This study externally validated a chemotherapy toxicity predictive model for older adults with cancer. This predictive model should be considered when discussing the risks and benefits of chemotherapy with older adults.

Survival of cancer cells relies on the unfolded protein response (UPR) to resist stress triggered by the accumulation of misfolded proteins within the endoplasmic reticulum (ER). The IRE1α-XBP1 pathway, a key branch of the UPR, is activated in many cancers. Here, we show that the expression of both mature and spliced forms of XBP1 (XBP1s) is up-regulated in acute myeloid leukemia (AML) cell lines and AML patient samples. IRE1α RNase inhibitors [MKC-3946, 2-hydroxy-1-naphthaldehyde (HNA), STF-083010 and toyocamycin] blocked XBP1 mRNA splicing and exhibited cytotoxicity against AML cells. IRE1α inhibition induced caspase-dependent apoptosis and G1 cell cycle arrest at least partially by regulation of Bcl-2 family proteins, G1 phase controlling proteins (p21cip1, p27kip1 and cyclin D1), as well as chaperone proteins. Xbp1 deleted murine bone marrow cells were resistant to growth inhibition by IRE1α inhibitors. Combination of HNA with either bortezomib or AS2O3 was synergistic in AML cytotoxicity associated with induction of p-JNK and reduction of p-PI3K and p-MAPK. Inhibition of IRE1α RNase activity increased expression of many miRs in AML cells including miR-34a. Inhibition of miR-34a conferred cellular resistance to HNA. Our results strongly suggest that targeting IRE1α driven pro-survival pathways represent an exciting therapeutic approach for the treatment of AML.

QUESTION ASKED: Does a computer-based approach for collecting geriatric assessment information provide a practical and efficient means of obtaining reliable and reproducible data from older adults with cancer?SUMMARY ANSWER: Computer-based geriatric assessment provides a feasible, reliable, and valid approach in older adults with cancer. WHAT WE DID:Older patients ($ 65 years) with cancer were randomly assigned to one of four treatment arms to compare the feasibility, reliability, and validity of two computer-based platforms for geriatric assessment with traditional paper-and-pencil data capture.WHAT WE FOUND: Completion times were similar for computer-based and paper-and-pencil assessments (Fig), and data gathered via computer-based assessment showed high test-retest reliability as well as internal consistency. BIAS, CONFOUNDING FACTOR(S), REAL-LIFE IMPLICATIONS:Many of the patients in our study were white, non-Hispanic, and college-educated older adults. This patient population may be more comfortable using computer technologies than other demographic groups; thus our results may not be generalizable to other segments of the patient population. Older patients with cancer are at increased risk for treatment toxicity. Geriatric assessment captures a range of physiological and psychological metrics that predict toxicity and survival, and thus have high utility in guiding interventions. In the current study, we found that computer-based geriatric assessment provides an efficient method for acquiring reliable and valid data. Adoption of computer-based geriatric assessment into oncology practice thus can provide a cost-and time-efficient approach for acquiring high-value data to be used in formulating treatment decisions for older adults with cancer. Completion Time (minutes) Abstract PurposeThe goal of this study was to evaluate the feasibility, reliability, and validity of a computerbased geriatric assessment via two methods of electronic data capture (SupportScreen and REDCap) compared with paper-and-pencil data capture among older adults with cancer. MethodsEligible patients were $ 65 years old, had a cancer diagnosis, and were fluent in English.Patients were randomly assigned to one of four arms, in which they completed the geriatric assessment twice: (1) REDCap and paper and pencil in sessions 1 and 2; (2) REDCap in both sessions; (3) SupportScreen and paper and pencil in sessions 1 and 2; and (4) SupportScreen in both sessions. The feasibility, reliability, and validity of the computer-based geriatric assessment compared with paper and pencil were evaluated. ResultsThe median age of participants (N = 100) was 71 years (range, 65 to 91 years) and the diagnosis was solid tumor (82%) or hematologic malignancy (18% ). There were no significant differences in completion times between SupportScreen and paper and pencil (P = .50). The computer-based geriatric assessment was feasible. Few participants (8%) needed help with completing the geriatric assessment (REDCap, n = 7 and SupportScreen, n = 1), 89% reported th...

BACKGROUND/OBJECTIVES Caregivers of older adults with cancer assist both with cancer care and other health issues, which may make them vulnerable to consequences of caregiving. Hospitalization may represent a time when a caregiver's ability to provide care at home is exceeded. We sought to characterize caregivers of hospitalized older adults with cancer, determine their quality of life (QOL), and identify factors associated with caregiver QOL. METHODS Patients (n = 100), aged 65 years and older, with an unplanned hospitalization and their caregivers were included. Caregivers completed a questionnaire about their health, social support, caregiving relationship, QOL (Caregiver Quality of Life Index‐Cancer [CQOLC] tool), and patient function. Patient medical history was obtained via chart review. The association between patient, caregiving, and caregiver factors and CQOLC was determined using multivariate linear regression. RESULTS Most patients (73%) had metastatic/advanced disease, and 71% received treatment for their cancer within 30 days of hospitalization. Median Karnofsky Performance Status (KPS) was 60%, and 89% required help with instrumental activities of daily living, as reported by caregivers. Median caregiver age was 65 years (range = 29‐84 years). The majority (60%) had no major comorbidities and rated their health as excellent/good (79%), though 22% reported worsening health due to caregiving. Caregivers had a median Mental Health Inventory‐18 score of 70 (range = 0–97), a median Medical Outcomes Study (MOS)‐social activity score of 56 (range = 0–87.5), and a median MOS‐Social Support Survey score of 68 (range = 0–100). Caregivers provided a median of 35 hours of care per week (range = 0‐168 hours of care per week). Mean CQOLC was 84.6 ± 23.5. Lower caregiver QOL was associated with poorer caregiver mental health, less social support, and poorer patient KPS (P < .05). CONCLUSION Caregivers of hospitalized older adults with cancer are older but generally in good health. Those with poorer mental health, less social support, and caring for patients with poorer performance status are more likely to experience lower QOL. J Am Geriatr Soc 67:978–986, 2019.

Purpose Age-based reduction of chemotherapy dose with the first cycle (primary dose reduction, PDR) is not routinely guideline recommended. Few studies, however, have evaluated how frequently PDR is utilized in the treatment of older patients with cancer and which factors may be associated with this decision. Methods We conducted a secondary analysis of a multi-institutional prospective cohort study of patients age ≥65 years treated with chemotherapy. The dose and regimen were at the discretion of the treating oncologist. The prevalence of PDR and its association with treatment intent (palliative vs. curative), tumor type, patient characteristics (sociodemographics and geriatric assessment variables), and chemotherapy-associated toxicity were evaluated. Results Among 500 patients (mean age 73, range 65–91 years), 179 patients received curative intent chemotherapy and 321 patients received palliative intent chemotherapy, with PDR being more common in the latter sub-group (15% vs. 25%, p = 0.005). Increasing age was independently associated with PDR in both sub-groups. Comorbidity (prior cancer or liver/kidney disease) was independently associated with PDR in the palliative sub-group alone while Karnofsky Performance Status (KPS) was not associated with PDR in either subgroup. There was no significant difference in the rates of grades 3–5 toxicity, dose reductions, or delays with PDR. Patients in the palliative sub-group treated with PDR had higher rates of hospitalization compared to those treated with standard doses. Conclusion PDR is more common in the palliative setting, but is also utilized among patients treated with curative intent. Factors associated with PDR include age and comorbid conditions, but not KPS.

Author contributions: Fakih M designed and supervised the trial; Fakih M and Cho M wrote the paper; Telatar M, Afkhami M, Sentovich S and Melstrom K contributed to the analysis; Cho M, Akiba C and Lau C collected and analysed data; Smith D did the statistical analysis.Institutional review board statement: This study was reviewed and approved by the City of Hope National Medical Center.Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymous clinical data. Conflict-of-interest statement:We have no pertinent financial relationships to disclose. METHODS:In this retrospective study, we investigated the impact of RAS and BRAF mutational status on pattern of metastatic disease and CEA production. Only patients presenting with a newly diagnosed metastatic colorectal cancer (CRC) were included. Patients' characteristics, primary tumor location, site of metastatic disease and CEA at presentation were compared between those with and without RAS and BRAF mutations. RESULTS:Among 174 patients, mutations in KRAS , NRAS and BRAF were detected in 47%, 3% and 6% respectively. RAS mutations (KRAS and NRAS ) were more likely to be found in African American patients (87% vs 13%; P value = 0.0158). RAS mutations were associated with a higher likelihood of a normal CEA (< 5 ng/mL) at presentation. BRAF mutations were more likely to occur in females. We were not able to confirm

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Survival of cancer cells rely on the unfolded protein response (UPR) to resist stress triggered by the accumulation of misfolded proteins within the endoplasmic reticulum (ER). IRE1α-XBP1 pathway, one of the most important branches of the UPR, is activated in different types of cancer. Upon IRE1α activation, the spliced form of XBP1 (XBP1s) is generated and acts as a transcription factor for many pro-survival genes to prevent cellular death and relieve cellular stress. Blockade of the IRE1α-XBP1 pathway can be considered as a potential anti-cancer strategy. Acute myeloid leukemia (AML) is the most common acute leukemia in adults. We find that XBP1 and XBP1s are up-regulated in AML cell lines and samples from patients. IRE1α RNase inhibitors including STF-083010, HNA and MKC-204 blocked XBP1 mRNA splicing and exhibited modest cytotoxicity in liquid culture against AML cell lines (HNA, mean IC50, 31 µM, n=8) and AML samples from patients (HNA, mean IC50, 35 µM, n=18). Notably, the IRE1α inhibitor HNA caused a significant inhibition (mean IC50, 6 µM, n=6) of clonogenic growth in soft agar of AML cells from patients of different leukemic subtypes. In contrast, HNA had very little toxicity against normal human marrow committed myeloid colony forming cells (mean IC50, 123 µM, n=4). IRE1α inhibition in AML cells induced caspase-dependent apoptosis and G1 cell cycle arrest which was associated with regulation of Bcl-2 family proteins, G1 phase controlling proteins (p21cip1, p27kip1 and Cyclin D1) and Chaperone proteins (CHOP, HERPUD1, DNAJC3, DNAJB9 and EMDM). Absence of Xbp1 (Cre-induced deletion of floxed XBP1) resulted in the myeloid cells becoming resistant to IRE1α inhibitors. Combination of HNA with either bortezomib or As2O3 synergistically inhibited growth of NB4 acute promyelocytic leukemia cells associated with enhanced levels of p-JNK and reduced expression of p-PI3K and p-MAPK. Also, in a dose- and time- dependent manner, inhibition of IRE1α RNase activity increased expression of many miRNAs (especially miR-17, -21, -34a, -96, -125b and -150) in AML cells. Furthermore, HNA treatment inhibited mRNA levels of several miR-34a targeted genes (c-Myc, Cyclin D1 and CDK4). The inhibition of miR-34a conferred cellular resistance to HNA, as measured by significant increase of cell viability. Addition of a miR-34a antagonist restored protein expression levels of c-Myc and Cyclin D1 that had been inhibited by HNA, suggesting a crucial role of miR-34a in the IRE1α-mediated stress response pathway. Taken together, our results strongly suggest that targeting the IRE1α driven pro-survival pathways is an exciting therapeutic approach for the treatment of AML. Note: This abstract was not presented at the meeting. Citation Format: Haibo Sun, Behzad Kharabi Masouleh, Sigal Gery, Qi Cao, Serhan Alkan, Takayuki Ikezoe, Chie Akiba, Ronald Paquette, Wenwen Chien, Carsten Müller-Tidow, Yang Jing, Kharabi Masouleh, Markus Müschen, H. Phillip Koeffler. Inhibition of IRE1α-driven pro-survival pathways is a promising therapeutic application in acute myeloid leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 510. doi:10.1158/1538-7445.AM2014-510