Estimating survival in patients with gastrointestinal cancers and brain metastases: An update of the graded prognostic assessment for gastrointestinal cancers (GI-GPA).

BackgroundPatients with gastrointestinal cancers and brain metastases (BM) represent a unique and heterogeneous population. Our group previously published the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) for patients with GI cancers (GI-GPA) (1985-2007, n = 209). The purpose of this study is to update the GI-GPA based on a larger contemporary database.MethodsAn IRB-approved consortium database analysis was performed using a multi-institutional (18), multi-national (3) cohort of 792 patients with gastrointestinal (GI) cancers, with newly-diagnosed BM diagnosed between 1/1/2006 and 12/31/2017. Survival was measured from date of first treatment for BM. Multiple Cox regression was used to select and weight prognostic factors in proportion to their hazard ratios. These factors were incorporated into the updated GI-GPA.ResultsMedian survival (MS) varied widely by primary site and other prognostic factors. Four significant factors (KPS, age, extracranial metastases and number of BM) were used to formulate the updated GI-GPA. Overall MS for this cohort remains poor; 8 months. MS by GPA was 3, 7, 11 and 17 months for GPA 0-1, 1.5-2, 2.5-3.0 and 3.5-4.0, respectively. >30% present in the worst prognostic group (GI-GPA of ≤1.0).ConclusionsBrain metastases are not uncommon in GI cancer patients and MS varies widely among them. This updated GI-GPA index improves our ability to estimate survival for these patients and will be useful for therapy selection, end-of-life decision-making and stratification for future clinical trials. A user-friendly, free, on-line app to calculate the GPA score and estimate survival for an individual patient is available at brainmetgpa.com

Author Correction: Drivers of seedling establishment success in dryland restoration efforts

1 Pág. Correción errata.In the version of this Article originally published, the surname of author Tina Parkhurst was incorrectly written as Schroeder. This has now been corrected.Peer reviewe

Structural approaches in HIV prevention

Recognition that social, economic, political, and environmental factors directly affect HIV risk and vulnerability has stimulated interest in structural approaches to HIV prevention. Progress in the use of structural approaches has been limited for several reasons: absence of a clear definition; lack of operational guidance; and limited data on the effectiveness of structural approaches to the reduction of HIV incidence. In this paper we build on evidence and experience to address these gaps. We begin by defining structural factors and approaches. We describe the available evidence on their effectiveness and discuss methodological challenges to the assessment of these often complex efforts to reduce HIV risk and vulnerability. We identify core principles for implementing this kind of work. We also provide recommendations for ensuring the integration of structural approaches as part of combined prevention strategies

Isolation of T-Cell Receptors Specifically Reactive with Mutated Tumor-Associated Antigens from Tumor-Infiltrating Lymphocytes Based on CD137 Expression

The adoptive transfer of lymphocytes genetically modified to express tumor reactive T-cell receptors (TCR) can mediate tumor regression. Some tumor-infiltrating lymphocytes (TIL) recognize somatic mutations expressed only in the patient's tumors, and evidence suggests that clinically effective TILs target tumor-specific neoantigens. Here we attempted to isolate neoantigen-reactive TCRs as a prelude to the treatment of patients with autologous T cells genetically modified to express such TCRs. Mutations expressed by tumors were identified using whole-exome and RNA sequencing. Tandem minigene (TMG) constructs encoding 12-24 mutated gene products were synthesized, each encoding the mutated amino acid flanked by 12 amino acids of the normal protein sequence. TILs were cultured with autologous dendritic cells (DC) transfected with transcribed (IVT) mRNAs encoding TMGs and were evaluated for IFNγ secretion and CD137 expression. Neoantigen-reactive T cells were enriched from TILs by sorting for CD137 CD8 T cells and expanded Dominant TCR α and β chains were identified in the enriched populations using a combination of 5' rapid amplification of cDNA ends, deep sequencing of genomic DNA, PairSeq analysis, and single-cell RT-PCR analysis. Human PBL retrovirally transduced to express the TCRs were evaluated for recognition of relevant neoantigens. We identified 27 TCRs from 6 patients that recognized 14 neoantigens expressed by autologous tumor cells. This strategy provides the means to generate T cells expressing neoantigen-reactive TCRs for use in future adoptive cell transfer immunotherapy trials for patients with cancer.

Abstract LB-221: Diversity of tumor infiltrating lymphocyte recognition of diverse mutated antigens in cutaneous melanoma

Abstract The adoptive transfer of autologous tumor infiltrating lymphocytes (TIL) can mediate long term tumor regression in some patients with metastatic melanoma. Recent observations suggest that autologous melanoma TIL administered to patients in adoptive T cell therapy (ACT) protocols may frequently recognize multiple tumor-specific somatic mutations, findings that have been facilitated by advances in whole exome sequencing and RNAseq methods. In an attempt to evaluate the antigenic diversity of TIL and gain some insights into the potential association between the recognition of mutated antigens and clinical responses to TIL therapy, we analyzed between 7 and 30 individual cultures derived from resected melanoma tumor fragments and pooled populations of administered TIL from each of 5 patients for their ability to recognize mutated antigens expressed by patients’ autologous tumors. Two of the patients who were evaluated exhibited durable complete tumor regressions, 1 exhibited a partial response, and 2 were non-responders to ACT. Screening assays were carried out by evaluating the interferon gamma release stimulated by the co-culture of autologous patient TIL with autologous dendritic cells or EBV transformed B cells transfected with mini-genes encoding mutated antigens identified by exomic sequencing of patient tumors. Using this approach, we identified 10, 3, and 2 mutated antigens targeted by TIL from the 3 patients who responded to ACT. The TIL that were administered to 1 of the non-responders appeared to recognize at least 4 mutated antigens, whereas TIL administered to the second non-responder failed to recognize any of the mutated minigenes that were tested. Immuno-dominant mutated antigens that were recognized by the majority of the evaluated TIL fragment cultures, as well as the bulk population of infusion TIL, could be identified in each of the 4 patients in this study for whom mutated antigen targets could be identified. In addition, 1 or more sub-dominant mutated antigens that were recognized by one or a relatively small percentage of the screened TIL fragment cultures were identified from each of these same 4 patients. Future studies will be directed at developing methods for enriching T cells reactive with mutated epitopes from TIL or peripheral blood in an attempt to enhance the effectiveness of ACT for the treatment of patients with metastatic melanoma and that will hopefully lead to the development of effective therapies for the treatment of patients with other malignancies. Note: This abstract was not presented at the meeting. Citation Format: Jessica S. Crystal, Todd Prickett, Yong-Chen Lu, Jared J. Gartner, Maria Parkhurst, Alena Gros, Yong F. Li, Mona El-Gamil, Steven A. Rosenberg, Paul F. Robbins. Diversity of tumor infiltrating lymphocyte recognition of diverse mutated antigens in cutaneous melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-221. doi:10.1158/1538-7445.AM2015-LB-22