Pauline A. Obale was the lead author and organized the case study through Dr. Luis Gabriel Cuervo, who as a mentor provided guidance and inspiration, reviewed and edited the final drafts and update. This case study was peer-reviewed by Christopher Khanoyan, Ana Castro, Johanna Fedorovsky, Louisa Stuwe, and Dr. Lyda Osorio (Aug 10, 2016). The updated version was reviewed by Dr. Roberto Montoya (Jan 2018 and released for publication on 13 March 2018).


Alexandria Kristensen-Cabrera was the lead author and organized the case study through interviews with Dr. Juan Pablo Peña-Rosas who provided substantial additions to the case study. Dr. Luis Gabriel Cuervo as a mentor provided guidance and inspiration and reviewed and approved the final version. Ruben Grajeda, Michele Gilbert and Louisa Stuwe reviewed and edited the final drafts. Louisa Stuwe translated the document into Spanish, which was reviewed by María Medina. Christopher Khanoyan assisted with formatting. The photos illustrating the case study are from the exhibit "Research on the Move" by photographer Jane Isabelle Dempster, and are part of PAHO's Art for Research Project (www.paho.org/artforresearch) ©PAHO/WHO


Joana Santos wrote this case study. Eleana C. Villanueva provided guidance and reviewed the case study. Kira Fortune and Ana Ragonesi peer reviewed this case study.

Non Communicable Diseases (NCDs) and their consequences are preventable. Previous programs in high income countries have shown that approaching the risk factors and working with other sectors is key to improve health. Indeed, as we elaborate here this is true for NCDs as for all health problems. For example, injuries with transportation sector; communicable diseases and water and sanitation; respiratory diseases and environment. In Latin America and the Caribbean NCDs' related morbidity and mortality is expanding so it is of major interest to promote and support this approach in this region.

WHAT'S THE ISSUE?

Non Communicable Diseases (NCDs) are increasing worldwide (1). In 2008, 56 million of total deaths (63%) were due to NCDs namely cardiovascular diseases, diabetes, cancer and chronic respiratory diseases (1). In 2010 about 54% of all years of healthy life lost due to disability (measured as DALYs - the Disability Adjusted Life Year is a measure for the burden of disease. It is measured by the sum of Years of Life Lost  (YLL) + Years of Life lived with Disability (YLD)) were related to NCDs; only 35% due to communicable diseases and the remaining 11% related to injuries (2). Even more, according to projections this percentage will rise over the next coming years (1) (2) (3). In addition, 80% of total deaths occurred in low and middle income countries (LMIC) (1) where the health epidemiological profile is in transition (3). Also, research has shown these countries are struggling with a double burden (4) that has a major impact not only at the health sector, but also on economics and development of the country (5).

RESEARCH TO PRACTICE

Finland tackling NCDs
In the 1970's Finland counted for a high number of mortality due to coronary heart disease (6).  Such levels were of concern in North Karelia, so the WHO, the Finnish Government and local stakeholders started designing a program to decrease cardiovascular morbidity and mortality in that region.  A program started in 1972 was created taking into account evidence showing that risk factors (According to WHO, a risk factor is an attribute, characteristic or exposure of an individual that increases the likelihood of developing a disease or injury) for NCDs were unhealthy diet, smoking and high blood pressure. The program was conceived aiming at reaching the whole population of the targeted city, North Karelia. Given the variety of risk factors, it soon became clear that many sectors of society had to join efforts. Contributions came from different parties: political institutions providing guidance, the legislative sector to change legislation regarding label contents and smoking sellers restrictions; media campaigns to promote and disseminate information about healthy lifestyles; Non Governmental Organizations (NGO), medical community and other institutions to assure engagement, ownership and impact. Several obstacles had to be overcome - in particular dealing with the food industry. Finland was a main producer of cream, butter and meat - and studies had just shown that consumption of those items was associated with Cardiovascular Diseases. Hence, it was important to engage work with this sector to assure adaptations to healthier diet with low fat products would result in minimum loss to the sector. Stakeholders were properly engaged in the project. Promotion strategies, campaigns, industry and legal reforms were set up to assure that common objectives were achieved (7).

The North Karelia Project
The North Karelia project (1972-82) aimed at reducing mortality rates from coronary heart disease (CHD) in the whole population, especially middle-aged man. From 1982 onwards, it also targeted related major cardiovascular diseases and aimed at promoting health in the entire population. For such purposes, a comprehensive and cross sectional approach using epidemiological knowledge gathered to date was planned and carried out. Main risk factors - tobacco, lifestyle, diet - were tackled and community and local services and structures were engaged.

The intervention (72-82) aimed at reducing CHD mortality and a preventive action was carried out, directing the focus on risk factors. Three risk factors were identified in North Karelia - blood pressure, elevated serum levels and smoking. In addition, studies also showed that high risk groups are responsible for a limited number of cases and that most cases were arising among moderate risk groups. So, the individual approach turned into a community wide level approach that aimed at changing the entire population lifestyle, with emphasis on health determinants.

It was, therefore, important to change behaviors. Again, supported by evidence, one knew that the communication strategy had to be coherent and assertive, involving all parties. In particular, the intervention was about media activities, promoting preventive services, training professionals, facilitating environmental changes, monitoring and feed back - all sharing and working towards promoting the same message. Practical activities were designed and planned by the office and the field teams - which endorsed the engagement and commitment of the community.

Outcomes
An evaluation was carried out 5 years later and findings showed major changes of risk related lifestyles and risk factors in people in North Karelia:

  • The incidence of coronary heart disease among working aged man also decreased by 65% (9)
  • All causes related mortality among working man decreased more than 50% and life expectancy increased.
  • The Finnish lifestyle changed and a new concept of health and well being arose (9, 10). Due to the multi sectorial nature of determinants involved to reduce CVD, health emerged as a crosscutting issue to be considered by all sectors. Also, it was clear that inequities in health were coming from outside the health sector, so it was important to tackle social, environmental, and economic determinants to improve health, equity and, in turn, governance. And good governance is a pillar to build well being in society.
  • Thirty years later rates still fall and we observed a 85% decrease of mortality for coronary heart disease among working age men in relation to 1977 (9).

WHAT'S NEXT?

health in all policies-amer"Rather than a number of vertical disease specific program, an integrated approach targets the main common behavioral risk factors" (8).

Also as a result of their epidemiological transition, the burden of disease associated with NCDs in Latin America and the Caribbean is greater than that associated with CD or injuries (11) (12). Heart disease, stroke, cancer and diabetes account for three of every four deaths and for two of every three DALYS lost in the region (13) (14). The economic burden is also high - health care costs related to diabetes in Latin America is 65 billion USD annually, representing 2% to 4% of GDP (1). Indeed, this has a major impact in all sectors with a high cost for society.  Therefore, investing on health is key to promote development, so effective approaches are needed. The Finnish intervention for tackling CVD has proven to be successful and it was scaled up.  It was the root of a new health policy making framework- the Health in All Policies (HiAP) - which is being adopted in many countries nowadays (15). HiAP is a comprehensive approach towards health - Health as a tool for people's happiness and well being; a concept that is to be at the center of policy making decisions, since its determinants are key in health (in) equalities (16). Thus, it is utmost importance to work with different sectors and assure health is considered in all public policies. It is important to assure engagement, achievable through participatory processes. As a result, accountability is enhanced as well as democratic processes - opening the road to equity and good governance.

At this point, PAHO is seriously committed with the integration of Health in All Policies and a Plan of Action on Health in All Policies was discussed and approved during the 2014 Executive Committee, that took place in June. Major recommendations are enhancing health equity and universal health coverage; take effective measures as well as institutional capacity; transparency of decision making; active participation within other sectors (17)

Hence, we anticipate this will support Member States improving their populations´ health and well being. Although we are aware it might take time to be implemented and obstacles must be overcome, it will be a leap forward in LAC.

REFERENCES

(1) WHO. (2010). WHO Global Status report on Non Communicable Diseases. Geneve: WHO.
(2) Murray, J. L. (2012). Diability Adjusted Life years (DALYS) for 291 diseases and injuries in 291 countries, 1990-2010: a systeamtic analysis for the Global Burden of Disease study 2010. Lancet, 2197-223.
(3) GBC Health. (2012, April). Mobilizing Business for a Healhier World. NCD in the America and the Caribbean.
(4) Amuna, P., & Zotor, F. B. (2008). The epidemiological transition and nutrition in developing countries: evolving trends and their impact on public health and development. Proceedings of the Nutrition Society, 67 (1), 82-90.
(5) PAHO/WHO and UNite in the fight agaisnt NCD. (n.d.). The economic burden of NCD in the Americas.
(6) Pukka, P. (2002). Successful prevention of non communicable diseases: 25 years experiences with North Karelia Project in Finland. Public Health Medicine 4 (1), 5-7.
(7) McAlister, A. e. (1982). Theory and Action for health promotion ilustrations frm the North Karelia project. Am J Public health 72 (1), 43-50.
(8) Puska, P. e. (May 2008). Prevention in Action. The Northe karelia project. 30 years successfully preventing chronic diseases (53). Diabetes voice. Prevention in Action.
(9) Puska, P. e. (1995). The North karelia project 20 years results and experiences. Helsinki: National Public Health Institute.
(10) Melkas, T. (2013). Health in All Policies as a priority in Finnish Health Policy. A Case study on national health policy development. Scan J Public Health.
(11) USAID. (2009). NCD in LAC. USAID.
(12) De Maio, F. G. (2011). Understanding non communicable diseases. Globalization and Health, 7-36.
(13) Bonilla-Chacín, M. E. (2014). Promoting healthy living in the America and the Caribbean . Washington DC: The World Bank.
(14) WHO. (2004, May). The burden of disease. Retrieved june 4, 2014, from WHO: https://www.who.int/healthinfo/global_burden_disease/GBD_report_2004update_part4.pdf
(15) Health in All Policies. (2013). HiAP. Retrieved from www.hiap2013.com
(16) Leppo, K. e. (2013). Health in All Policies - seizing opportunities, implementing policies. Finland: Ministry of Social Affairs and Health.
(17) PAHO/WHO (2014) . Plan of Action on Health in All Policies for 2014-2019 . Washington DC, Executive Commitee.

Jimmy Toan Le was the lead author and organized the case study through interviews with Dr. Nathalie Charpak, who reviewed and approved the final version. Dr. Luis Gabriel Cuervo, who as a mentor provided guidance and inspiration, reviewed and edited the final drafts. The photos illustrating the case study are from the exhibit "Research on the Move" by photographer Jane Isabelle Dempster, and are part of PAHO's Art for Research Project (www.paho.org/artforresearch) ©PAHO/WHO

The issue

kangaroo-motherKangaroo Mother Care (KMC) according to Dr. Nathalie Charpak, an internationally respected pediatrician and daughter of the Nobel Prize-winning physicist George Charpak, represents a way of humanizing neonatal healthcare. Like other forms of "kangaroo care," KMC is an incubation method to keep newborns weighing 2000 grams or less at birth and those unable to regulate their own body temperatures warm 1. Rather than isolating babies in loud, mechanical neonatal intensive care units (NICUs)—which have been shown to cause both psychological stress and adverse physiological changes—KMC positions preterm and low-birth weight babies in direct skin-to-skin contact with a parent or caregiver once stabilized. While KMC was originally conceived in 1978 in response to overcrowding and inadequate resources for NICUs in Colombia, more recent research studies have shown that skin-to-skin contact works as an effective technique not only for thermal control but for breastfeeding, and bonding irrespective of clinical settings, gestational age, or weight 2 3. This case study recounts a conversation with Dr. Charpak to highlight how research evidence has drawn attention to important aspects of neonatal development.

Research to Practice

During an interview with PAHO, Dr. Charpak outlined three types of surrogate benefits emerging from an intervention like KMC. Firstly, from a sociological standpoint, placing babies in direct contact with their parents presents an immediate opportunity to establish a parent-child relationship without delay and avoids separating the neonate from caregivers simply because of illness. She argued that by involving them directly, parents and caregivers are naturally compelled to assume the roles of providers for their preterm babies. For the infant, investigators have observed a stronger tendency for babies to quickly settle down into a deep sleep (lower state of consciousness) or become less fussy before feeding when in KMC position 4. By enhancing the parent-infant bonding, KMC facilitates the psychological bonding process necessary to overcome the initial stress and shock already associated with a premature birth.

kangaroo-fatherSecondly, kangaroo care promotes growth and development. Notably, KMC encourages exclusive breastfeeding and lactation which contribute to proper nutrition needed to sustain appropriate growth and weight-gain rates 3. Dr. Charpak also alludes to neural stimuli: "It's favorable for the baby to smell his/her mother, hear the heartbeat, and experience tactile stimulation which resembles the comfort experienced in-utero." Research done at the Université Laval supports these claims 5. Comparing the motor cortex of premature adolescents (39 who underwent KMC and 18 who underwent NICU), the investigators discovered that premature infants under KMC had better brain functions in adolescence than their counterparts who underwent incubator care. When comparing brain maturation, the KMC-patients had brain connectivity more similar to patients born at term. This research suggests an association between KMC and optimized neuroplasticity during critical stages of infancy by reproducing intrauterine environments that NICUs cannot simulate.

Thirdly, Kangaroo Mother Care has led to some changes to standard of care that has improved how neonates are treated. The implementation of KMC units is a 24/7 service requiring clinics to operate non-stop. In contrast, in some low and middle income settings babies in NICUs are left alone while attached to monitors, ventilators, and other mechanical contraptions. Further, NICUs are subject to the dangers of outdated equipment or inconsistent electricity grids found in resource-poor hospital settings 6. However, KMC, by removing the automation, obliges hospital staff to treat newborns like regular patients (e.g. respecting sleep patterns, reducing exposure to stressors such as noise). This has been associated with dramatic reductions in negative physiological responses such as sleep apnea and fluctuations in heart rate, blood pressure, and oxygen saturation 7. At the same time, they also they lessen the hospital workload by introducing parents as additional caregivers.

In practice, maternity wards, for example in Nicaragua, have shown KMC to be a cost-saving implementation because it decreases the average lengths of stay in hospitals and thus lowers resource consumption 8. Additionally, for hospital units surrounded by varying road conditions and surface disruptions, KMC position provides a safer form of transportation. While little data about this adaptation exists in the Americas, studies from Belgium show that the mother and her body provides adequate safety and comfort 9. This data suggest that KMC as an intervention decreases parental stress and increases quality of care for the infant while gaining high satisfaction among hospital staff.

What's Next

Although KMC originated in response to limitations of resource-poor hospitals, the benefits attributable to this health service has undoubtedly extended beyond its original purposes and generated new knowledge to improve the standards of care for newborns. From discussion with Dr. Charpak, we arrive at the conclusion that KMC is neither a return to ancestral practice nor an alternative to more conventional means of neonatal care; instead, it complements the NICU. By adopting a more holistic form of medicine and introducing an intervention that looks natural despite of not actually being "natural in nature," research presents one cost-effective, functional care system that improves the way preterm and low birth weight babies are cared for in hospitals.

At the same time, Dr. Charpak cautions that in addition to implementation, "numbers must be published and guidelines must be actualized." More published observations will be needed to more comprehensively understand the returns of health services like KMC in varying settings. The strength behind this intervention, nevertheless, is that it has been and continues to be extensively researched, thus further pushing the boundaries of knowledge for better health.

References

  1. WHO. (2003). Kangaroo Mother Care: A Practical Guide. Geneva: World Health Organization.
  2. Charpak, N., Ruiz-Peláez, J. G., Figueroa de C, Z., & Charpak, Y. (1997). Kangaroo Mother Versus Traditional Care for Newborn Infants ?2000 Grams: A Randomized, Controlled Trial. Pediatrics, 682-688.
  3. Charpak, N., Ruiz, J. G., Zupan, J., Cattaneo, A., Figueroa, Z., Tessier, R., . . . Worku, B. (2005). Kangaroo Mother Care: 25 years after. Acta Paediatrica, 94(5), 514-522.
  4. Anderson, G. (1999). Kangaroo care of the premature infant. In Nurturing the premature infant: Developmental interventions in the neonatal intensive care nursery. New York: Oxford University Press.
  5. Schneider, C., Charpak, N., Ruiz-Peláez, J., & Tessier, R. (2012). Cerebral motor function in very premature-at-birth adolescents: a brain stimulation exploration of kangaroo mother care effects. Acta Paediatrica, 101, 1045-1053.
  6. Ruiz-Peláez, J. G., Charpak, N., & Cuervo, L. G. (2004). Kangaroo Mother Care, an example to follow from developing countries. BMJ, 329.
  7. Brown, G. (2009). NICU Noise and the Preterm Infant. Neonatal Network: The Journal of Neonatal Nursing, 28(3), 165-173.
  8. Broughton, E., Gomez, I., Sanchez, N., & Vindell, C. (2013). The cost-savings of implementing kangaroo mother care in Nicaragua. Revista Panamericana de Salud Pública, 34(3).
  9. Grevesse, L., & Hennequin, Y. (2012). Neonatal Back Transfer: Kangaroo Mother Care (KMC) or Incubator Transport? Poster Presentations - IX International Conference on Kangaroo Mother Care. Ahmedabad.

Natalia Godoy wrote the case study. Luis Gabriel Cuervo provided guidance and reviewed the case study. Photos: ©Mustard gas Creative Commons ©PAHO by Jane Dempster from PAHO Art for Research Project. This case-study was peer-reviewed by Dr Silvana Luciani and Dr Xavier Bonfill.

 

"Chance favors only the prepared mind"
-Louis Pasteur

What's the issue? Unlikely sources for cancer treatment

As with many discoveries in science, chance and coincidence have favored innovation in the creation of new medications or treatments. The origins of the first effective chemotherapy for cancer relied both on rigorous research but also on accidental findings during World War I (WWI) when mustard gas was used as a weapon. Until then, most treatments for advanced cancer were ineffective [1].

mustard gas-01Mustard gas is a vesicant chemical warfare agent synthesized by Frederick Guthrie in 1860 [2]. It was widely used as a weapon during WWI by both sides of the conflict with particularly harmful and deadly effects. It was responsible for 1,205,655 non-fatal casualties and 91,198 deaths [3]. The toxicity of this agent is dose-dependent [4]. The effects range from minor symptoms such as skin irritation and conjunctivitis to severe lung damage when inhaled. Sulfur mustard can also have chronic sequelae: surviving victims might exhibit nausea, vomiting, alopecia and increased vulnerability to infection. These symptoms are the result of the poison acting as an alkylating agent: it damages the DNA, a vital component of cells in the body, resulting in a decreased formation of blood cells (aplastic anemia) or a decreased red or white blood cells and platelets (pancytopenia) [5]. The bone-marrow and the gastrointestinal tract were the organs mainly affected by the chronic exposure to sulfur mustard. Despite the horrific use of mustard gas during WWI, there was a silver lining: the discovery of the first modern chemotherapeutic agent, based on observations from WWI survivors exposed to mustard gas.

Research to practice: How the first chemotherapeutic agents were identified

The effects of mustard gas on blood cells and bone marrow were first reported by Dr Eward Krumbhaar in 1919 after treating exposed patients in France [6]. He noticed that even if the early clinical course of these patients was accompanied by an increase in the total number of white blood cells, those individuals who survived for several days developed a profound decrease in blood cells. During WWII, the US Office of Scientific Research and Development (OSRD) funded Yale University to conduct chemical welfare research in secrecy [2]. The research team was led by Dr Alfred Gilman, a pharmacologist and Dr Louis Goodman, a physician and pharmacologist. Their studies supported the previous observations of leukopenia (low white blood cell count) by demonstrating that lymphomas in experimental animals dramatically decreased in size when exposed to mustard gas [7].

However, what brought the medical community's attention to the Yale group's studies and really launched the era of cancer chemotherapy was a WWII mustard gas incident. Humans were accidentally exposed to mustard gas during the bombardment of the Italian town of Bari on December 2, 1943 [2]. The SS John Harvey, a Liberty ship which was stationed on Italy's Bari harbor had a stockpile of 100 tons of mustard gas [4]. As a result of the bombardments of that night, seventeen ships sank, including the SS John Harvey thus emitting the stockpile of mustard gas. Nobody aboard the SS John Harvey survived and as a consequence the townspeople of Bari did not know they were under mustard gas intoxication. In the days and weeks following this catastrophe, the other military and civilian victims from the accident began to develop the familiar signs of mustard gas exposure. Lieutenant Colonel Stewart F Alexander, an American physician trained in chemical warfare confirmed the exposure to mustard gas, based on autopsies of the victims that had profound medullar damage, particularly a low white blood cell count [4].

mustard gas-02White blood cells are capable of rapidly dividing which prompted the attention that this chemical agent could be useful in killing rapidly dividing cancer cells as well. As a consequence, the event at Bari enhanced the suspicion that the effect of mustard gas on blood cells could have medical use.

The first clinical trial investigating the use of mustard gas was conducted by Louis Goodman and Alfred Gilman in 1942, just before the events at Bari [9]. The clinical trial involved a patient identified as JD [10] diagnosed with advanced lymphosarcoma who received the first therapeutic trial with nitrogen mustard in low doses (Ten doses of 0.1 to 1.0 mg/kg intravenously). To everyone's amazement, the tumor regressed considerably but the effects were not permanent.

In 1946, all the results and findings were published and more research was conducted on chemical agents like nitrogen mustard giving rise to the first alkylating agents such as mechloretamine [10]. This also motivated other cancer research such as the study on folic acid that gave rise to methotrexate [11]. These events changed the perception of cancer therapy. In the late 1960s, with the introduction of combination of chemotherapy agents like nitrogen mustard, vincristine, methotrexate and prednisone (MOMP protocol) more and more patients had longer remission from cancer, allowing it to be conceived as a curable disease, particularly for diseases like lymphomas and leukemia [11].

mustard gas-03

What's next? What more can be done for cancer control

Since the 1970s, overall death rates from cancer have declined in the USA [12]. The five year survival rate for all cancer diagnosed between 1999 and 2005 was 68%, a substantial increase from the 50% reported in 1975 and 1977 [10]. Despite the improvements in cancer treatment, this condition still constitutes an important burden for health systems, particularly in low and middle income countries where the cancer burden is increasing. Every year almost 12.7 million new cancer cases are diagnosed globally and in the region of Latin America and the Caribbean, cancer is the second leading cause of death and responsible for approximately 2.5 million new cases and 1.2 million deaths [13]. In low and middle income countries the main challenges for cancer control are poorer access to cancer screening and treatment and as a consequence presentation at more advances stages, when they are less amenable to cure.

Even if the mustard gas accidents of Bari were the pivotal events that launched the research for cancer chemotherapy, nowadays more research must be done not only to encourage individuals to adopt healthy behaviors to prevent cancer, but also to develop more effective screening methods to detect cancer at earlier stages and also to orient national health systems to make affordable and effective cancer treatments available to everybody.

More on www.paho.org/researchportal/casestudies

References

[1] R. J. Papac, Origins of Cancer Therapy, Yale Journal Of Biology And Medicine , 2001; 74: 391-398.
Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2588755/pdf/yjbm00015-0028.pdf
(Last accessed: 17 April 2014)

[2] G. Faguet, The War on Cancer: An Anatomy of Failure, a Blueprint for the Future, Dordrecht, Netherlands: Springer press, 2005.

[3] G. Reminick, Nightmare un Bari: The World War II Liberty Ship Poison Gas Disaster and Coverup, Palo Alto, Calif: The Glencannon Press, 2001.

[4] J. Frunzi, "From Weapon to Wonder Drug," The Hospitalist, 2007.
Available at: http://www.the-hospitalist.org/details/article/243771/From_Weapon_to_Wonder_Drug.html
(Last accessed: 17 April 2014)

[5] Pratt WB, Ruddon RW, Ensminger WD, et al, The Anticancer Drugs 2nd Edition, 1994. New York: Oxford University Press, 352 pages

[6]     K. H. Krumbhaar EB, The blood and bone marrow in yellow cross gas (mustard gas) poisoning, Pensylvania: John Herr Musser Department of Research Medicine, 1919. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2104437/pdf/jmedres00019-0266.pdf
(Last accessed 17 April 2014)

[7] C. Rhoads, The Edward Gamaliel Janeway Lecture: the sword and the ploughshare, Journal of Mt Sinai Hospital, 1946.; 13: 299-309

[8] Hirsch J. An anniversary for cancer chemotherapy. JAMA. 2006; 296:1518-1520.

[9] L. Goodman, M. Wintrobe, W. Dameshek, M. Goodman, A. Gilman and M. McLennan, Nitrogen mustard therapy: use of methyl-bis (beta-choloethyl)amuine hydrochloride abd tris (beta-chloroethyl) amine hydrochloride for Hodgkin's disease, lymphosarcoma, leukema and certain allied and miscellaneous disorder [landmark article]. JAMA, 1946; 132: 126-132.

[10] P. Christakis, The Birth of Chemotherapy at Yale,Yale Journal of Biology and Medicine ; 84: 169-172., 2011.
Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117414/pdf/yjbm_84_2_169.pdf
(Last accessed: 17 April 2014)

[11] T. De Vita and E. Chu.  A History of Cancer Chemotherapy. American Association for Cancer Research, 2008; 68: 8643-8653.
Available at: http://cancerres.aacrjournals.org/content/68/21/8643.long
(Last accessed: April 17 2014)

[12] American Cancer Society. Cancer Facts and Figures 2013.
Available at: http://www.cancer.org/research/cancerfactsstatistics/index?ssSourceSiteId=null
(Last accessed: April 17 2014)

[13] The Lancet Oncology Commission. Planning cancer control in Latin America and the Caribbean. The Lancet, 2013; 14: 391-436.
Available at: http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70048-2/abstract (Last accessed: April 17 2014)


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