Search

Plant compounds associated with herbivore defence occur widely in floral nectar and can impact pollinator health. We showed previously that Rhododendron ponticum nectar contains grayanotoxin I (GTX I) at concentrations that are lethal or sublethal to honeybees and a solitary bee in the plant's non-native range in Ireland. Here we further examined this conflict and tested the hypotheses that nectar GTX I is subject to negative pollinator-mediated selection in the non-native range, but that phenotypic linkage between GTX I levels in nectar and leaves acts as a constraint on independent evolution. We found that nectar GTX I experienced negative directional selection in the non-native range, in contrast to the native Iberian range, and that the magnitude and frequency of pollinator limitation indicated that selection was pollinator-mediated. Surprisingly, nectar GTX I levels were decoupled from those of leaves in the non-native range, which may have assisted post-invasion evolution of nectar without compromising the anti-herbivore function of GTX I (here demonstrated in bioassays with an ecologically relevant herbivore). Our study emphasizes the centrality of pollinator health as a concept linked to the invasion process, and how post-invasion evolution can be targeted toward minimizing lethal or sub-lethal effects on pollinators. This article is part of the theme issue ‘Natural processes influencing pollinator health: from chemistry to landscapes’.

Background: Gastrointestinal Stromal Tumors (GIST) treatment was revolutionized by the introduction of the tyrosine kinase inhibitor imatinib. More recently, sunitinib, has prolonged survival in patients (pts) with metastatic disease resistant to imatinib. 10-year survival for high-risk pts treated with adjuvant imatinib is 79%. Median overall survival for pts with unresectable or metastatic GIST is 4.8 years. In order to bring access to these life-saving medications to pts in low- and middle- income countries (LMICs), The Max Foundation (TMF) developed its Max Access Solutions (MAS) program in 2017, after administering Novartis’ imatinib (Glivec) International Patient Assistance Program (GIPAP) since 2002. We analyzed the outcomes of pts enrolled in these programs from 2002-2020 for both adjuvant (n=2100) or metastatic (n=9,867) GIST across 67 countries. Methods: Demographic data and treatment indications were reported by treating physicians. The clinical status of each enrolled pt was reviewed with TMF every 3-4 months. Pts who were lost to follow-up (LTFU) (n=2282) with metastatic or unresectable disease were presumed to be deceased. Alternatively, for patients treated in the adjuvant setting an imputation based informed censoring model was used to estimate events for LTFU patients (n=477). Kaplan-Meier analysis was used to estimate the distribution of progression-free (PFS) and overall survival (OS). Results: The median age at diagnosis was 54 and 55 years in the adjuvant and metastatic groups, respectively. Males comprised 59.5% of all metastatic/unresectable cases and females 51.3% of adjuvant cases. Median OS for pts treated with imatinib for unresectable or metastatic disease was 5.8 years (CI: (5.6, 6.1)) and PFS was 3.5 years (CI: (3.5, 3.7)). Pts treated with imatinib in the adjuvant setting had a 10-year OS of 72% and PFS of 70%. Median OS of pts with metastatic disease treated with sunitinib was 2 years (CI: (1.5, 2.5)); PFS was 1.2 years (CI: (0.9, 1.6)). Multivariate analysis showed that male sex was a negative prognostic factor in both the metastatic and adjuvant setting. Other variables including World Bank Income groups and frequency of contact were not associated with increased mortality or progression in any group. Discussion: This is the largest known cohort of GIST outcomes and the first study to present outcomes from predominantly low- and middle-income countries. Additionally, studies in LMICs are challenged by high rates of lost to follow-up which can falsely prolong or shorten survival times due to censoring. Therefore, we employed an informed censoring model to better reflect survival in the adjuvant setting. We demonstrate that access to a targeted oral anti-cancer therapy results in outcomes similar to those in high resource countries and provides a model to help close the global gap in cancer outcomes. Citation Format: Edward Lloyd Briercheck, J. Michael Wrigglesworth, Philip Stevenson, Alicia A. Annamalay, Pat Garcia-Gonzalez, Michael Wagner. Outcomes of an expanded access program for patients with gastrointestinal stromal tumors in low- and middle-income countries [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 495.

Cancer centers are beginning to emerge in low- and middle-income countries despite having relatively few oncologists and specialists in related fields. Uganda, like many countries in sub-Saharan Africa, has a cadre of highly motivated clinician-scientists-in-training who are committed to developing the capacity for cancer care and research. However, potential local mentors for these trainees are burdened with uniquely high demands on their time for clinical care, teaching, institutional development, advocacy, and research. Facilitated peer mentoring helps to fill skills and confidence gaps and teaches mentoring skills so that trainees can learn to support one another and regularly access a more senior facilitator/role model. With an added consultant component, programs can engage limited senior faculty time to address specific training needs and to introduce junior investigators to advisors and even potential dyadic mentors. Two years after its inception, our facilitated peer mentoring career development program at the Uganda Cancer Institute in Kampala is successfully developing a new generation of researchers who, in turn, are now providing role models and mentors from within their group. This program provides a practical model for building the next generation of clinical scientists in developing countries.