bluuebunny/crossref_metadata_2025 huggingface dataset:
Western medical ethics taught to junior medical students can cross cultural and linguistic boundaries
Authors: Ypinazar Valmae A , Margolis Stephen A
Published: August 2004

Background

Little is known about teaching medical ethics across cultural and linguistic boundaries. This study examined two successive cohorts of first year medical students in a six year undergraduate MBBS program.

Methods

The objective was to investigate whether Arabic speaking students studying medicine in an Arabic country would be able to correctly identify some of the principles of Western medical ethical reasoning. This cohort study was conducted on first year students in a six-year undergraduate program studying medicine in English, their second language at a medical school in the Arabian Gulf. The ethics teaching was based on the four-principle approach (autonomy, beneficence, non-malfeasance and justice) and delivered by a non-Muslim native English speaker with no knowledge of the Arabic language. Although the course was respectful of Arabic culture and tradition, the content excluded an analysis of Islamic medical ethics and focused on Western ethical reasoning. Following two 45-minute interactive seminars, students in groups of 3 or 4 visited a primary health care centre for one morning, sitting in with an attending physician seeing his or her patients in Arabic. Each student submitted a personal report for summative assessment detailing the ethical issues they had observed.

Results

All 62 students enrolled in these courses participated. Each student acting independently was able to correctly identify a median number of 4 different medical ethical issues (range 2–9) and correctly identify and label accurately a median of 2 different medical ethical issues (range 2–7) There were no significant correlations between their English language skills or general academic ability and the number or accuracy of ethical issues identified.

Conclusions

This study has demonstrated that these students could identify medical ethical issues based on Western constructs, despite learning in English, their second language, being in the third week of their medical school experience and with minimal instruction. This result was independent of their academic and English language skills suggesting that ethical principles as espoused in the four principal approach may be common to the students' Islamic religious beliefs, allowing them to access complex medical ethical reasoning skills at an early stage in the medical curriculum.
Brain choline concentrations may not be altered in euthymic bipolar disorder patients chronically treated with either lithium or sodium valproate
Authors: Wu Ren H , O'Donnell Tina , Ulrich Michele , Asghar Sheila J , Hanstock Christopher C , Silverstone Peter H
Published: August 2004

Background

It has been suggested that lithium increases choline concentrations, although previous human studies examining this possibility using 1H magnetic resonance spectroscopy (1H MRS) have had mixed results: some found increases while most found no differences.

Methods

The present study utilized 1H MRS, in a 3 T scanner to examine the effects of both lithium and sodium valproate upon choline concentrations in treated euthymic bipolar patients utilizing two different methodologies. In the first part of the study healthy controls (n = 18) were compared with euthymic Bipolar Disorder patients (Type I and Type II) who were taking either lithium (n = 14) or sodium valproate (n = 11), and temporal lobe choline/creatine (Cho/Cr) ratios were determined. In the second part we examined a separate group of euthymic Bipolar Disorder Type I patients taking sodium valproate (n = 9) and compared these to controls (n = 11). Here we measured the absolute concentrations of choline in both temporal and frontal lobes.

Results

The results from the first part of the study showed that bipolar patients chronically treated with both lithium and sodium valproate had significantly reduced temporal lobe Cho/Cr ratios. In contrast, in the second part of the study, there were no effects of sodium valproate on either absolute choline concentrations or on Cho/Cr ratios in either temporal or frontal lobes.

Conclusions

These findings suggest that measuring Cho/Cr ratios may not accurately reflect brain choline concentrations. In addition, the results do not support previous suggestions that either lithium or valproate increases choline concentrations in bipolar patients.
Mapping the distribution of Loa loain Cameroon in support of the African Programme for Onchocerciasis Control
Authors: Thomson Madeleine C , Obsomer Valérie , Kamgno Joseph , Gardon Jacques , Wanji Samuel , Takougang Innocent , Enyong Peter , Remme Jan H , Molyneux David H , Boussinesq Michel
Published: August 2004

Background

Loa loa has recently emerged as a filarial worm of significant public health importance as a consequence of its impact on the African Programme for Onchocerciasis Control (APOC). Severe, sometimes fatal, encephalopathic reactions to ivermectin (the drug of choice for onchocerciasis control) have occurred in some individuals with high Loa loa microfilarial counts. Since high density of Loa loa microfilariae is known to be associated with high prevalence rates, a distribution map of the latter may determine areas where severe reactions might occur. The aim of the study was to identify variables which were significantly associated with the presence of a Loa microfilaraemia in the subjects examined, and to develop a spatial model predicting the prevalence of the Loa microfilaraemia.

Methods

Epidemiological data were collected from 14,225 individuals living in 94 villages in Cameroon, and analysed in conjunction with environmental data. A series of logistic regression models (multivariate analysis) was developed to describe variation in the prevalence of Loa loa microfilaraemia using individual level co-variates (age, sex, μl of blood taken for examination) and village level environmental co-variates (including altitude and satellite-derived vegetation indices).

Results

A spatial model of Loa loa prevalence was created within a geographical information system. The model was then validated using an independent data set on Loa loa distribution. When considering both data sets as a whole, and a prevalence threshold of 20%, the sensitivity and the specificity of the model were 81.7 and 69.4%, respectively.

Conclusions

The model developed has proven very useful in defining the areas at risk of post-ivermectin Loa-related severe adverse events. It is now routinely used by APOC when projects of community-directed treatment with ivermectin are examined.
Emerging resistance among bacterial pathogens in the intensive care unit – a European and North American Surveillance study (2000–2002)
Authors: Jones Mark E , Draghi Deborah C , Thornsberry Clyde , Karlowsky James A , Sahm Daniel F , Wenzel Richard P
Published: August 2004

Background

Globally ICUs are encountering emergence and spread of antibiotic-resistant pathogens and for some pathogens there are few therapeutic options available.

Methods

Antibiotic in vitro susceptibility data of predominant ICU pathogens during 2000–2 were analyzed using data from The Surveillance Network (TSN) Databases in Europe (France, Germany and Italy), Canada, and the United States (US).

Results

Oxacillin resistance rates among Staphylococcus aureus isolates ranged from 19.7% to 59.4%. Penicillin resistance rates among Streptococcus pneumoniae varied from 2.0% in Germany to as high as 20.2% in the US; however, ceftriaxone resistance rates were comparably lower, ranging from 0% in Germany to 3.4% in Italy. Vancomycin resistance rates among Enterococcus faecalis were ≤ 4.5%; however, among Enterococcus faecium vancomycin resistance rates were more frequent ranging from 0.8% in France to 76.3% in the United States. Putative rates of extended-spectrum β-lactamase (ESBL) production among Enterobacteriaceae were low, <6% among Escherichia coli in the five countries studied. Ceftriaxone resistance rates were generally lower than or similar to piperacillin-tazobactam for most of the Enterobacteriaceae species examined. Fluoroquinolone resistance rates were generally higher for E. coli (6.5% – 13.9%), Proteus mirabilis (0–34.7%), and Morganella morganii (1.6–20.7%) than other Enterobacteriaceae spp (1.5–21.3%). P. aeruginosa demonstrated marked variation in β-lactam resistance rates among countries. Imipenem was the most active compound tested against Acinetobacter spp., based on resistance rates.

Conclusion

There was a wide distribution in resistance patterns among the five countries. Compared with other countries, Italy showed the highest resistance rates to all the organisms with the exception of Enterococcus spp., which were highest in the US. This data highlights the differences in resistance encountered in intensive care units in Europe and North America and the need to determine current local resistance patterns by which to guide empiric antimicrobial therapy for intensive care infections.
Stress echocardiography in heart failure
Authors: Agricola Eustachio , Oppizzi Michele , Pisani Matteo , Margonato Alberto
Published: August 2004

Echocardiography has the ability to noninvasively explore hemodynamic variables during pharmacologic or exercise stress test in patients with heart failure. In this review, we detail some important potential applications of stress echocardiography in patients with heart failure. In patients with coronary artery disease and chronic LV dysfunction, dobutamine stress echocardiography is able to distinguish between viable and fibrotic tissue to make adequate clinical decisions. Exercise testing, in combination with echocardiographic monitoring, is a method of obtaining accurate information in the assessment of functional capacity and prognosis. Functional mitral regurgitation is a common finding in patients with dilated and ischaemic cardiomyopathy and stress echocardiography in the form of exercise or pharmacologic protocols can be useful to evaluate the behaviour of mitral regurgitation. It is clinical useful to search the presence of contractile reserve in non ischemic dilated cardiomyopathy such as to screen or monitor the presence of latent myocardial dysfunction in patients who had exposure to cardiotoxic agents. Moreover, in patients with suspected diastolic heart failure and normal systolic function, exercise echocardiography could be able to demonstrate the existence of such dysfunction and determine that it is sufficient to limit exercise tolerance. Finally, in the aortic stenosis dobutamine echocardiography can distinguish severe from non-severe stenosis in patients with low transvalvular gradients and depressed left ventricular function.
A randomised controlled trial to measure the effect of chest pain unit care upon anxiety, depression, and health-related quality of life [ISRCTN85078221]
Authors: Goodacre Steve , Nicholl Jon
Published: August 2004

Background

The chest pain unit (CPU) has been developed to provide a rapid and accurate diagnostic assessment for patients attending hospital with acute, undifferentiated chest pain. We aimed to measure the effect of CPU assessment upon psychological symptoms and health-related quality of life.

Methods

We undertook a single-centre, cluster-randomised controlled trial. Days (N = 442) were randomised in equal numbers to CPU or routine care. Patients with acute chest pain, undiagnosed by clinical assessment, ECG and chest radiograph, were recruited and followed up with self-completed questionnaires (SF-36 and HADS) at two days and one month after hospital attendance.

Results

Patients receiving CPU assessment had significantly higher scores on the physical functioning (difference 5.1 points; 95% CI 1.1 to 9.0), vitality (4.6; 1.3 to 8.0), and general health (5.7; 2.3 to 9.2) dimensions of the SF-36 at two days, and significantly higher scores on all except the emotional role dimension at one month. They also had significantly lower depression scores on the HADS depression scale at two days (0.93; 0.34 to 1.51) and one month (1.0; 0.36 to 1.66). However, initially lower anxiety scores at two days (0.89; 0.21 to 1.56) were not maintained at one month (0.48; -0.26 to 1.23). CPU assessment was associated with reduced prevalence (OR 0.71; 95% CI 0.52 to 0.97) and severity (6.5 mm on 100 m visual analogue scale; 95% CI 2.2 to 10.8) of chest pain at one month, but no significant difference in the proportion of patients taking time off work (OR 0.82; 95% CI 0.54 to 1.04).

Conclusion

CPU assessment is associated with improvements in nearly all dimensions of quality of life and with reduced symptoms of depression.
Evaluation of in vivo labelled dendritic cell migration in cancer patients
Authors: Ridolfi Ruggero , Riccobon Angela , Galassi Riccardo , Giorgetti Gianluigi , Petrini Massimiliano , Fiammenghi Laura , Stefanelli Monica , Ridolfi Laura , Moretti Andrea , Migliori Giuseppe , Fiorentini Giuseppe
Published: August 2004

Background

Dendritic Cell (DC) vaccination is a very promising therapeutic strategy in cancer patients. The immunizing ability of DC is critically influenced by their migration activity to lymphatic tissues, where they have the task of priming naïve T-cells. In the present study in vivo DC migration was investigated within the context of a clinical trial of antitumor vaccination. In particular, we compared the migration activity of mature Dendritic Cells (mDC) with that of immature Dendritic Cells (iDC) and also assessed intradermal versus subcutaneous administration.

Methods

DC were labelled with 99mTc-HMPAO or 111In-Oxine, and the presence of labelled DC in regional lymph nodes was evaluated at pre-set times up to a maximum of 72 h after inoculation. Determinations were carried out in 8 patients (7 melanoma and 1 renal cell carcinoma).

Results

It was verified that intradermal administration resulted in about a threefold higher migration to lymph nodes than subcutaneous administration, while mDC showed, on average, a six-to eightfold higher migration than iDC. The first DC were detected in lymph nodes 20–60 min after inoculation and the maximum concentration was reached after 48–72 h.

Conclusions

These data obtained in vivo provide preliminary basic information on DC with respect to their antitumor immunization activity. Further research is needed to optimize the therapeutic potential of vaccination with DC.
Specific TATAA and bZIP requirements suggest that HTLV-I Tax has transcriptional activity subsequent to the assembly of an initiation complex
Authors: Ching Yick-Pang , Chun Abel CS , Chin King-Tung , Zhang Zhi-Qing , Jeang Kuan-Teh , Jin Dong-Yan
Published: August 2004

Background

Human T-cell leukemia virus type I (HTLV-I) Tax protein is a transcriptional regulator of viral and cellular genes. In this study we have examined in detail the determinants for Tax-mediated transcriptional activation.

Results

Whereas previously the LTR enhancer elements were thought to be the sole Tax-targets, herein, we find that the core HTLV-I TATAA motif also provides specific responsiveness not seen with either the SV40 or the E1b TATAA boxes. When enhancer elements which can mediate Tax-responsiveness were compared, the authentic HTLV-I 21-bp repeats were found to be the most effective. Related bZIP factors such as CREB, ATF4, c-Jun and LZIP are often thought to recognize the 21-bp repeats equivalently. However, amongst bZIP factors, we found that CREB, by far, is preferred by Tax for activation. When LTR transcription was reconstituted by substituting either κB or serum response elements in place of the 21-bp repeats, Tax activated these surrogate motifs using surfaces which are different from that utilized for CREB interaction. Finally, we employed artificial recruitment of TATA-binding protein to the HTLV-I promoter in "bypass" experiments to show for the first time that Tax has transcriptional activity subsequent to the assembly of an initiation complex at the promoter.

Conclusions

Optimal activation of the HTLV-I LTR by Tax specifically requires the core HTLV-I TATAA promoter, CREB and the 21-bp repeats. In addition, we also provide the first evidence for transcriptional activity of Tax after the recruitment of TATA-binding protein to the promoter.
The expanding role of Tax in transcription
Authors: de la Fuente Cynthia , Kashanchi Fatah
Published: August 2004

The viral transactivator of HTLV-I, Tax, has long been shown to target the earliest steps of transcription by forming quaternary complexes with sequence specific transcription factors and histone-modifying enzymes in the LTR of HTLV-I. However, a new study suggests that Tax preferentially transactivates the 21-bp repeats through CREB1 and not other bZIP proteins. The additional transactivation of Tax-responsive promoters subsequent to initiation is also presented. This result highlights a potentially novel role of Tax following TBP recruitment (i.e. initiation) and may expand the mechanism of Tax transactivation in promoter clearance and transcriptional elongation.
Research Fundamentals: Follow‐up of Subjects in Clinical Trials: Addressing Subject Attrition
Authors: Woolard Robert H. , Carty Kathleen , Wirtz Philip , Longabaugh Richard , Nirenberg Ted D. , Minugh P. Allison , Becker Bruce , Clifford Patrick R.
Published: August 2004

Many published clinical trials have less than adequate follow‐up. When conducting a clinical trial, researchers attempt to minimize data loss; however, some data may not be collected, particularly when subjects are lost to follow‐up. Careful planning of research protocols, including comprehensive initial data collection, identification of locators, flexible scheduling, systematic subject tracking, monitoring subject loss, and systematically approaching problem cases can ensure high follow‐up rates. This article presents a compendium of techniques and procedures that researchers can use to enhance follow‐up and address attrition in their studies. Finally, this article outlines statistical techniques that can be used to address the effects of missing data, particularly when patients are lost to follow‐up.
Emergency Department Orientation Utilizing Web‐based Streaming Video
Authors: Mahadevan Swaminatha V. , Gisondi Michael A. , Sovndal Shannon S. , Gilbert Gregory H.
Published: August 2004

To assure a smooth transition to their new work environment, rotating students and housestaff require detailed orientations to the physical layout and operations of the emergency department. Although such orientations are useful for new staff members, they represent a significant time commitment for the faculty members charged with this task. To address this issue, the authors developed a series of short instructional videos that provide a comprehensive and consistent method of emergency department orientation. The videos are viewed through Web‐based streaming technology that allows learners to complete the orientation process from any computer with Internet access before their first shift. This report describes the stepwise process used to produce these videos and discusses the potential benefits of converting to an Internet‐based orientation system.
Comparison of Responses to a $2 Bill versus a Chance to Win $250 in a Mail Survey of Emergency Physicians
Authors: Tamayo‐Sarver Joshua H. , Baker David W.
Published: August 2004

Objectives: To evaluate whether small monetary incentives improve physicians' responses to surveys. To the best of the authors' knowledge, no one has evaluated emergency physicians' response rate and cost per participant of a small monetary incentive relative to a chance to win a more substantial sum. The authors compared emergency physicians' responses and per‐participant costs between a $2 bill and a $250 lottery. Methods:Two groups of 288 emergency physicians were randomly selected and mailed a survey. Within each group of 288, half received a $2 bill and the other half received an offer that respondents would be entered into a drawing to win $250. Nonresponders received a reminder postcard one week later, and persistent nonresponders received a second mailing of the survey three weeks after the initial mailing. Results: Of the 576 surveys that were mailed, nine (2%) subjects were ineligible or undeliverable, leaving 567 eligible subjects, of whom 301 (53%) participated in the survey. The $2 bill had a substantially higher response rate: 170 (56%) of those receiving a $2 bill participated versus 131 (44%) of those receiving a chance to win $250 (95% confidence interval = 5% to 22%; p < 0.001). The $2 bill offer was less expensive per participant than the $250 offer. The cost of postage and incentives was $997.33 for 170 participants, or $5.87 per participant, for the $2 bill and $979.29 for 131 participants, or $7.48 per participant, for the chance to win $250. Conclusions: Mailing a $2 bill incentive produces a better response rate with lower cost per participant than offering a chance to win $250.
Basic Cardiac Life Support Providers Checking the Carotid Pulse: Performance, Degree of Conviction, and Influencing Factors
Authors: Lapostolle Frederic , Le Toumelin Philippe , Agostinucci Jean Marc , Catineau Jean , Adnet Frederic
Published: August 2004

The American Heart Association recently abolished the carotid pulse check during cardiopulmonary resuscitation for lay rescuers, but not for health care providers. Objectives: The aim of the study was to evaluate health care providers' performance, degree of conviction, and influencing factors in checking the carotid pulse. Methods:Sixty‐four health care providers were asked to check the carotid pulse for 10 or 30 seconds on a computerized mannequin simulating three levels of pulse strength (normal, weak, and absent). Health care providers were asked whether they felt a pulse and how certain were they that they felt a pulse. Performance was evaluated, as well as degree of conviction about the answer, using a visual analog scale. Data were compared by using a general linear model procedure. Results: In the pulseless situations, the answers were correct in 58% and 50% when checking the pulse for 10 and 30 seconds, respectively. In the situation with a weak pulse, the answer was correct in 83% when checking the pulse for 10 seconds. In situations with a normal pulse, the answers were correct in 92%, 84%, and 84%, respectively, when checking the pulse for 10 (twice) and 30 seconds. The exactitude of the answer was correlated with the pulse strength (p < 0.05). The degree of conviction about the answer was correlated with the exactitude of the answer (p < 0.01) and the pulse strength (p < 0.0001). Conclusions: These results question the routine use of the carotid pulse check during cardiopulmonary resuscitation, including for health care providers.
Effects of 4‐Methylpyrazole on Ethanol Neurobehavioral Toxicity in CD‐1 Mice
Authors: Páez Ana Maria , Shannon Michael , Maher Timothy , Quang Lawrence
Published: August 2004

Objectives: 4‐Methylpyrazole (4‐MP), an alcohol dehydrogenase (ADH) antagonist, is used for the treatment of ethylene glycol and methanol ingestions. However, ethanol is frequently coingested by those who ingest these more toxic alcohols. Several in vitro and in vivo studies have shown a decrease in the elimination rate of ethanol after the administration of 4‐MP, but none has evaluated the effects of 4‐MP administration on the neurobehavioral toxicity of ethanol. This was a study to determine whether ADH blockade with 4‐MP prolongs ethanol neurobehavioral toxicity in a murine model. Methods:CD‐1 mice were pretreated with 4‐MP, with observation of its effect on ethanol dose–response curves. 4‐MP (25 mg/kg) or an equal volume of saline was administered intraperitoneally. Ten minutes later, incremental ethanol doses of 1–5 g/kg were administered intraperitoneally. Pretreated and control groups were composed of ten mice each for each dose of ethanol tested. Outcomes for assessing ethanol neurobehavioral toxicity were successful performance on the rotarod test and presence of the righting reflex, two established and validated outcome measures for ethanol‐induced neurobehavioral toxicity in mice. Results: The dose of ethanol at which 50% of the animals failed a particular outcome test (toxic dose 50 [TD50]) was decreased with 4‐MP administration for both the rotarod test and the righting reflex. The TD50 intergroup differences (control vs. 4‐MP) were statistically significant at 60, 120, and 180 minutes (p < 0.05). Conclusions: Pretreatment with 4‐MP significantly prolonged ethanol neurobehavioral toxicity in CD‐1 mice, presumably by inhibiting its metabolism by ADH. Further investigation is warranted to evaluate this interaction.
Initial Emergency Department Trauma Scores from the OPALS Study: The Case for the Motor Score in Blunt Trauma
Authors: Al‐Salamah Majid A. , McDowell Ian , Stiell Ian G. , Wells George A. , Perry Jeff , Al‐Sultan Mohammed , Nesbitt Lisa ,   for the OPALS Study Group
Published: August 2004

Objectives: To compare the predictive accuracy of the Revised Trauma Score (RTS), the Glasgow Coma Scale (GCS), and their components in blunt trauma patients. Methods:This multicenter prospective cohort study was conducted in 20 communities as part of the Ontario Prehospital Advanced Life Support (OPALS) Study. It included adult trauma patients with Injury Severity Scores >12. The assessments made by trauma team leaders for the RTS, GCS, and their subscales were analyzed: 1) receiver operating characteristic (ROC) curve areas and Kendall's tau c correlation coefficient (Tc) for survival to hospital discharge, 2) Mann‐Whitney U test and Tc correlations for intensive care unit admission, and 3) Spearman correlations with the disability measure Glasgow Outcome Scale. Results: The authors analyzed data from 795 blunt trauma patients with these characteristics: median age of 40 years, 70% male, and 18% mortality. The scores that best predicted survival were the RTS (ROC = 0.83, Tc = 0.39), the GCS (ROC = 0.82, Tc = 0.38), the motor component of the GCS (ROC = 0.81, Tc = 0.37), and the verbal component of the GCS (ROC = 0.81, Tc = 0.36). Only scores for the RTS (p = 0.03), the GCS (p = 0.02), and the motor component of the GCS (p = 0.03) showed a significant association with admission to the intensive care unit. The associations with disability were weak in all scores. Conclusions: The initial emergency department motor score showed the highest predictive validity among all of the other components. These results suggest its validity for blunt trauma triage when compared with the GCS or RTS.
Individual Patient Data–Based Meta-Analysis of Patients Aged 16 to 60 Years With Core Binding Factor Acute Myeloid Leukemia: A Survey of the German Acute Myeloid Leukemia Intergroup
Authors: Schlenk R.F. , Benner A. , Krauter J. , Büchner T. , Sauerland C. , Ehninger G. , Schaich M. , Mohr B. , Niederwieser D. , Krahl R. , Pasold R. , Döhner K. , Ganser A. , Döhner H. , Heil G.
Published: August 2004

Purpose

To evaluate prognostic factors for relapse-free survival (RFS) and overall survival (OS) and to assess the impact of different postremission therapies in adult patients with core binding factor (CBF) acute myeloid leukemias (AML).

Patients and Methods

Individual patient data–based meta-analysis was performed on 392 adults (median age, 42 years; range, 16 to 60 years) with CBF AML (t(8;21), n = 191; inv(16), n = 201) treated between 1993 and 2002 in prospective German AML treatment trials.

Results

RFS was 60% and 58% and OS was 65% and 74% in the t(8;21) and inv(16) groups after 3 years, respectively. For postremission therapy, intention-to-treat analysis revealed no difference between intensive chemotherapy and autologous transplantation in the t(8;21) group and between chemotherapy, autologous, and allogeneic transplantation in the inv(16) group. In the t(8;21) group, significant prognostic variables for longer RFS and OS were lower WBC and higher platelet counts; loss of the Y chromosome in male patients was prognostic for shorter OS. In the inv(16) group, trisomy 22 was a significant prognostic variable for longer RFS. For patients who experienced relapse, second complete remission rate was significantly lower in patients with t(8;21), resulting in a significantly inferior survival duration after relapse compared with patients with inv(16).

Conclusion

We provide novel prognostic factors for CBF AML and show that patients with t(8;21) who experience relapse have an inferior survival duration.
Prognostic Factors of Thin Cutaneous Melanoma: An Analysis of the Central Malignant Melanoma Registry of the German Dermatological Society
Authors: Leiter Ulrike , Buettner Petra G. , Eigentler Thomas K. , Garbe Claus
Published: August 2004

Purpose

The increasing number of thin cutaneous melanomas (CM) with tumor thickness up to 1 mm demands a detailed analysis of prognostic factors for the classification and grading of these tumors. The aim of the present study was to identify prognostic factors in thin CM.

Patients and Methods

A series of 12,728 patients with thin incident primary invasive CM and follow-up data recorded between 1976 and 2000 by the German-based Central Malignant Melanoma Registry was analyzed using the multivariate Cox proportional hazard model to evaluate prognostic factors, and classification and regression trees analysis (CART) to define prognostic groups.

Results

Multivariate analysis found tumor thickness, sex, age, body site, and histopathologic subtype to be significant prognostic factors of thin CM. Ulceration and regression did not affect prognosis significantly. Prognostic classification based on the results of CART analysis resulted in three groups defined by tumor thickness, age, and sex. Ten-year survival rates of these groups varied between 91.8% and 98.1%, with improved classification as compared with subgroups by tumor thickness alone.

Conclusion

Classification by tumor thickness identified prognostic subgroups with highest significance in thin CM, and the classification was improved by the introduction of age and sex. However, neither ulceration nor the level of invasion included in the new American Joint Committee on Cancer TNM system classification, revealed statistical significance as prognostic factors in thin CM.
Chemotherapy Sensitivity and Resistance Assays: A Systematic Review
Authors: Samson David J. , Seidenfeld Jerome , Ziegler Kathleen , Aronson Naomi
Published: August 2004

Purpose

This systematic review evaluates evidence comparing therapy guided by chemotherapy sensitivity and resistance assays with empiric chemotherapy, emphasizing survival outcomes.

Methods

Prospective studies were sought comparing patients treated contemporaneously by assay-guided chemotherapy and empiric therapy. An initial MEDLINE search and a search performed by a Working Group of the American Society of Clinical Oncology were reviewed with attention to prespecified study selection criteria.

Results

This review identified 10 studies meeting selection criteria, plus one retrospective study, using seven different assays. Only two studies randomly assigned patients to assay-guided treatment or empiric treatment. Five of nine nonrandomized studies found significantly higher response rates for patients who received assay-guided therapy compared with those treated empirically. One of the two randomized trials found a significantly higher response rate in the assay-guided group. Four additional studies found response rates favoring assay-guided therapy, but comparisons did not achieve statistical significance. Two nonrandomized studies found overall survival to be significantly improved with assay-guided therapy. One randomized study used a cross-over design that made it difficult to determine whether survival differed between groups, while the other randomized trial found no difference in survival. Six studies provided no comparison of groups on baseline patient characteristics. Only one study reported adverse events data.

Conclusion

While higher response rates for assay-guided therapy have been observed, differences may be attributable to bias or confounding. Little evidence on survival is available. These results do not establish the relative effectiveness of assay-guided treatment and empiric treatment. Randomized trials are needed.
American Society of Clinical Oncology Technology Assessment: Chemotherapy Sensitivity and Resistance Assays
Authors: Schrag Deborah , Garewal Harinder S. , Burstein Harold J. , Samson David J. , Von Hoff Daniel D. , Somerfield Mark R.
Published: August 2004

Purpose

To develop a technology assessment of chemotherapy sensitivity and resistance assays in order to define the role of these tests in routine oncology practice.

Methods

The American Society of Clinical Oncology (ASCO) established a Working Group to develop the technology assessment. The Working Group collaborated with the Blue Cross and Blue Shield Association (BCBSA) Technology Evaluation Center. The Working Group developed independent criteria for selecting articles for inclusion in the ASCO assessment, and developed a structured data abstraction tool to facilitate review of selected manuscripts. One Working Group member and an ASCO staff member independently reviewed the 1,139 abstracts identified by the BCBSA comprehensive literature search, and by an updated literature search performed by ASCO using the BCBSA search strategy (1966 to January 2004). Of the 12 articles included in this technology assessment, eight were identified by the original BCBSA systematic review, one was provided by industry, and three were identified by the ASCO updated literature review.

Results

Review of the literature does not identify any CSRAs for which the evidence base is sufficient to support use in oncology practice.

Recommendations

The use of chemotherapy sensitivity and resistance assays to select chemotherapeutic agents for individual patients is not recommended outside of the clinical trial setting. Oncologists should make chemotherapy treatment recommendations on the basis of published reports of clinical trials and a patient's health status and treatment preferences. Because the in vitro analytic strategy has potential importance, participation in clinical trials evaluating these technologies remains a priority.
Compliance With Consensus Recommendations for Systemic Therapy Is Associated With Improved Survival of Women With Node-Negative Breast Cancer
Authors: Hébert-Croteau Nicole , Brisson Jacques , Latreille Jean , Rivard Michèle , Abdelaziz Nadia , Martin Ginette
Published: August 2004

Purpose

The impact of consensus recommendations for systemic therapy on outcome of disease is unclear. We evaluated if compliance with guidelines for systemic adjuvant treatment is associated with improved survival of women with node-negative breast cancer.

Patients and Methods

The study population included women diagnosed with invasive node-negative breast cancer in Québec, Canada, in 1988 to 1989, 1991 to 1992, and 1993 to 1994. Information was collected by chart review, linkage with administrative databases, and queries to attending physicians. Guidelines from the 1992 St Gallen conference were used as standard of care. Survival was estimated by Kaplan-Meier and Cox proportional hazards analyses.

Results

Among 1,541 women, 358 died before December 1999. Median follow-up was 6.8 years. Seven-year event-free and overall survivals were 66% and 81%, respectively. Survival was 88%, 84%, and 74% in women at minimal, moderate, or high risk of recurrence. Virtually all women at minimal risk were treated according to the consensus (98.4% of 370). In comparison, adjusted hazard ratios of death were 1.0 (95% CI, 0.6 to 1.7) and 2.3 (95% CI, 1.3 to 4.0) among women at moderate risk treated according to the consensus or not, respectively. Among women at high risk, adjusted hazard ratios of death were 2.0 (95% CI, 1.4 to 2.8) and 2.7 (95% CI, 1.9 to 3.9), respectively. Both risk category (P < .0005) and compliance with guidelines (P < .0005) were independent significant predictors of survival.

Conclusion

Treatment according to consensus recommendations is associated with improved survival of women with breast cancer in the community. Promoting the adoption of guidelines for treatment is an effective strategy for disease control.
Prospective, Multicenter, Randomized Phase II Trial of the Herbal Supplement, PC-SPES, and Diethylstilbestrol in Patients With Androgen-Independent Prostate Cancer
Authors: Oh William K. , Kantoff Philip W. , Weinberg Vivian , Jones Graham , Rini Brian I. , Derynck Mika K. , Bok Robert , Smith Matthew R. , Bubley Glenn J. , Rosen Robert T. , DiPaola Robert S. , Small Eric J.
Published: August 2004

Purpose

To evaluate the herbal combination, PC-SPES, and diethylstilbestrol (DES) in patients with androgen independent prostate cancer (AIPC).

Patients and Methods

A randomized phase II study was conducted with cross-over design. Patients were randomly assigned to receive either three PC-SPES capsules orally three times a day or DES 3 mg orally once a day. Prophylactic warfarin was administered. At clinical or prostate-specific antigen progression, patients received the other therapy. The study closed prematurely after PC-SPES was withdrawn from the market. Chemical analyses were performed on multiple lots of PC-SPES.

Results

Ninety patients were enrolled, of whom 85 were assessable for response. Prostate-specific antigen declines ≥ 50% were noted in 40% (95% CI, 25% to 56%) with PC-SPES, and 24% (95% CI, 12% to 39%) with DES. Median response duration was not reached with PC-SPES, and was 3.8 months with DES. Median time to progression for randomly assigned patients was 5.5 months for PC-SPES and 2.9 months for DES. Common toxicities included mild fatigue, gynecomastia, and mastodynia. Five thromboembolic events occurred (one PC-SPES, four DES). Responses in the cross-over phase were inconclusive. Four lots of PC-SPES had measurable quantities of DES, ranging from 0.01% to 3.1% of the dose used in the DES arm. Ethinyl estradiol was also detected in PC-SPES lots.

Conclusion

PC-SPES and DES demonstrate activity in AIPC and are well tolerated. However, the synthetic estrogens, DES and ethinyl estradiol, were detected in various lots of PC-SPES, including those used in this trial. Clinical trials that utilize herbal therapies must account for issues of purity and consistency.
Thin Primary Cutaneous Malignant Melanoma: A Prognostic Tree for 10-Year Metastasis Is More Accurate Than American Joint Committee on Cancer Staging
Authors: Gimotty Phyllis A. , Guerry DuPont , Ming Michael E. , Elenitsas Rosalie , Xu Xiaowei , Czerniecki Brian , Spitz Francis , Schuchter Lynn , Elder David
Published: August 2004

Purpose

The majority of invasive primary melanomas are thin (≤ 1.00 mm). Since the current staging system imperfectly predicts outcome in patients with such lesions, we sought to develop a more effective classification scheme to better identify both patients at high risk of metastasis who are candidates for further staging and therapy and those with little risk.

Patients and Methods

This prospective cohort study included 884 patients who had thin invasive melanomas. A tree-structured analysis of 10-year metastasis was used to develop a new classification scheme.

Results

The overall 10-year metastasis rate was 6.5% (95% CI, 4.8% to 8.1%). The prognostic tree defined four risk groups: high-risk: men with vertical growth phase (VGP) lesions that had mitotic rates (MRs) greater than 0, and for whom the 10-year metastasis rate was 31% (22% to 42%; n = 90); moderate-risk: women with VGP lesions that had MRs greater than 0 and for whom the rate was 13% (9% to 18%; n = 136); low-risk: patients with VGP lesions that had MR of 0 for whom the rate was 4% (2% to 7%; n = 247); and minimal-risk: patients with invasive lesions without VGP for whom the rate was 0.5% (0% to 1.2%; n = 411). Survival curves differed significantly among the four groups (P < .001).

Conclusion

Growth phase, mitotic rate, and sex are important prognostic factors for patients with thin melanomas, and they identify subgroups at substantial risk for metastasis. After validation in other populations, the proposed prognostic tree will be useful in the design of clinical trials and clinical management.
Localization of Osteoprotegerin, Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand, and Receptor Activator of Nuclear Factor-κB Ligand in Mönckeberg’s Sclerosis and Atherosclerosis
Authors: Schoppet Michael , Al-Fakhri Nadia , Franke Folker E. , Katz Norbert , Barth Peter J. , Maisch Bernhard , Preissner Klaus T. , Hofbauer Lorenz C.
Published: August 2004

Vascular calcification may occur at different areas of the vessel wall, including the intima in atherosclerosis and the media in Mönckeberg’s sclerosis. Medial calcification of arteries is common in patients with diabetes mellitus or chronic renal failure. Osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand are essential modulators of bone homeostasis and may be involved in the process of vascular calcification. In this study we investigated arteries from patients with Mönckeberg’s sclerosis and atherosclerosis. Apoptosis, which precedes vascular calcification in vitro, was assessed by an in situ ligation assay and was localized to the medial layer of arteries (Mönckeberg’s sclerosis) and the neointima (atherosclerosis). Immunohistochemistry and in situ hybridization revealed OPG immunoreactivity and mRNA expression surrounding calcified areas in the medial layer (Mönckeberg’s sclerosis), whereas OPG was mainly expressed adjacent to calcified neointimal lesions (atherosclerosis). Receptor activator of nuclear factor-κB ligand protein and mRNA were barely or not detectable. Of note, TNF-related apoptosis-inducing ligand, an inducer of apoptosis that is also blocked by OPG, displayed a similar spatial distribution as OPG. In summary, we demonstrate enhanced apoptosis adjacent to vascular calcification, and the concurrent expression of regulators of apoptosis and osteoclastic differentiation, TNF-related apoptosis-inducing ligand and OPG, suggesting their involvement in the pathogenesis of vascular calcification.
Ovarian Age-Related Responsiveness to Human Chorionic Gonadotropin in Women with Polycystic Ovary Syndrome
Authors: Piltonen Terhi , Koivunen Riitta , Perheentupa Antti , Morin-Papunen Laure , Ruokonen Aimo , Tapanainen Juha S.
Published: August 2004

Ovarian steroid secretion capacity starts to decline as early as around the age of 30 yr. Whether an age-related decrease in androgen secretion, as in normal women, also occurs in women with polycystic ovary syndrome (PCOS) and whether the enhanced androgen production in PCOS remains throughout the fertile period of life are not known. The aim of this study was to determine the age-related serum basal and gonadotropin-stimulated androgen levels in women with PCOS and to compare the results with those obtained from our previous study in healthy women with normal ovaries. Human chorionic gonadotropin (hCG) stimulation tests were carried out among 42 women with PCOS (age, 16–44 yr; body mass index, 31.02 ± 1.1 kg/m2). An im injection of 5000 IU hCG was given 2–4 d after spontaneous or progestin-induced menstrual bleeding, and blood samples for LH, FSH, inhibin B, 17-hydroxyprogesterone, androstenedione (A), testosterone (T), and estradiol assays were collected at 0, 24, 48, and 96 h. In women with PCOS, basal serum T and A levels were about 50% higher than in healthy women. The responses of A and T to hCG [area under the curve (AUC), 96 h)] were significantly higher in women with PCOS than in normal women [A, 1183.6 ± 60 (±se) vs. 814.4 ± 39 (P ≤ 0.001); T, 192.9 ± 12 vs. 117.4 ± 6; P ≤ 0.001]. In PCOS women, the hCG-stimulated A levels correlated negatively with age (AUC of A: r = −0.044; P = 0.004), and a similar trend was also observed in AUC T levels (AUC of T: r = −0.125, P = 0.425). Despite the higher androgen secretion capacity in PCOS, the basal and hCG-stimulated serum estradiol levels were similar to those observed in normal women. LH correlated positively with age, but basal FSH and inhibin B levels remained unchanged. In conclusion, in PCOS basal serum levels of androgens and ovarian androgen secretion capacity are markedly increased and remain high throughout the reproductive years, although the decreasing ovarian capacity to release androgens in response to hCG stimulation seen in healthy women also occurs in PCOS.
Presence of Luteinizing Hormone/Human Chorionic Gonadotropin Receptors in Male Breast Tissues
Authors: Carlson Harold E. , Kane Philip , Lei Z. M. , Li X. , Rao C. V.
Published: August 2004

Receptors for LH/human chorionic gonadotropin (hCG) have been found in a variety of nongonadal tissues including the female breast. Using in situ hybridization and immunohistochemistry, we demonstrated the presence of LH/hCG receptor mRNA and protein in normal male breast tissue obtained at autopsy (n = 4) and archival samples of benign gynecomastia (n = 14) and male breast carcinoma (n = 5). Although the function of these receptors remains to be determined, the findings suggest the possibility that LH and hCG may play a role in the pathogenesis of male breast disorders.
Human Endocrine Gland-Derived Vascular Endothelial Growth Factor: Expression Early in Development and in Leydig Cell Tumors Suggests Roles in Normal and Pathological Testis Angiogenesis
Authors: Samson Michel , Peale Franklin V. , Frantz Gretchen , Rioux-Leclercq Nathalie , Rajpert-De Meyts Ewa , Ferrara Napoleone
Published: August 2004

Angiogenesis is essential for tumor growth and metastasis. A new human angiogenic mitogen, endocrine gland-derived vascular endothelial growth factor (EG-VEGF), has been recently identified; its expression pattern is restricted to endocrine glands, with the highest expression in testis. We used in situ hybridization and newly generated monoclonal antibodies to investigate the expression of EG-VEGF in normal human prenatal and adult testis and in 48 human testicular tumors of different subtypes. We found that EG-VEGF was expressed from 14 wk until birth in human fetal testis. In the adult testis, EG-VEGF was strongly expressed only in Leydig cells. In testicular tumors, EG-VEGF was expressed specifically in Leydig cell tumors, whereas germ cell-derived neoplasms, including carcinoma in situ, seminoma, and nonseminomatous germ cell tumors, were negative for this antigen. In contrast, VEGF, another powerful angiogenic factor, was expressed in seminoma, but very weakly in Leydig cell tumors. Interestingly, we found that Leydig cell tumors presented vessel surface density 3.2-fold higher than seminoma. These findings argue that human EG-VEGF may play a role in angiogenesis both during the early endocrine development of testis and in the adult testis as well as in Leydig cell tumor growth.