventions are initiated by a computerized information management system in the existing network of health care services. The patient's out-of-pocket mammography expense has been eliminated in three of the five sites. Although their efficacy as individual interventions has been well established, a controlled trial of computer prompts to physicians, reduced expense for patients, and patient appointment reminders as an integrated system in inner-city medical care settings has not been previously described. We have implemented the prompting, facilitated rescheduling procedures, and eliminated patient expense for mammography at three of five eventual clinical sites. This report provides an overview of the study's design, data management system, and methodology for evaluation.

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.

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.

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.

Chloralose alters circulatory response to alpha-receptor stimulation and blockade.

Chloralose anesthesia is commonly used in animals for cardiovascular research despite limited data on possible receptor-drug interactions. To investigate potential interactions with alpha-adrenergic receptors, we studied the response of chronically instrumented, spontaneously breathing young lambs to alpha-receptor stimulation (by methoxamine) and blockade (by phentolamine) after infusion of 30 mg/kg of chloralose or an equal volume of vehicle. Both experiments were performed in each animal on different days and in alternate order. Chloralose altered the systemic arterial pressure and heart rate response to both alpha-agonist challenge and to alpha-blockade when compared with control. Despite potentiating the systemic arterial pressor response to methoxamine, chloralose attenuated the reflex decrease in heart rate after alpha-agonist-induced hypertension. This observation suggests that the baroreceptor reflex was blunted. Chloralose, commonly considered an ideal anesthetic for cardiovascular studies, may have important effects on the cardiovascular response to alpha-adrenergic test agents. The potential for interactive effects should be considered in experimental designs that couple the use of chloralose and alpha-adrenergic agents.

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.

Patterns of use of mammography among inner-city Detroit women: contrasts between a health department, HMO, and private hospital.

This study assessed the pattern of utilization of mammography among 2,880 inner-city minority women 40 years of age or older who received ongoing primary care services during 1988 or 1989 at four practice sites operated by a health department (two sites), Health Maintenance Organization (HMO), and private hospital. Mammography referral could be documented for 23% to 32% of age eligible women and completed mammograms for 15% to 26%. Among women without a mammogram, 85% had never been referred while 15% were referred but unable to complete the procedure. In multiple logistic regression analysis, factors associated with mammography include age less than 70 years, presence of a breast cancer risk factor and more frequent clinic visits. Mammography was somewhat more frequent at the HMO and hospital clinic than at the health department, but this relationship varied with the women's previous visit and mammography experience. At sites serving uninsured women, mammography use was not associated with the presence or absence of health insurance. It is concluded that the underutilization of mammography is a substantial barrier to the early detection of breast cancer in each of the three different health care organizations studied, and that interventions to improve breast cancer control should focus upon facilitating physician referral practices.

Pulmonary and systemic vascular response to promethazine in conscious lambs.

Promethazine is an antihistamine commonly used for sedation in clinical pediatric medicine. We studied the cardiovascular effects of promethazine in normoxic, conscious, chronically instrumented neonatal lambs. Eight lambs received 1.3 mg/kg of promethazine intravenously (i.v.) while at rest. In all lambs, promethazine led to elevations of pulmonary vascular resistance, mean pulmonary arterial pressure, mean transpulmonary pressure, mean left atrial pressure, and the ratio of pulmonary-to-systemic vascular resistance. In addition, five (63%) of the lambs demonstrated an increase in mean systemic arterial pressure and systemic vascular resistance to promethazine. A subgroup of three lambs, which tended to be younger, failed to demonstrate the systemic vascular response to promethazine. Promethazine given i.v. has important cardiovascular effects. We hypothesize that promethazine used for sedation before cardiac catheterization in children may alter subsequent hemodynamic observations.

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.

Protective effect of chorionic gonadotropin on DMBA-induced mammary carcinogenesis.

The effect of the placental hormone chorionic gonadotropin (hCG) on 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumours was studied in young virgin Sprague-Dawley rats. This hormone when administered at a dose of 100 IU day-1 does not induce toxic effects, measured as alterations in body weight or weight of endocrine organs, and has a reversible effect on oestrous cycle. The lack of toxicity and the fact that hCG treatment terminated prior to administration of the chemical carcinogen DMBA protects the mammary gland from malignant transformation, led us to test the effect of hCG treatment on DMBA-initiated mammary tumours. Fifty day-old virgin Sprague-Dawley rats received intragastrically 8 mg DMBA per 100 g body weight and were divided into two groups: group I animals were treated with DMBA only and group II received DMBA at age 50 and in addition, a daily intraperitoneal injection of 100 IU hCG for days 21-81 post carcinogen administration. Tumorigenic response was evaluated by biweekly palpation of all animals and by complete autopsy 24 weeks after DMBA treatment. Group I animals developed an incidence of 100% of both tumours and adenocarcinomas. Group II animals developed a significantly lower incidence of tumours and adenocarcinomas, 51.5% and 45.5% respectively. In both groups lesions developed more frequently in thoracic than in abdominal mammary glands. It is postulated that hCG treatment, probably through stimulation of ovarian oestrogen and progesterone synthesis, induces differentiation of mammary epithelium that although affected by the carcinogen can still be rescued from malignant transformation.

Factors associated with age of onset of necrotizing enterocolitis.

To investigate factors associated with risk and age of onset for necrotizing enterocolitis (NEC), a retrospective case-control review was performed of patients with NEC and control infants matched for birthweight and date of admission. NEC cases were defined by Bell staging criteria and were included if pneumatosis intestinalis, histologic confirmation, or a recognized complication of NEC was identified in association with clinical signs and symptoms. NEC was significantly related to birthweight and premature post-conceptional age. In contrast to control infants, patients with NEC had higher 5 minute Apgar scores, less significant respiratory disease, and more rapid feeding practices. Two distinct subgroups of patients with NEC based on postnatal age of onset were apparent. Patients with early onset NEC (21 days or less postnatal age) had less significant respiratory disease and were fed more rapidly than late onset patients. Late onset NEC (more than 21 days postnatal age) occurred frequently in convalescing, relatively well premature infants who were still, however, of preterm postconceptional age. Relatively well premature infants with minimal respiratory disease are still at risk for NEC. Advances in neonatal care and survival of very low birthweight infants may account for a shift in prevalence to older infants who are yet of preterm postconceptional age.