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Despite the rising burden of noncommunicable diseases, access to quality decentralized noncommunicable disease services remain limited in many low- and middle-income countries. Here we describe the strategies we employed to drive the process from adaptation to national endorsement and implementation of the 2016 Botswana primary healthcare guidelines for adults. The strategies included detailed multilevel assessment with broad stakeholder inputs and in-depth analysis of local data; leveraging academic partnerships; facilitating development of supporting policy instruments; and embedding noncommunicable disease guidelines within broader primary health-care guidelines in keeping with the health ministry strategic direction. At facility level, strategies included developing a multimethod training programme for health-care providers, leveraging on the experience of provision of human immunodeficiency virus care and engaging health-care implementers early in the process. Through the strategies employed, the country's first national primary health-care guidelines were endorsed in 2016 and a phased three-year implementation started in August 2017. In addition, provision of primary health-care delivery of noncommunicable disease services was included in the country's 11th national development plan (2017-2023). During the guideline development process, we learnt that strong interdisciplinary skills in communication, organization, coalition building and systems thinking, and technical grasp of best-practices in low- and middle-income countries were important. Furthermore, misaligned agendas of stakeholders, exaggerated by a siloed approach to guideline development, underestimation of the importance of having policy instruments in place and coordination of the processes initially being led outside the health ministry caused delays. Our experience is relevant to other countries interested in developing and implementing guidelines for evidence-based noncommunicable disease services.

Malgré la charge de morbidité croissante des maladies non transmissibles, l'accès à des services décentralisés de qualité pour lutter contre ces maladies reste limité dans de nombreux pays à revenu faible ou intermédiaire. Dans cet article, nous décrivons les stratégies qui ont été employées pour mener les étapes d'adaptation, de validation et de mise en œuvre à l'échelle nationale des Lignes directrices 2016 du Botswana sur les soins de santé primaires pour l'adulte. Ces stratégies ont inclus: une évaluation multiniveau détaillée avec une large implication des parties prenantes et une analyse approfondie des données locales; le recours à des partenariats universitaires; la promotion de l'élaboration d'instruments politiques propices; l'intégration de lignes directrices portant spécifiquement sur les maladies non transmissibles dans les lignes directrices générales sur les soins primaires, en écho à l'orientation stratégique du ministère de la Santé. Au niveau des établissements de santé, les stratégies ont inclus: la création d'un programme de formation multiméthode à destination des prestataires de soins; l'exploitation de l'expérience acquise dans la prise en charge du virus de l'immunodéficience humaine et l'implication des prestataires de soins très tôt dans le processus. Grâce aux stratégies employées, les premières lignes directrices nationales sur les soins de santé primaires ont été validées en 2016, et une étape de mise en œuvre graduelle, sur trois ans, a commencé en août 2017. De plus, la prestation de soins de santé primaires contre les maladies non transmissibles a été incluse dans le 11e plan national de développement du pays (2017-2023). Pendant la phase d'élaboration des lignes directrices, nous avons constaté toute l'importance, dans les pays à revenu faible et intermédiaire, de pouvoir compter sur de solides compétences interdisciplinaires en matière de communication, d'organisation, de création de coalitions et de réflexion systémique et d'obtenir une bonne compréhension technique des meilleures pratiques. Nous avons par ailleurs observé des retards provoqués par des problèmes d'incompatibilité d'agendas entre les différentes parties prenantes, exagérés par des approches cloisonnées lors de la phase d'élaboration des lignes directrices, par la sous-estimation de l'importance d'avoir des outils politiques déjà en place et par des difficultés de coordination des processus initialement pilotés hors du ministère de la Santé. Notre expérience peut être utile pour d'autres pays qui souhaiteraient élaborer et mettre en œuvre des lignes directrices pour des services de soins contre les maladies non transmissibles fondés sur des données probantes.

A pesar de la creciente carga de las enfermedades no transmisibles, el acceso a servicios de calidad descentralizados para estas enfermedades sigue siendo limitado en muchos países de bajos y medianos ingresos. A continuación, describimos las estrategias que empleamos para impulsar el proceso desde la adaptación a la aprobación nacional y la implementación de las directrices de atención primaria de la salud para adultos de Botswana de 2016. Las estrategias incluían una evaluación detallada a varios niveles con amplias aportaciones de las partes interesadas y un análisis a fondo de los datos locales; el aprovechamiento de las asociaciones académicas; la facilidad para elaborar instrumentos normativos de apoyo; la incorporación de directrices sobre las enfermedades no transmisibles en las directrices más amplias sobre la atención primaria de la salud, de conformidad con la dirección estratégica del Ministerio de Salud. A nivel de los centros de salud, las estrategias incluían la elaboración de un programa de capacitación multimétodo para los proveedores de servicios de salud, el aprovechamiento de la experiencia en la prestación de servicios de atención del virus de la inmunodeficiencia humana y la participación de los encargados de la ejecución de los servicios de salud en las primeras etapas del proceso. Gracias a las estrategias empleadas, en 2016 se aprobaron las primeras directrices nacionales de atención primaria de la salud del país y en agosto de 2017 se inició una aplicación por etapas de tres años. Además, la prestación de servicios de atención primaria de la salud para las enfermedades no transmisibles se incluyó en el 11º plan nacional de desarrollo del país (2017-2023). Durante el proceso de desarrollo de las directrices, aprendimos que eran importantes las buenas habilidades interdisciplinarias en comunicación, organización, formación de coaliciones y pensamiento sistémico, así como la comprensión técnica de las mejores prácticas en los países de ingresos bajos y medios. Por otra parte, las agendas desalineadas de las partes interesadas, exageradas por el enfoque aislado del desarrollo de las directrices, la subestimación de la importancia de contar con instrumentos de política y la coordinación de los procesos que inicialmente se llevaban a cabo fuera del ministerio de salud causaron retrasos. Nuestra experiencia es relevante para otros países interesados en desarrollar e implementar directrices para servicios de enfermedades no transmisibles basados en la evidencia.

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Recent analysis of relapse data from 1173 untreated early stage breast cancer patients with 16-20 year follow-up shows that frequency of relapse has a double peaked distribution. There is a sharp peak at 18 months, a nadir at 50 months and a broad peak at 60 months. Patients with larger tumors more frequently relapse in the first peak while those with smaller tumors relapse equally in both peaks. No existing theory of tumor growth predicts this effect. To help understand this phenomenon, a model of metastatic growth has been proposed consisting of three distinct phases: a single cell, an avascular growth, and a vascularized lesion. Computer simulation of this model shows that the second relapse peak can be explained by a steady stochastic progression from one phase to the next phase. However, to account for the first relapse peak, a sudden perturbation of the development at the time of surgery is necessary. Model simulations predict that patients who relapse in the second peak would have micrometastases in states of relatively low chemosensitivity when adjuvant therapy is normally administered. The simulation predicts that 15% of T1, 39% of T2, and 51% of T3 staged patients benefit from adjuvant chemotherapy, partially offsetting the advantage of early detection. This suggests that early detection and adjuvant chemotherapy may not be symbiotic strategies. New therapies are needed to benefit patients who would relapse in the second peak.

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The breast cancer treatment failure rate remains unacceptably high. The current breast cancer treatment paradigm, based primarily on Gompertzian kinetics and animal models, advocates short-course, intensive chemotherapy subsequent to tumor debulking, citing drug resistance and host toxicity as the primary reasons for treatment failure. To better understand treatment failure, we have studied breast cancer from the perspective of computer modeling. Our results demonstrate breast cancers grow in an irregular fashion; this differs from the Gompertzian mode of animal models and thus challenges the validity of the current paradigm. Clinical and laboratory data support the concept of irregular growth rather than the common claim that human tumors grow in a Gompertzian fashion. Treatment failure mechanisms for breast cancer appear to differ from those for animal models, and thus treatments optimize on animal models may not be optimal for breast cancer. A failure mechanism consistent with our results involves temporarily dormant tumor cells in anatomical or pharmacological sanctuary, which eventually result in aggressive metastatic disease.

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Since adjuvant chemotherapy and hormonal therapy generally extend disease free survival in breast cancer rather than provide a cure, we have examined the current breast cancer paradigm. Heterogeneity is a fundamental characteristic of breast cancer tissue and a well recognized aspect of the disease. There are variations in natural history, histopathology, biochemistry and endocrinology, and molecular biology of cancer tissues and cells within the tissues. A variety of data indicate that growth kinetics are also variable, not only from tumor to tumor, but also during the natural history of an individual's tumor. To better understand kinetic heterogeneity, a stochastic numeric computer model of the natural history of breast cancer has been developed. To be consistent with inter- and intratumor kinetic heterogeneity and with late relapse, the model predicts that tumors grow in an irregular fashion with alternating periods of growth and periods of dormancy rather than the generally accepted modified exponential, or Gompertzian fasion. The prediction of irregular growth has been compared to data relevant to growth characteristics of human breast cancer. Much data support the concept of irregular kinetics and temporary dormancy rather than steady, Gompertzian growth of human breast cancer. Thus, in addition to drug resistance, kinetic heterogeneity may help explain the limited impact that traditional chemotherpeutic treatment has had on mortality from breast cancer. Although the mechanisms underlying irregular growth need to be better understood, non-Gompertzian growth kinetics indicates that there may be alternative approaches for breast cancer treatment.

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It is generally accepted that human cancers grow in an exponential or Gompertzian manner. This assumption is based on analysis of the growth of transplantable animal tumors and on averages of tumor growth in human populations. A computer model of breast cancer in individual patients has raised some doubts about this assumption. The computer model predicts an irregular pattern of tumor growth that incorporates plateaus or dormant periods separated by Gompertzian growth spurts. Since growth patterns involving plateaus are not predicted by conventionally accepted exponential or Gompertzian kinetics, sufficient documentation of their existence may be regarded as some evidence that the computer model is correct. The literature has been surveyed to identify growth patterns specifically predicted by the model. The literature contains clinical evidence from individual patients of this growth pattern in primary breast, large intestine and rectum, and pulmonary cancers and metastatic pulmonary cancer. Much data, including the only breast data, are not consistent with exponential or Gompertzian kinetics but are explainable by irregular growth kinetics. Exponential growth is valid for some tumors and for short times, but there are many papers citing significant deviations from that growth. Exponential growth may accurately describe averages of human tumor growth and growth of multipassaged experimental tumors, but it is not valid for all individual tumors.

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