Absence Of Benefit Research Articles

The employment effects of terminating disability benefits

Few social security disability insurance (DI) beneficiaries return to the labor force, making it hard to assess their likely employment in the absence of benefits. Using administrative data, I examine the employment of individuals who lost DI eligibility after the 1996 removal of drug and alcohol addictions as qualifying conditions. Approximately 22% started working at levels that would have disqualified them for DI, an employment response that is large relative to their work histories. Those who received DI for 2–3years had the largest response, suggesting that a period of public assistance may maximize the employment of some disabled individuals.

The Employment Effects of Terminating Disability Benefits

Few Social Security Disability Insurance (DI) beneficiaries return to the labor force, making it hard to assess their likely employment in the absence of benefits. Using administrative data, I examine the employment of individuals who lost DI eligibility after the 1996 removal of drug and alcohol addictions as qualifying conditions. Approximately 22 percent started working at levels that would have disqualified them for DI, an employment response that is large relative to their work histories. Those who received DI for 2-3 years had the largest response, suggesting that a period of public assistance may maximize the employment of some disabled individuals.

Should risk from medical imaging be assessed in the absence of benefit and vice versa?

Diagnostic radiology has an image problem. In its effort to develop a better understanding of benefit-risk in medical radiology, data on potential risks associated with medical imaging have been welcomed into the medical community. As such, risk perspectives and mantras from the occupational health profession have been adopted and applied to patients. These perspectives often focus on risk with only casual, incidental, or no reference to the benefits experienced by patients. These occupational health viewpoints have accumulated over decades, have overshadowed a very limited perspective about the benefits of medical X-rays, and have become an integrated part of our profession. This review argues that the medical profession should abandon perspectives on risk that are adopted from occupational health professions and focus on perspectives that realistically focus on the medical benefit-risk for patients.

Managing safety in early phase trials: is there a gold standard?

Early clinical studies are intended to define safety and tolerability of a new investigational medicinal product (IMP). In such studies there is no benefit for the human subject participating and therefore the risk for harm for the subjects should be avoided. Since every change observed in clinical studies may currently be considered as harm, a framework for assessment needs to be defined. However, no definition of harm exists in the context of early clinical studies, so it is unknown what exactly we are preventing. If modest use of alcohol is considered acceptable, it may be inconsistent that a drug-induced increase in liver enzymes equaling one glass of wine is considered as harm. Equally, in a Phase I study, we may take precautions to prevent harm in the form of an increase in heart rate, which equals an effort comparable to walking up three flights of stairs or ten genuflexions. The human body is able to cope with this level of change as part of daily life, therefore it may be time to start taking this resilience into consideration. We should explore if the body can cope with limited effects of the IMP as well as it does with living. Understanding these processes is likely to improve early clinical safety characterization. Before initiation of any clinical trial, the risks for the subject are balanced against the (potential) gains, such as improvements in the disease: the so-called risk–benefit assessment. Over many years a common practice has developed which allows the risk–benefit to be acceptable in the absence of benefit. There is not a gold standard for identifying and managing risk in early clinical trials, but there is a well-practiced sequence of steps which leads to adequate risk assessment and risk minimization for the subjects. This best practice is a forward-looking approach and starts with the interpretation of the results of nonclinical studies and knowledge with respect to the mode of action (MoA). A risk assessment does not only takes the study results into consideration but also has to take the weight of evidence into account. Although the sequence of steps involved in the risk assessment are the same for each IMP, the outcomes and the minimization measures may differ significantly.

Identification of VKORC1 genotype leading to resistance to tecarfarin.

The VKORC1 gene codes for the VKORC1 enzyme that is responsible for the reduction of vitamin K epoxide into vitamin K. VKORC1 enzyme is the target of vitamin K antagonists (VKA). The use of VKA in human medicine is difficult because of inter-individual variability in VKA requirements. This variability is partly due to basic physiological parameters but also to genetic polymorphisms in CYP2C9 involved in VKA metabolism. Tecarfarin, a new VKA, was developed to avoid the CYP2C9-dependent metabolism. This molecule is metabolized by carboxylesterases. Nevertheless, genetic variations in the VKORC1 gene are also associated with inter-individual variability in VKA requirements. This study was performed to estimate the benefit of using tecarfarin versus traditional VKA in human patient carrier for hVKORC1 mutation. Wild type hVKORC1 and its spontaneous mutants were expressed in Pichia pastoris and susceptibility to tecarfarin was assessed by the in vitro determination of inhibition constants. Among the 14 mutated VKORC1 proteins analyzed in this study, 6 mutations (i.e., A26P, A41S, V54L, H68Y, I123N, and Y139H) led to resistant to traditional VKAs, while only 4 mutations (i.e., A26P, V54L, I123N, and Y139H) led to resistant to tecarfarin. Compared to other VKAs, a clear benefit of tecarfarin is observed for the mutants A26P, A41S, H68Y, and I123N and an absence of benefit for the mutant Y139H. Finally, tecarfarin is particularly inefficient on V54L-VKORC1.

BENEFICIAL OUTCOMES AFTER PCV PLUS RT IN OLIGODENDROGLIAL TUMORS ARE ASSOCIATED WITH DETECTION OR RISK OF AN IDH MUTATION

BACKGROUND: Oligodendroglial tumors harbor IDH mutations and risk of this type of cancer is associated with a germ-line polymorphism at 8q. In addition, when these tumors harbor a co-deletion of 1p19q, they can be highly chemo-sensitive. Indeed, patients with anaplastic tumors (i.e., AO/AOA) with 1p19q co-deletion lived nearly twice as long after chemotherapy and radiation (CRT; 14-16 years) as radiotherapy alone (RT; 7-9 years) in two large randomized trials. In RTOG 9402, some patients with non-co-deleted AO/AOA also lived longer after CRT: for these participants, the survival curves separated after the median had been reached, and significantly more lived 10 years or longer after CRT than RT (25% vs. 10%). Since co-deletion status did not identify all patients benefiting from CRT, we asked whether other molecular hallmarks of AO/AOA – IDH or G-allele status – might be more inclusive markers of benefit from CRT. METHODS: We used tissues and data from RTOG 9402 to explore this hypothesis. RESULTS: IDH status was evaluable in 210 of 291 participants: 156 (74%) had a mutation of IDH1/2. The G allele of rs55705857 was evaluable in 245 of 291 participants: 76 (31%) carried the risk-allele in their germ-line. Presence of either an IDH mutation or the G risk-allele was associated with significantly longer progression-free survival after CRT, and an IDH mutation with much longer overall survival [9.4 vs. 5.7 years, hazard ratio (HR) 0.59, 95% confidence interval (CI) (0.40, 0.86), P = 0.006]. For cases in which IDH was intact, CRT did not prolong median survival time [1.3 vs. 1.8 years, HR 1.14, CI (0.63, 2.04), P = 0.67] or 10-year survival rates (CRT 6% vs. RT 4%). As expected, patients with mutated, co-deleted AO/AOA lived longer after CRT than RT (14.7 vs. 6.8 years, HR 0.49, CI (0.28, 0.85), P = 0.01], but so too did those with mutated, non-co-deleted AO/AOA [5.5 vs. 3.3 years, HR 0.56, CI (0.32, 0.99), P < 0.05]. Among the latter, ATRX positive and negative cases had longer overall survival after CRT than RT, but these differences were not significant. CONCLUSIONS: In AO/AOA cases in RTOG 9402, the presence or risk of an IDH mutation was associated with ‘benefit’ from CRT. Wild-type IDH was associated with poor overall and long-term survival, and absence of benefit from CRT. IDH mutation status identified more patients who benefited from CRT than did 1p/19q co-deletion status, but patients with co-deleted AO/AOA lived much longer.

Duration Targeting: No Magic for High-Yield Investors

Over time, the annualized return of a duration-targeting, investment-grade corporate bond portfolio will nearly match its initial yield. A high-yield bond portfolio’s performance is not similarly predictable. Furthermore, the difference between the high-yield universe’s initial yield and annualized return has a sharply negative bias. The absence of benefits from duration targeting has a bearing on valuation of the high-yield asset class and helps explain the instability in its investor base.

Cognitive therapy: at last an alternative to antipsychotics?

Schizophrenia causes substantial disability and premature mortality, and is one of the top causes of disease burden worldwide.1 Antipsychotic drugs revolutionised schizophrenia treatment when introduced in the 1950s, and numerous studies have shown that antipsychotics are effective for acute episodes, and as maintenance treatment, with a number needed to treat of 3 to prevent relapse.2 Evidence has also shown that some drugs could reduce mortality, mainly through a reduction in suicide rates.3 However, the clinical reality is that many patients stop taking antipsychotics for various reasons: side-effects, absence of benefit, disorganisation, and because they do not perceive they have an illness.

Preoperative (preop) chemosensitivity testing as predictor of treatment benefit in adjuvant stage III colon cancer (CC): Interim analysis of the PEPITA study.

385 Background: Adjuvant chemotherapy (CT) improves stage III CC outcome but is not effective for all patients (pts). PePiTA’s main hypothesis is that absence of metabolic response (MR) of the primary tumor after 1 preop CT course predicts absence of benefit from adjuvant CT (at 3-year DFS). This strategy's aim is to spare pts from useless toxicities, improve healthcare resource allocation, and guide translational research. This interim analysis was performed for safety and feasibility of MR assessment (MRA). Methods: Pts ≥ 18 years, with PS ≤ 1, diagnosed with CC considered for curative resection are eligible, after signed consent. Baseline PET is repeated after 1 CT cycle, followed by surgery. PET quality insurance and MRA are performed centrally and the result is blinded for investigators. Results: From 2010 to 2013, 114 pts—M/F (55%/45%), median age 66 (26-81), ECOG 0/1(92%/8%)—were included in 15 Belgian centers. 11 pts were excluded from analysis: 2 hyperglycemia at baseline PET; 2 withdrew consent; 6 PET-revealed stage IV CC; and 1 second cancer. Preop CT was associated with 5% grade (gr) 3-4 neutropenia, 1% gr 3 diarrhea, 1% gr 3 hypokaliemia, 1% peritonitis and 1% gr 3 thromboembolic events. Colectomies were performed in all pts after a median of 20 days (interquartile interval 18-21): 32 right (31%), 69 left (67%), and 2 procedures not detailed. Pathology showed stages 0 (1%), I (13%), II (34%), III (47%), IV (7%), without lymph node downstaging. Postoperative morbidity is 9% (95%CI 5-16%) and includes fistulas (4%), transient ischemic attack (1%), ileus (2%), and evisceration (1%), but no death. Technical or methodological reasons prevented MRA in 19/103 pts. Median SUVmax was 14.4 (4.9-47.8) at baseline, and 10.9 (0-39.3) on day 14. 2 pts presented with complete MR. For the others, median delta SUVmax was -22% (-60 to +31%). MR was observed in 60% of pts, and was absent in 40%, with equal distribution for stages II and III (p = 1.00). Conclusions: 1 course of CT is feasible before curative surgery for CC, without inducing excessive toxicity, delay or surgical morbidity. MRA indicated metabolic signs of chemoresistance in 40% of the primary tumors. Clinical trial information: NCT00994864.

Submassive Pulmonary Embolism: Risk Evaluation and Role of Fibrinolysis

Submassive pulmonary embolism (PE) is characterized by hemodynamic stability with evidence of right ventricular dysfunction or myocardial necrosis, and represents a heterogeneous population at risk for adverse outcomes. Although patients with this subtype of PE are at higher risk of death, it is unclear whether escalation of care with fibrinolytic therapy mitigates this risk. The controversial role of fibrinolytic therapy for submassive PE is driven by a paucity of data, conflicting results from clinical trials, and lack of reliable positive predictive markers of mortality in this population. When compared with anticoagulation therapy alone, systemic fibrinolytic therapy leads to a more rapid improvement in pulmonary artery hemodynamics, restoration of right ventricular function, improved lung perfusion, and fewer episodes of clinical deterioration. The clinical significance of these findings remains uncertain because fibrinolytic therapy has not been demonstrated to improve mortality or reduce recurrent PE in patients with submassive PE. However, it is unclear whether this reflects methodological limitations such as small sample size and rescue fibrinolytic therapy in those assigned placebo, the absence of benefit in all patients with submassive PE, or the benefit is limited to an undefined, high-risk subset. The decision to administer adjunctive fibrinolytics in patients with submassive PE should be made on an individual basis, with serious consideration given to those with severe PE-related clinical manifestations and an acceptable risk of bleeding.

SOCIAL RESPONSIBILITY OF BUSINESS IN GEORGIA: DEVELOPMENT AND PROBLEMS

In the recent period the problems of social responsibility of business and its role in socioeconomic development of the countries are widely discussed all over the world. Currently international conferences, forums and numerous other public events dealing with the issues of social responsibility of businesses are arranged in all parts of the world. Goal of this research is assessment, how far this trend is reflected in business practices of Georgian companies. Currently, in Georgia, all efforts are oriented towards creation of civilized business and favorable business environment. In this situation, it is decisive that the necessary element of these efforts was adoption of ethical principles and social responsibility into the practice of business relations. Article provides discussion of wide circle of issues related to participation of businesses in the programs of corporative social responsibility, trends of development of partnerships between business sector, state and NGOs. In Georgia, many companies are engaged in charity activities; they participate in sponsoring of socially significant projects, they publish social reports. In December 2006, in Georgia, UN Global Compact was launched and with its support the network of socially oriented Georgian companies was created. In many companies the codes of conduct and ethics are adopted. They describe ethical principles and norms providing basis for the activities of all employees of the company – from the specialists to top managers. In result of researches we have identified three key factors limiting SRB development in Georgia: high taxes, absence of benefits and availability of soft loans for the socially responsible organizations; lack of understanding of significance of socially responsible behavior. In Georgia, there is no legislative framework for charity activities. Government’s policies with respect of charity remain unclear. In realization of their charity work, the companies still frequently face significant bureaucratic obstacles. In the end of the article there is mentioned that the state should make its best efforts to stimulate development of SRB in Georgia – tax exemptions, cheap credits for social projects etc. State support to development of social responsibility of business in Georgia, being the important instrument for sustainable development of the companies in long run, would promote activation of social investments of the companies, expansion of the platform of partnership between the state and business and make significant contribution to creation of the new sources of sustainable economic growth and finally, would facilitate achievement of one of the key priorities of Georgia – integration into the European structures and market. DOI: http://dx.doi.org/10.5755/j01.em.18.2.3655

Commentary

Commentary

Mammography May Benefit Some Women Over 75

Mammography May Benefit Some Women Over 75

Response from Drs Hoffman and Cooper to Stroke thrombolysis: Leaving the past, understanding the present and moving forward …

We were pleased to read the letter by Bladin et al., even despite its barely civil tone, because it reflects so clearly the quality of thinking of many of those who insist that thrombolysis has been proven to be beneficial in acute ischemic stroke.1 As we noted in our editorial,2 we believe this is far from the truth, and that the best evidence – supported by the IST-3 Trial,3 despite its manifest flaws – strongly suggests not only an absence of benefit, but also probable harm. Bladin et al. start out by claiming that our editorials are ‘full of distortions and factual errors’, but it is hard to find any specifics in their letter.1 Perhaps they are referring to our statement that IST-3's authors relied inappropriately on a secondary outcome measure, as they note that it was actually a ‘preplanned secondary outcome measure!’ We plead guilty, and our only defence is to ask readers to decide for themselves whether our calling a ‘preplanned secondary outcome measure’ a ‘secondary outcome measure’ is indeed a factual error. Other than that, they fail to cite even one single instance to support such a broad and damning claim. This, of course, makes it difficult for us to respond, but we will reiterate that there is nothing remotely inaccurate about stating that the primary analysis of IST-3 – the proportion of patients alive and independent, as defined by an Oxford Handicap Score of 0–2 at 6 months – found no difference between treatment groups. Bladin et al. next go on to pillory the graphic reanalysis of NINDS,4 of which one of us was the first author, claiming that it has already been ‘thoroughly discredited’. The evidence they provide for such a comprehensively definitive statement is … a letter to the editor of the journal in which that paper was published, disagreeing with its conclusions!5 We will not review here the assertions in that letter, but are happy to refer readers to the paper itself,4 the dissenting letter5 and our reply6 – unlike these correspondents, we ask only that each reader decide for himself or herself. Perhaps in the future they will cite their current letter as proof that this editorial has been thoroughly discredited. Bladin et al. then make the claim that ‘the purported methodologic weaknesses of IST-3 are actually its strengths’. Based on our long careers as teachers of clinical epidemiology and critical appraisal, we are confident that few, if any, methodologists would agree with this rather extraordinary comment. But unlike some of our critics, we have no interest in relying on supposed expertise to make our point; instead, we merely ask readers to decide for themselves about the methodologic quality of such ‘strengths’ as the study's relying for its primary outcome on a non-specified analysis, by an unblinded family member, of a metric that – even when done in person, based on a complete neurologic evaluation, by a trained neurologist, who has been blinded to treatment group – has been shown to be highly unreliable. Finally, Bladin et al. accuse us of making tired arguments that have previously been answered. We agree that we have long made many of these same arguments, to which we believe the evidence from IST-3 – despite its biases – adds even more weight. As to their being ‘answered’, however, that is only true if one considers ignoring the facts we cite (none of which are in fact inaccurate). Their letter, like the positive ‘spin’ that is being widely applied to IST-3, takes evidence and blithely turns it on its head and insists that ‘expert’ claims, no matter how outrageous, dare not be challenged. We reject such thinking and ask the journal's readership to do so as well – not because you have any need to trust us, but because you are each able to decide for yourselves. JRH has consulted on lawsuits involving allegations of negligence related to non-use of thrombolysis in stroke. He donates all fees from such consulting to charity and takes no personal reimbursement for any such work. He has no other potential conflict to declare. RJC has no competing interests to declare.

Targeted Therapy; From Advanced Melanoma to the Adjuvant Setting

Targeted Therapy; From Advanced Melanoma to the Adjuvant Setting

The evolution of breast cancer screening in the Medicare population: Clinical and economic implications.

1595 Background: Breast screening has evolved as newer approaches to mammography, ultrasound, and MRI have diffused into clinical practice. The use of these technologies and their impact on screening-related costs and outcomes remain undefined, particularly among older women. Methods: Using the Surveillance Epidemiology and End Results – Medicare linked database, we identified women aged 66 and older without a diagnosis of breast cancer. We constructed two cohorts (2001 vs. 2006) and followed each for two years. We assessed changes in imaging technology, screening-related costs (defined as costs for screening and subsequent imaging and testing, adjusted to 2009 USD), and stage at diagnosis between the two cohorts. Results: There were 136,845 women in the 2001-2002 (earlier) cohort and 137,733 in the 2006-2007 (later) cohort. The mean age was 76.9 and 77.2 respectively, (p&lt;.001). The proportion of women receiving any screening mammogram was 42.5% in the earlier cohort and 43.4% in the later cohort, (p&lt;.001). The use of digital mammography for screening increased from 2.2% to 15.0%, (p&lt;.001). The use of any computer aided detection (CAD) increased from 3.2% to 29.3% (p&lt;.001). MRI use increased from 0.03% to 0.2%, and ultrasound use from 4.0% to 4.5% (p &lt;.001 for both). Average screening-related cost increased 31%, from $101 to $132 (p&lt;.001). There was no significant difference in early stage at diagnosis over time (58.1% of women were in situ/stage I in early period vs. 57.2% in later period, p=.65). Conclusions: The use of digital mammography and CAD increased substantially between 2001 and 2007, contributing to a 31% increase in screening-related costs for women in the Medicare program. The increased cost of screening and downstream testing must be evaluated in context of an absence of benefit in terms of stage at diagnosis.

The metastasis suppressor KISS1 lacks antimetastatic activity in the C8161.9 xenograft model of melanoma

The objective of this study was to use the established xenograft model of human melanoma (C8161.9) to test a pharmacological approach to the effect of the metastasis suppressor KISS1. A KISS1 analog was used to inhibit the metastatic development of C8161.9 cells in nude mice. Further experiments were performed to test the validity of the C8161.9 model and test the connection between KISS1 expression and loss of metastatic potential. New clones of C8161.9 cells were obtained, with or without KISS1 expression, and were tested for metastasis formation. The absence of benefit in survival with the KISS1 analog compared with PBS prompted us to revisit the C8161.9 model. We found that the cells expressing KISS1, used in the previous study and obtained by transfection and single-cell cloning, were defective for both formation of orthotopic tumors and metastases. In mixing experiments, these cells could not suppress orthotopic tumor growth of KISS1-negative C8161.9 cells, suggesting that the suppression of metastasis by C8161.9-KISS1 cells may be intrinsic to the selected clone rather than related to KISS1 expression. Isolation of clones from parental C8161.9 cells in soft agar yielded cell populations that phenotypically and genotypically mimicked the KISS1-positive clone. In addition, new clones expressing KISS1 did not show any decrease in metastatic growth. These data demonstrate the heterogeneity of cell types in the C8161.9 cell line and the high risk of artifact linked to single-cell selection. A different xenograft model will be necessary to evaluate the use of KISS1 analogs as antimetastatic therapy.

Surveillance d’une femme traitée pour cancer du sein

Patient follow-up after treatment for a breast cancer is based on the local recurrence risk. Annual mammography remains the main point of this follow-up and tumor markers detection has still no interest. Absence of benefit of an intensive clinical, biological and radiological surveillance has been proved for a long time but expert recommendations still are a subject of discussion although they knew no evolution for more than 10 years. Evolution of those follow-up modalities will depend on the future indications of MRI and PET. About distant recurrence, a better knowledge of the risk is now possible thanks to the tumor biological profile study. Nevertheless, intensification of follow-up for some kind of high-risk tumors will have interest only if we can propose a therapeutic alternative in metastatic situation.

American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Immunohistochemical Testing of Estrogen and Progesterone Receptors in Breast Cancer (Unabridged Version)

To develop a guideline to improve the accuracy of immunohistochemical (IHC) estrogen receptor (ER) and progesterone receptor (PgR) testing in breast cancer and the utility of these receptors as predictive markers. The American Society of Clinical Oncology and the College of American Pathologists convened an international Expert Panel that conducted a systematic review and evaluation of the literature in partnership with Cancer Care Ontario and developed recommendations for optimal IHC ER/PgR testing performance. Up to 20% of current IHC determinations of ER and PgR testing worldwide may be inaccurate (false negative or false positive). Most of the issues with testing have occurred because of variation in pre-analytic variables, thresholds for positivity, and interpretation criteria. The Panel recommends that ER and PgR status be determined on all invasive breast cancers and breast cancer recurrences. A testing algorithm that relies on accurate, reproducible assay performance is proposed. Elements to reliably reduce assay variation are specified. It is recommended that ER and PgR assays be considered positive if there are at least 1% positive tumor nuclei in the sample on testing in the presence of expected reactivity of internal (normal epithelial elements) and external controls. The absence of benefit from endocrine therapy for women with ER-negative invasive breast cancers has been confirmed in large overviews of randomized clinical trials.

American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer.

To develop a guideline to improve the accuracy of immunohistochemical (IHC) estrogen receptor (ER) and progesterone receptor (PgR) testing in breast cancer and the utility of these receptors as predictive markers. The American Society of Clinical Oncology and the College of American Pathologists convened an international Expert Panel that conducted a systematic review and evaluation of the literature in partnership with Cancer Care Ontario and developed recommendations for optimal IHC ER/PgR testing performance. Up to 20% of current IHC determinations of ER and PgR testing worldwide may be inaccurate (false negative or false positive). Most of the issues with testing have occurred because of variation in preanalytic variables, thresholds for positivity, and interpretation criteria. The Panel recommends that ER and PgR status be determined on all invasive breast cancers and breast cancer recurrences. A testing algorithm that relies on accurate, reproducible assay performance is proposed. Elements to reliably reduce assay variation are specified. It is recommended that ER and PgR assays be considered positive if there are at least 1% positive tumor nuclei in the sample on testing in the presence of expected reactivity of internal (normal epithelial elements) and external controls. The absence of benefit from endocrine therapy for women with ER-negative invasive breast cancers has been confirmed in large overviews of randomized clinical trials.