Chronomodulated chemotherapy: clinical value and possibilities for dissemination in the United States

Modern medicine has been relatively slow to apply chronotherapeutic principles to standard oncologic practice. Despite the impressive body of evidence supporting the use of chronochemotherapy, with only a rare exception most oncology clinics in the United States lack the expertise and capability to implement it. At the same time, American medicine has increasingly come to recognize the importance of toxicity mitigation, cytoprotection, and quality of life for patients undergoing cancer treatment. However, toxicity mitigation strategies such as chronomodulated infusional chemotherapy and novel cytoprotective agents are not widely embraced by U.S. physicians. This article explores some reasons why this situation exists, including the influence of non-medical biases that may affect management decisions on the application of chemotherapy. The author conducted a survey of U.S. companies representing the three private insurance payers available (HMO, PPO, Indemnity) as well as representatives of Medicare and Medicaid. Responses to the survey confirmed that U.S. insurers do not at present officially reimburse for chronotherapy; however, changes will come about through educational efforts aimed at increasing awareness among insurers as to the clinical benefits and cost-effectiveness of this mode of treatment. At this juncture, the outlook for cancer chronotherapy as a first-line approach to the treatment of metastatic cancer in the United States remains uncertain. Under the current method of insurance reimbursement, the advancement of chronotherapy in the United States is threatened despite evidence that such treatment is both therapeutically sound and cost-effective.     

Cancer fatalism and adherence to national cancer screening guidelines: Results from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)

BackgroundSociocultural factors, such as health insurance status, income, education, and acculturation, predict cancer screening among U.S. Hispanics/Latinos. However, these factors can be difficult to modify. More research is needed to identify individual-level modifiable factors that may improve screening and subsequent cancer outcomes in this population. The aim of this study was to examine cancer fatalism (i.e., the belief that there is little or nothing one can do to lower his/her risk of developing cancer) as a determinant of adherence to national screening guidelines for colorectal, breast, prostate, and cervical cancer among Hispanics/Latinos.MethodsParticipants were from the multi-site Hispanic Community Health Study/Study of Latinos (HCHS/SOL) Sociocultural Ancillary Study (N = 5313). The National Cancer Institute (NCI) Health Interview National Trends Survey was used to assess cancer fatalism and receipt of cancer screening. Adherence was defined as following screening guidelines from United States Preventive Services Task Force and the American Cancer Society during the study period.ResultsAdjusting for well-established determinants of cancer screening and covariates (health insurance status, income, education, acculturation, age, Hispanic/Latino background), lower cancer fatalism was marginally associated with greater adherence to screening for colorectal (OR 1.13, 95% CI [.99–1.30], p = .07), breast (OR 1.16, 95% CI [.99–1.36], p = .08) and prostate cancer (OR 1.18, 95% CI [.97–1.43], p = .10), but not cervical cancer.ConclusionsThe associations of cancer fatalism were small and marginal, underlining that sociocultural factors are more robust determinants of cancer screening adherence among Hispanics/Latinos.     

Civilian and military genetics: nondiscrimination policy in a post-GINA world

Evidence is emerging of a growing societal consensus about appropriate and inappropriate uses of genetic information. The Genetic Information Nondiscrimination Act of 2008 provides new legal protections to Americans by prohibiting the discriminatory use of genetic information by health insurers and employers. Additionally, the United States military recently created new policies for fair use of genetic information in the determination of benefits for servicemen and servicewomen leaving military service. Although critical issues remain, such as the potential for genetic information to be used to deny people other forms of insurance, and how the military will use genetic medicine overall, significant progress has been made.     

Evidence-based methodology for obtaining commercial insurance coverage of stereotactic radiosurgery for intractable epilepsy

ObjectivesThe coverage policies of many commercial insurers in the United States do not include coverage of stereotactic radiosurgery (SRS) for intractable epilepsy despite recent Level I evidence supporting its efficacy. We sought to assess the efficacy of an evidence-based methodology in obtaining coverage approval of SRS for intractable epilepsy.Patients and MethodsThe clinical policy guidelines from five of the largest United States commercial insurers were reviewed for their language regarding coverage of SRS for epilepsy. An evidence-based questionnaire was created for temporal lobe epilepsy and extratemporal lobe epilepsy based on recent evidence. Telephone interviewers of Insurers assessed the likelihood of SRS coverage for an epilepsy patient meeting the clinical inclusion criteria in the questionnaire. This likelihood was assessed numerically based on interviewee response (2 = yes, 1 = dependent on peer-to-peer, 0 = no).ResultsOf the five policy guidelines, none included literature more recent than 2017. For TLE, 3/5 insurance companies indicated likely SRS coverage; 2/5 indicated peer-to-peer discussion dependence for patients meeting questionnaire criteria for a score of 8/10. For extratemporal TLE, 2/5 companies indicated likely SRS coverage and 3/5 indicated peer-to-peer discussion dependence for a total score of 7/10.ConclusionCreation of an evidence-based methodology in approaching commercial insurers greatly increased the likelihood of SRS coverage for an indication (intractable epilepsy) widely perceived as investigational. These results should pave the way for epilepsy patients to receive coverage should they be appropriate SRS candidates.     

'Genetics is not the issue': insurers on genetics and life insurance

This article offers an analysis of the way private insurers deal with the issue of genetics and insurance. Drawing on specific written insurance sources, a reconstruction is made of internal debates on genetics and insurance within the private insurance world in Europe and the United States. The article starts by analyzing the way insurers initially framed the issue of genetics. It proceeds by showing how ideas with respect to this issue developed beyond public policy debates in the nineties. Although not a strictly linear development, a trend towards a change in perspective can be demonstrated: at the beginning most insurance companies took another stance than they do nowadays. The article concludes by questioning the effect of these changes within the insurance world for the definition of the problem with respect to genetics and insurance. Does taking into account the public concerns around genetics also include taking genetics as a public problem?     

In-lieu fee mitigation: coming into compliance with the new Compensatory Mitigation Rule

Under Section 404 of the federal U.S. Clean Water Act, the U.S. Army Corps of Engineers and U.S. Environmental Protection Agency require compensatory mitigation for unavoidable impacts stemming from the permitted discharge of dredged or fill material into waters of the United States. There are three primary mechanisms supported by the Corps and EPA for permittees to meet their compensatory mitigation obligations: permittee-responsible mitigation, purchasing credits from a mitigation bank, or making a payment to an approved in-lieu fee mitigation program. In 2005, the Environmental Law Institute studied the 38 approved, active in-lieu fee programs operating in the US. This paper seeks to assess how the in-lieu fee programs that were approved and active as of October 2005 will need to update their administrative and procedural practices to come into compliance with new regulations on compensatory mitigation published in April 2008. Of the 10 new requirements for in-lieu fee reviewed here, three in particular will likely have the most significant impact on whether the 2005 programs are able to seek authorization and continue to operate. These are the compensation planning framework, the cap on the number of advance credits that can be sold, and the requirement to provide financial assurances for all projects. Those programs that make the investment in meeting the new requirements by the June 2010 deadline are likely to overcome past concerns over the ability for in-lieu fee mitigation to replace lost aquatic resources in a timely and efficient fashion.

乳腺癌化疗现状及相关研究进展

乳腺癌是除非上皮来源肿瘤中女性最常见的恶性肿瘤,在美国平均每3名女性中就有一名患乳腺癌,是女性肿瘤致死中的第二大原因,给政府经济造成了很大的损失。目前,乳腺癌主要是以手术治疗为主,而化疗,放疗等也作为相当重要的辅助治疗应用于临床。这种手术加化疗的治疗方法一直可以取得很好的疗效,甚至于可以保住乳房。近年来,乳腺癌的化疗已逐步成为其治疗的首选方式,包括术后辅助化疗和术前的新辅助化疗。但由于化疗药物的滥用和肿瘤本身的异质性或是其他原因,越来越多的肿瘤耐药性报道给乳腺癌的化疗带来了很大的挑战。而这种肿瘤耐药性的分子机制尚不是很清楚。本文将从乳腺癌的概述,乳腺癌化疗的现状及乳腺癌化疗的前景来综述这一灾难性疾病。     

Once-Daily Evening Administration of Uniphyl Tablets: Announcement of First Available Chronotherapy of Nocturnal Asthma

Theophylline chronotherapy recently became a reality for patients with reversible airways disease. Uniphyl^R 400 mg tablets (controlled-release theophylline, the Purdue Frederick Company, Norwalk, Connecticut) are now indicated for once-daily evening administration, both in the United States and Canada. This development follows the previous use of Uniphyl tablets in once-daily morning doses and marks the first-available antiasthmatic treatment in North America to incorporate dosing time as an important therapeutic dimension. It reflects increasing recognition, by the medical community, of the need to consider the individual patient's timing of symptoms in relation to the kinetics of the drug.     

Chronotherapy of colorectal cancer

Chronotherapy consists of chemotherapy delivery according to circadian rhythms. These genetically based rhythms modulate cellular metabolism and cell proliferation in normal tissues. As a result, both the host tolerance and antitumor efficacy of 5-fluorouracil (5-FU) and oxaliplatin (l-OHP), like 30 other anticancer drugs, vary largely according to the dosing time in laboratory rodents. The transfer of this concept to the clinic is aimed primarily at increasing the dose-intensity of the therapy through adjustment of drug-delivery to 24h rhythms in host tolerance. A specific technology (programmable-in-time infusion pumps) enables administration of chronotherapy to fully ambulatory patients. Phase I–III clinical trials show chronotherapy significantly increases tolerance to high doses of cancer drugs and improves antitumor activity in patients with metastatic colorectal cancer. These safe conditions of drug-delivery led to the first demonstration of the high activity of the 5-FU–leucovorin–l-OHP protocol. Chronotherapy with these three drugs also allows surgical removal of previously unresectable liver and lung metastases. This novel medico-surgical management provides hope for the cure of metastatic disease in patients with unresectable colorectal cancer metastases.     

Current and historical mortality from cancer and cardiovascular disease in relation to age: U.S. and world values

Data from the World Health Organization, U.S. Vital Statistics, the Historical Abstracts of the United States and the census of the United States were used to compare current world and states data on cancer death rate and age with historical data that shows the changing percentage of elderly. Current annual death rates from malignant neoplastic disease among the 73 countries for which data exist are highly correlated with the percent of the population ≥ 60 yrs of age and a virtually identical relation exists presently among the 50 states of the U.S. The current world and states data provide a remarkably accurate snapshot of U.S. cancer death rates over the past century during which time the U.S. elderly population increased substantially. Data on U.S. lung cancer death rates since 1940 were similarly examined and these historical numbers also show good agreement with current values among countries that today span the same proportion of elderly that the U.S. had over this period. The agreement of current and historical CA death rate and age contrasts sharply with the picture that emerges when cardiovascular death rates and death rate from all causes are examined. The geographic and time invariance seen in the cancer data seems incosistent with identical exposure to carcinogens and suggests that biological aging is an important intrinsic factor in cancer.     

Association of race and health insurance in treatment disparities of colon cancer: A retrospective analysis utilizing a national population database in the United States

BackgroundBoth health insurance status and race independently impact colon cancer (CC) care delivery and outcomes. The relative importance of these factors in explaining racial and insurance disparities is less clear, however. This study aimed to determine the association and interaction of race and insurance with CC treatment disparities.Study settingRetrospective cohort review of a prospective hospital-based database.Methods and findingsIn this cross-sectional study, patients diagnosed with stage I to III CC in the United States were identified from the National Cancer Database (NCDB; 2006 to 2016). Multivariable regression with generalized estimating equations (GEEs) were performed to evaluate the association of insurance and race/ethnicity with odds of receipt of surgery (stage I to III) and adjuvant chemotherapy (stage III), with an additional 2-way interaction term to evaluate for effect modification. Confounders included sex, age, median income, rurality, comorbidity, and nodes and margin status for the model for chemotherapy. Of 353,998 patients included, 73.8% (n = 261,349) were non-Hispanic White (NHW) and 11.7% (n = 41,511) were non-Hispanic Black (NHB). NHB patients were less likely to undergo resection [odds ratio (OR) 0.66, 95% confidence interval [CI] 0.61 to 0.72, p < 0.001] or to receive adjuvant chemotherapy [OR 0.83, 95% CI 0.78 to 0.87, p < 0.001] compared to NHW patients. NHB patients with private or Medicare insurance were less likely to undergo resection [OR 0.76, 95% CI 0.63 to 0.91, p = 0.004 (private insurance); OR 0.59, 95% CI 0.53 to 0.66, p < 0.001 (Medicare)] and to receive adjuvant chemotherapy [0.77, 95% CI 0.68 to 0.87, p < 0.001 (private insurance); OR 0.86, 95% CI 0.80 to 0.91, p < 0.001 (Medicare)] compared to similarly insured NHW patients. Although Hispanic patients with private and Medicare insurance were also less likely to undergo surgical resection, this was not the case with adjuvant chemotherapy. This study is mainly limited by the retrospective nature and by the variables provided in the dataset; granular details such as continuity or disruption of insurance coverage or specific chemotherapy agents or dosing cannot be assessed within NCDB.ConclusionsThis study suggests that racial disparities in receipt of treatment for CC persist even among patients with similar health insurance coverage and that different disparities exist for different racial/ethnic groups. Changes in health policy must therefore recognize that provision of insurance alone may not eliminate cancer treatment racial disparities.

Scarlett Hao and colleagues utilize a national population database to investigate the association of race and health insurance in treatment disparities of colon cancer in US.     

Canadian government financial intervention in a marine fishery: The case of newfoundland, 1972/73–1980/81

Abstract

Trade in fish products between Canada and the United States has been the subject of extensive legal activity in the latter country. United States fishing interests have repeatedly attempted to utilize provisions in U.S. law and in the General Agreement on Tariffs and Trade (GATT) to have countervailing duties imposed on imports of Canadian fish products, the prices of which are alleged to be artificially depressed by Canadian government financial support of the industry.

This paper summarizes the state of U.S. and international law on countervailing duties, and surveys recent legal activity on the matter. It then presents hitherto uncollected evidence on government financial support of a major Canadian fishery, the Newfoundland groundfishery. It is found that the total value of expenditures was equal to 31 percent of the value of total fish products in 1980/81. However, subsidies as defined by the U.S. International Trade Administration, in accordance with U.S. law and the GATT, amounted to only 4.5 percent of the value of total fish products in that year.     

Evaluation of antitumor effects of VEGFR-2 inhibitor F16 in a colorectal xenograft model

Biotechnology Letters - Colorectal cancer&nbsp;(CRC) is the third most prevalent type of cancer in the United States. The treatment options for cancer include surgery, chemotherapy, radiation,...     

Genetic diversity in major farm crops on the farm and in reserve

Genetic vulnerability does not at this time present a major threat to production of United States field crops, according to a 1981 survey of U.S. crop breeding directors. But plant breeders do regard genetic vulnerability as an important and potentially dangerous problem. The 1981 survey indicated that although the genetic base of U.S. field crop production is not as narrow as in 1970, it still is concentrated on a relatively small number of favored cultivars. Genetic diversity is provided, nevertheless, in other and less obvious ways. Survey responses indicated that the genetic base of the elite germplasm pool is wider and provides more useful diversity than is usually supposed. However, breeders also value the national germplasm repositories as indispensable sources of needed diversity.     

The Salish Sea Boundary Straits: “Historic Internal Waters” or Territorial Seas?

The legal classification of the boundary straits of the Salish Sea between the western United States and Canada as either historic internal waters or territorial seas, subject to a right of innocent or transit passage, has been the subject of periodic debate within the U.S. government since the United States and Great Britain entered into the 1846 Oregon Treaty. As neither state has made an express public claim of historic title to the waters, any evidence for such a claim must be sought in less explicit and sometimes conflicting sources. This article applies the United States' legal test for a historic waters claim, recently set out in the U.S. Department of State's analysis of China's claims in the South China Sea, and concludes that the boundary waters of the Salish Sea would not meet that test. Accordingly, the waters of the Salish Sea boundary straits on the United States' side of the international boundary must be considered a territorial sea.     

Subjects of Speculation: Emergent Life Sciences and Market Logics in the United States and India

This article traces systems of exchange concerning the life sciences and capital and how they configure subjectivity in the United States and India. This is done through case studies concerning the emergence of personalized medicine in the two locales. In the U.S. case, I argue for the configuration of the subjects of personalized medicine as sovereign consumers; in the Indian case, I argue for their configuration as experimental subjects. I situate these arguments in the context of epistemologies of genomics and the consolidation of systems of speculative capitalism.     

Pharmaco-economic comparative evaluation of combination chronotherapy vs. standard chemotherapy for colorectal cancer

Results of recent trials comparing combination chemotherapy consisting of 5-fluorouracil (5-FU), folinic acid (FOL), and oxaliplatin, given either as flat (A) or chronomodulated (B) infusion for metastatic colorectal cancer, were subjected to pharmaco-economic evaluation. The overall cost of treatment with the flat and chronomodulated protocols was equivalent. The expense of the delivery of medications with the chronotherapeutic arm (B) was greater than with the standard arm (A) because it was feasible to administer more courses (requiring more frequent doctor visits) and higher doses (high cost of medications) with containment of toxic reactions. Chrono-arm B was definitively more cost-effective than standard flat-arm A treatment since it made the outcome of treatment more effective; there was greater tumor response rate and longer time to progression with less treatment-associated toxicity. Finally, selection of the Melodie brand infusion pump to deliver the chronotherapy resulted in a further 18% reduction of overall costs and made it possible for patients to enjoy increased autonomy and improved quality of life.     

Climate change and historical biogeography of the barnacle Semibalanus balanoides

Aim Marine sessile inter‐tidal invertebrates are expected to undergo shifts in distribution due to climate change. Using a combination of survey and transplant data with thermal modelling, we investigated the role of climate on the poleward contraction of the southern range edge of the north temperate barnacle Semibalanus balanoides. Location Western Atlantic of the United States. Methods Barnacle surveys were conducted along the east coast of the United States in 1963 and 2007. Presence, absence and abundance data were collected and the time periods were compared. Transplant experiments monitoring survival with relation to temperature were conducted upon S. balanoides along the more southerly portion of their range, and modelling predicting barnacle survival with relation to biogeography was completed. Results The southern limit of S. balanoides has contracted approximately 350 km to the north. Main conclusions The changes thus far observed in climate along the east coast of the United States have contributed to the southern limit range contraction of S. balanoides. Further changes in the biogeography of S. balanoides are expected with continued climate warming.     

Pharmaco-economic comparative evaluation of combination chronotherapy vs. standard chemotherapy for colorectal cancer

Results of recent trials comparing combination chemotherapy consisting of 5-fluorouracil (5-FU), folinic acid (FOL), and oxaliplatin, given either as flat (A) or chronomodulated (B) infusion for metastatic colorectal cancer, were subjected to pharmaco-economic evaluation. The overall cost of treatment with the flat and chronomodulated protocols was equivalent. The expense of the delivery of medications with the chronotherapeutic arm (B) was greater than with the standard arm (A) because it was feasible to administer more courses (requiring more frequent doctor visits) and higher doses (high cost of medications) with containment of toxic reactions. Chrono-arm B was definitively more cost-effective than standard flat-arm A treatment since it made the outcome of treatment more effective; there was greater tumor response rate and longer time to progression with less treatment-associated toxicity. Finally, selection of the Melodie brand infusion pump to deliver the chronotherapy resulted in a further 18% reduction of overall costs and made it possible for patients to enjoy increased autonomy and improved quality of life.     

Trypanosoma cruzi: a considerable phylogenetic divergence indicates that the agent of Chagas disease is indigenous to the native fauna of the United States.

Thirty U.S. Trypanosoma cruzi stocks isolated mainly from wild mammals were characterized by multilocus enzyme electrophoresis at 22 genetic loci and random amplification of polymorphic DNA for 10 primers. Two main phylogenetic clusters, separated by large genetic distances, were discriminated by both methods, corresponding, respectively, to the formerly described zymodemes I and III. Two stocks isolated from indigenous human cases were identified as zymodeme I. Genetic diversity of the U.S. T. cruzi isolates was considerable, comparable to that scored in similarly sized samples from South America. These results favor the hypothesis that T. cruzi U.S. stocks were not imported at a historical time and are indigenous to the native fauna of the United States. The population structure of these stocks appeared to be basically clonal, as previously reported in South America, and no evidence of hybrid genotypes was found in the United States.