Patients In BC Research Articles

PD-(L)1 inhibitors plus bevacizumab and chemotherapy as first-line therapy in PD-L1 negative metastatic lung adenocarcinoma: A real-world data.

e20577 Background: Chemotherapies combined with immune checkpoint inhibitors (ICIs) and/or bevacizumab (named IC, BC and IBC respectively) are the preferred first-line options for PD-L1 negative and oncogenic driver wild-type metastatic lung adenocarcinoma. However, the optimal strategy is still undetermined. Methods: This retrospective real-world study enrolled PD-L1 negative metastatic lung adenocarcinoma patients from four cancer centers between January 1, 2018 and June 30, 2022. All the patients received IC, BC, or IBC as the first-line therapies. The efficacy and safety were evaluated. Results: A total of 205 patients were included, with 60, 83, and 62 patients in IC, BC, and IBC groups, respectively. Patients receiving IBC obtained the highest objective response rate (ORR) (43.5%) and disease control rate (DCR) (100%) relative to those receiving IC (40.4%, 84.2%) or BC (40.5%, 96.2%). Compared with the IC (6.74m) or BC (8.28m) group, IBC group improved significantly median progression-free survival (mPFS) (9.53m, P = 0.005). However, the difference in overall survival (OS) were not observed among the three groups. When analyzed based on different clinical and molecular information, we found that male gender, ever smoking, wild-type genes, and adrenal metastasis predicts superior PFS benefit when treated with IBC. In patients with liver metastasis, IBC or BC treatment achieved better PFS compared with IC. No additional adverse reactions were observed in IBC group compared with other two groups. Conclusions: Combined IBC treatment achieved superior DCR and PFS compared with IC or BC treatment in patients with PD-L1 negative metastatic lung adenocarcinoma, while did not increase the adverse events.

Initial health care costs for COVID-19 in British Columbia and Ontario, Canada: an interprovincial population-based cohort study.

Background:COVID-19 imposed substantial health and economic burdens. Comprehensive population-based estimates of health care costs for COVID-19 are essential for planning and policy evaluation. We estimated publicly funded health care costs in 2 Canadian provinces during the pandemic’s first wave.Methods:In this historical cohort study, we linked patients with their first positive SARS-CoV-2 test result by June 30, 2020, in 2 Canadian provinces (British Columbia and Ontario) to health care administrative databases and matched to negative or untested controls. We stratified patients by highest level of initial care: community, long-term care, hospital (without admission to the intensive care unit [ICU]) and ICU. Mean publicly funded health care costs for patients and controls, mean net (attributable to COVID-19) costs and total costs were estimated from 30 days before to 120 days after the index date, or to July 31, 2020, in 30-day periods for patients still being followed by the start of each period.Results:We identified 2465 matched people with a positive test result for SARS-CoV-2 in BC and 28 893 in Ontario. Mean age was 53.4 (standard deviation [SD] 21.8) years (BC) and 53.7 (SD 22.7) years (Ontario); 55.7% (BC) and 56.1% (Ontario) were female. Net costs in the first 30 days after the index date were $22 010 (95% confidence interval [CI] 19 512 to 24 509) and $15 750 (95% CI 15 354 to 16 147) for patients admitted to hospital, and $65 828 (95% CI 58 535 to 73 122) and $56 088 (95% CI 53 721 to 58 455) for ICU patients in BC and Ontario, respectively. In the community and long-term care settings, net costs were near 0. Total costs for all people, from 30 days before to 30 days after the index date, were $22 128 330 (BC) and $175 778 210 (Ontario).Interpretation:During the first wave, we found that mean costs attributable to COVID-19 were highest for patients with ICU admission and higher in BC than Ontario. Reducing the number of people who acquire COVID-19 and severity of illness are required to mitigate the economic impact of COVID-19.

The evolution of the education module for men with metastatic prostate cancer (mPC) in the prostate cancer supportive care (PCSC) program.

279 Background: The PCSC Program was initiated in 2013 at the Vancouver Prostate Centre to provide a comprehensive program for patients and partners with prostate cancer. This program provides educational sessions (ES) and clinical services, including decision-making for primary therapy, sexual health, pelvic floor physiotherapy, hormone therapy, counseling, exercise, and nutrition for patients in BC, Canada. In 2016, the PCSC Program expanded to BC Cancer Victoria and in 2017 to other BC Cancer sites. In 2018, medical oncologists (MDs) in Victoria (JR, SP) developed an Education Module addressing treatment options for men with metastatic hormone sensitive (mHSPC) and metastatic castration resistant (mCRPC) disease. MDs delivered in-person ES in Victoria in 2018 and, in 2019, added a virtual platform (VP) option. From 3-5/2020, the ESs were on hold due to the COVID pandemic and parental leaves. In 6/2020, the ESs resumed only on VP, and the PCSC Oncology Nurse Practitioner (NP), NI, gave the presentations for the MDs on leave. In 10/2020, due to a changing standard of care for mHSPC, the PCSC team consolidated the two ESs into one. We report on the evolution of this Education Module in response to both the changing standard of care and the COVID pandemic. Methods: We prospectively collected attendance and patient characteristic metrics from all ES for men with mPC. We tracked presenter type (MD vs. NP) and prospectively collected anonymous patient satisfaction questionnaires. Results: From 1/2018 to 1/2021, 100 men registered for 27 ES; 81 men, 41 partners, and 2 family members actually attended. 48/75 (64%) men were white, 39/75 (52%) retired, and 56/75 (74.7%) married. 47 men attended 12 mHSPC ES, 13 men attended ten mCRPC ES, and 17 attended four consolidated ES. MDs presented 15 ES, and the NP presented 12 ES. Responses to questions on 70 satisfaction surveys were similar for MD vs. NP presenters. 9 responders to the recently added VP-specific questions said they agreed (4) or strongly agreed (5) that it was beneficial to watch the ES at home on a computer. The Table below shows attendance per site per year. Conclusions: The ESs for men with mPC were well-received. Although there was a VP option before COVID, attendance increased significantly after the lockdown as patients and providers became more familiar with VPs. Satisfaction surveys confirmed that an NP could deliver the ES rather than MD. Consolidation of the mHSPC and mCRPC ES reflected the changing standard of care and resulted in more efficient use of presenter time. Virtual delivery of the sessions provided greater access to those living in distant or remote areas of the province and those in lockdown during the COVID pandemic. [Table: see text]

Contribution of MIR9 on Disease Progression of Chronic Myelogenous Leukemia

We have reported that MIR9, a microRNA, is overexpressed in leukemic cells derived from a certain fraction of patients with acute myeloid leukemia (AML). The aberrant expression confers poor clinical course. These lines of our evidence suggest that overexpression of MIR9 in leukemic blasts stimulates further malignant transformation in leukemic cells. This made us analyze expression levels of MIR9 in the bone marrow cells from patients with chronic myelogenous leukemia. Among 25 patients analyzed, (chronic phase (CP): n=19, accelerated phase (AP): n=1, myeloblastic phase (BP): n=5), three in BP showed aberrantly high expression of MIR9, while none of them in CP or AP did. Furthermore, we performed targeted sequencing on the genomic DNA derived from the bone marrow cells of the same series of patients to screen for known mutations in 104 genes associated with myeloid malignancies. As a result, four patients (80%) in BC showed some numbers of gene mutations (one mutation in one patients, and two, three and six mutations in one each patient), while only four patients (21%) in CP revealed up to 2 gene mutations. Mutations in epigenetics-regulating genes such as DNMT3A were detected in patients in both CP and BP, but those in BCOR, CBL, NRAS and TP53 were only in BP. In addition, aberrant MIR9 expression was associated with multiple gene mutations in two patients in BC. These data suggested that overexpression of MIR9 could at least partly contribute to disease progression of CML. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Baseline characteristics of systemic lupus erythematosus patients included in the Lupus Italian Registry of the Italian Society for Rheumatology.

To report baseline data of SLE patients enrolled in the Lupus Italian Registry (LIRE). Patients affected by SLE aged ≥ 16 years were consecutively recruited in a multicenter prospective study comparing two cohorts: patients starting biologic immunosuppressants (BC) and patients starting non-biologic immunosuppresants (NBC). 308 patients were enrolled, 179 in NBC and 129 in BC. Mean age at disease onset and at diagnosis was significantly higher in NBC (p = 0.023, p = 0.045, respectively). Disease duration was longer in BC (p = 0.022). Patients in BC presented arthritis more frequently (p = 0.024), those in NBC nephropathy (p = 0.03). Quality of life was worse in BC (p = 0.031). Anti-dsDNA, low C3, were significantly more frequent in BC (p < 0.001, p = 0.009, respectively). Mycophenolate, methotrexate and azathioprine were the drugs more frequently prescribed in NBC, Belimumab and Rituximab in BC. The predominant organ involvement was different in the two cohorts: kidney involvement predominated in NBC, joint involvement in BC. Despite the younger age at disease onset, patients of the BC had a longer disease duration and more frequently had taken a cumulative prednisone dosage greater than 10 g. Even the pattern of clinical manifestations inducing to prescribe biological rather than conventional immunosuppressants was quite different.Keywords: Autoantibody(ies), autoimmune disease, belimumab, cohort studies, glucocorticoids, immunosuppressants, rituximab, systemic lupus erythematosus.

Abstract PS4-22: Prevalence of HER2-low and HER2-zero subgroups and correlation with response to neoadjuvant chemotherapy (NACT) in patients with HER2-negative breast cancer

Abstract INTRODUCTION Current definition of HER2-positive BC follows ASCO/CAP guidelines using immunohistochemistry (IHC) and/or in situ hybridization (ISH)-based techniques. However, HER2 expression can be variable in cells that lack ERBB2 amplification. For example, HER2-negative tumors can express some level of HER2 protein by IHC (i.e. 1+ or 2+ and a negative ISH result) and are identified as HER2-low. Others have no expression and are considered HER2-zero. Innovative therapies have shown promising activity in patients in HER2-low BC. The aim of this study is to evaluate the association of HER2-low and HER2-zero status with response to NACT in HER2-negative BC. METHODS Retrospective cohort of patients with HER2-negative BC treated with NACT in four institutions in Brazil. Protocols of diagnosis, treatment and follow-up were standardized and based on international guidelines. Tumors with HER2 IHC score 0 were classified as HER2-zero whereas tumors with HER2 score 1+ and those with HER2 score 2+ with FISH-negative were classified as HER2-low. Patients were treated with anthracycline- and taxane- based chemotherapy. The following clinicopathological data were evaluated, when available: age, ER, Ki67, tumor size, lymph node (LN) status and response to NACT according to pCR status and residual cancer burden (RCB) index. Primary objective was to evaluate the prevalences and compare pCR rates among HER2-zero and HER2-low cases. Secondary objectives were to perform the same comparison within the HR-positive (HR+) and HR-negative subgroups. Pearsons chi squared tests were performed and a p value of &amp;lt;0.05 was considered statistically significant. RESULTS 331 patients were included in this analysis. 63% were HR+and 37% were TNBC. 50% were HER2-zero and 50% HER-low (36% HER2 IHC 1+ and 14% HER2 IHC 2+/FISH-negative). Median age, initial tumor size, clinical LN status and Ki67 expression were similar among HER2-zero and HER2-low subgroups. In HR+ tumors, 42% (86/207) were HER2-zero and 58% (121/207) were HER2-low. In TNBC, 63% (78/124) were HER2-zero and 37% (46/124) were HER2-low (p&amp;lt;0.001, Pearsons chi squared test). The pCR rate was 26% (85/331) in the entire cohort. As expected, there was a higher rate of pCR in TNBC vs HR+ (50% vs 11%, p&amp;lt;0.001). We found a statistically significant difference in the pCR rates when comparing the HER2-zero versus HER2-low subgroups (31% vs 20%, p=0.03). However, this difference is mostly related to an imbalance between groups (HER2-zero subgroups had a higher proportion of TNBC). Among HR+ tumors, there was no difference in the pCR rates between HER2-zero and HER2-low subgroups (8% vs 13%, p=0.35). In TNBC, we identified an interesting but non-statistically significant difference in pCR in HER2-zero vs. HER2-low tumors (56% vs. 39%, p=0.09). In the TNBC cohort we identified a non-statistically significant difference in RCB 0-I in HER2-zero vs. HER2-low tumors (p=0.06). With a 30 month median follow-up, PFS and OS data are immature. CONCLUSION The distribution of HER2-zero and HER2-low cases is different in HR+ and TNBC. HER2-low is more frequent in HR+ and HER2-zero in TNBC. We identified a higher pCR rate in HER2-zero compared to HER2-low tumors, even though this difference is associated with an imbalance between the two groups. Still, we identified a trend to higher pCR rate in HER2-zero compared to HER2-low tumors even within the TNBC subgroup. Identification of HER2-low and HER2-zero tumors may have clinical implications that should be further explored. Citation Format: Tomas Reinert, Guilherme Parisotto Sartori, Alessandra AB Souza, Rodrigo Pellegrini, Mahira L Rosa, Nathalia Rossatto, Guilherme P Coelho, Isnard E Litvin, Felipe Zerwes, Eduardo Millen, Francisco P Cavalcante, Antonio L Frasson, Marcia S Graudenz, Carlos H Barrios. Prevalence of HER2-low and HER2-zero subgroups and correlation with response to neoadjuvant chemotherapy (NACT) in patients with HER2-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-22.

Aberrant RAG-mediated recombination contributes to multiple structural rearrangements in lymphoid blast crisis of chronic myeloid leukemia.

Blast crisis of chronic myeloid leukemia is associated with poor survival and the accumulation of genomic lesions. Using whole-exome and/or RNA sequencing of patients at chronic phase (CP, n = 49), myeloid blast crisis (MBC, n = 19), and lymphoid blast crisis (LBC, n = 20), we found 25 focal gene deletions and 14 fusions in 24 patients in BC. Deletions predominated in LBC (83% of structural variants). Transcriptional analysis identified the upregulation of genes involved in V(D)J recombination, including RAG1/2 and DNTT in LBC. RAG recombination is a reported mediator of IKZF1 deletion. We investigated the extent of RAG-mediated genomic lesions in BC. Molecular hallmarks of RAG activity; DNTT-mediated nucleotide insertions and a RAG-binding motif at structural variants were exclusively found in patients with high RAG expression. Structural variants in 65% of patients in LBC displayed these hallmarks compared with only 5% in MBC. RAG-mediated events included focal deletion and novel fusion of genes associated with hematologic cancer: IKZF1, RUNX1, CDKN2A/B, and RB1. Importantly, 8/8 patients with elevated DNTT at CP diagnosis progressed to LBC by 12 months, potentially enabling early prediction of LBC. This work confirms the central mutagenic role of RAG in LBC and describes potential clinical utility in CML management.

Population-based assessment of relationship between volume of practice and outcomes in head and neck cancer patients treated in a provincially coordinated radiotherapy program

Background and purposeLiterature suggests that higher volumes of practice are associated with better survival outcomes for head and neck cancer (HNC) patients. The objective of this study was to evaluate the effect of treatment center on the overall survival (OS) and cancer-specific survival (CSS) in a provincially coordinated program. Materials and methodsA population-based provincial database was used to identify all patients in BC diagnosed for the first time with a primary non-thyroid HNC and treated with radiotherapy between 2006 and 2011. Results2330 HNC patients were included. On multivariable analysis, after controlling for age, gender, cancer stage, anatomical site, treatment and physician case frequency, OS (HR range=0.91–1.05; p=0.60–0.88) did not significantly differ by center. OS was also not significantly different for patients treated by physicians with low case frequency (HR=0.96; 0.81–1.13; p=0.60) and medium case frequency (HR=1.12; 0.84–1.49; p=0.43) in reference to high case frequency. There was no effect on OS or head and neck CSS when physician case frequency was treated as a continuous variable. ConclusionsIn our provincially coordinated radiotherapy program, there was no significant difference in survival between cancer centers after controlling for differences in rurality, physician case volume and other potential confounding variables.

Detection of BRCA1 Founder Mutation 185DELAG in Breast Cancer Patients using Pyrosequencing Technique

Background: Hereditary breast and ovarian cancer due to mutations in BRCA1 and BRCA2 is the most common cause of hereditary forms of both breast and ovarian cancer and occurs in all ethnic and racial populations. Till now, no assessments of the BRCA1 founder mutation have been performed by sequencing in Egyptian population. The aim of this pilot study was to detect the prevalence BRCA1 founder mutation 185DELAG in familial and sporadic breast cancer patients. Blood samples of 100 Egyptian female including 40 patients who had no significant family history of BC in their families (sporadic BC), 40 patients had at least 2 positive family history in their first degree relatives (familial BC), 20 control patients with no BC or history of breast cancer in their families. All subjects went for detection for 185DELAG mutation using Pyrosequencing technique. There were significant differences between familial and sporadic BC as regards their age (P=0.004) and in the premenopausal patients in familial BC than sporadic BC (P=0.02). Moreover, sporadic BC showed a significant increase in the ER and PR +ve, HER2/neu -ve (luminal A) than familial BC patients (P=0.012). As regards the mutation, we found a carrier frequency of 2.5% (95% confidence interval 1.1-2.4). There was no significant relation between mutation and type of BC, or between the hormonal profile of BC tumor and 185DELAG carriers. Conclusion: The prevalence of BRCA1 185AG deletion mutation is significantly lower than previously reported using other molecular techniques.

Data capture and communication during transfers to definitive care in an inclusive trauma system

IntroductionBackground trauma survivors in rural areas transferred to urban centers have higher mortality than trauma patients admitted directly to urban centers. Transfer data in trauma registries is important for injury control. Prehospital and early physiologic data may reflect processes of pre-hospital care. British Columbia currently has no standardized process for trauma patient data transfer. Patients and methodsWe performed a retrospective data analysis for major trauma patients (ISS>15) transferred to a Level I trauma center over a 1year period (n=243). Completion rates of paramedic form and ATLS primary survey variables were extracted. Nominal and interval descriptives were calculated. Documentation rates were considered deficient at <80% and severely deficient <60%. Odds ratios were calculated for primary facility data based on ISS ≥30 vs ISS <30, with 2-sided p-values for confidence intervals ResultsTwo hundred forty-three patients met inclusion criteria with a mean ISS of 26. Most injured patients were male (79%), the predominant mechanism was blunt (93%) and the average age at injury was 51 years old. Two hundred eighteen patients arrived by Emergency Health Services, and 140 (64%) of EHS pre-hospital forms were transferred with the patient chart. Pre-hospital airway, physiologic data, and GCS completion rates were severely deficient (43–49%). Primary facility data was adequately completed for airway management, systolic blood pressure, and heart rate in (80–83%). Completion rates were deficient for respiratory rate, GCS and temperature (60–77%). An ISS score ≥30 was significantly associated with a lower completion rate for GCS. Discussion and conclusionOverall, documentation for inter-hospital transfer of major trauma patients in BC has significant deficiencies. Physiologic and basic ATLS variables are often omitted in transferred charts. The potential for adverse events is high but performance improvement is achievable. We recommend education, training and a standardized trauma transfer protocol to improve system-wide information transfer.

Abstract P4-11-09: A randomized controlled trial of postoperative adjuvant therapy for elderly breast cancer patients: Comparison of health-related quality of life between clinical trial participants and decliners

Abstract Background: Health-related quality of life (HRQoL) is one of the important outcomes in cancer control trials and has increasingly become the one of the primary foci. Obtaining informed consent from participants is essential for participation in randomized controlled trials (RCTs), but the participation in these RCTs may directly influence HRQoL, because treatment options are determined according to the allocation schedule. To date, only a few studies have compared HRQoL between clinical trial participants and decliners. Patients and Method: The National Surgical Adjuvant Study of Breast Cancer 07 (N-SAS BC 07) is a randomized controlled trial in women with HER2-positive primary breast cancer who are over 70 years of age. The primary aim was to investigate the benefit of trastuzumab monotherapy compared with combination therapy using trastuzumab and chemotherapy. The study concept and design were published in concept paper (Sawaki M. et al., Jpn J Clin Oncol. 2011). In this study, patients were randomized to receive either trastuzumab plus chemotherapy or trastuzumab monotherapy. The primary endpoint was disease-free survival, and the secondary endpoints were overall survival, relapse-free survival, safety, HRQoL, comprehensive geriatric assessment (CGA) and cost effectiveness (protocol ID; NCT01104935). HRQoL and CGA were assessed at registration (baseline), 2 month, 1 year, and 3 years after the start of protocol treatments using the Functional Assessment of Cancer Therapy-General (FACT-G), Hospital Anxiety and Depression Scale (HADS), EuroQol 5 Dimension (EQ-5D), Tokyo Metropolitan Institute of Gerontology (TMIG) index of competence, and the Philadelphia Geriatric Center (PGC) Morale Scale. The patients who declined to participate in N-SAS BC 07 were registered in a cohort study to prospectively evaluate the subsequent treatment options and prognosis (07-Cohort). The same questionnaire that was used in N-SAS BC 07 was used in 07-Cohort to evaluate HRQoL and CGA at entry. Results: Patients were enrolled from October 2012 to October 2016. During this period, 275 and 123 patients were registered in N-SAS BC 07 and 07-Cohort, respectively. The mean age at entry of the patients in the N-SAS BC 07 and 07-Cohort groups was 73.9 and 74.6 years, respectively. The questionnaire response rates at baseline in the patients in N-SAS BC 07 and 07-Cohort groups were 89% and 82%, respectively. There were no significant differences in FACT-G, HADS, EQ-5D, or TMIG index of competence at baseline between the groups, but the mean (standard deviation) scores of PGC Morale Scale in N-SAS BC 07 and 07-Cohort groups were 10.8 (3.3) and 9.9 (3.7), respectively, with the scores being significantly greater in the N-SAS BC 07 group (p=0.020, t-test). Conclusion: The PGC Morale Scale provides a multidimensional approach to assess the psychological state of older people. This study indicated that participation in the RCT did not affect the baseline QoL of elderly patients but suggested that the baseline QoL of the RCT participants was better than decliners. Citation Format: Saito T, Sawaki M, Hozumi Y, Sagawa N, Iwata H, Kashiwaba M, Kawashima H, Kobayashi K, Taira N, Takashima T, Takahashi M, Tsuneizumi M, Nakayama T, Baba S, Bando H, Mizuno T, Yamaguchi M, Yamamoto Y, Uemura Y, Ohashi Y, Mukai H. A randomized controlled trial of postoperative adjuvant therapy for elderly breast cancer patients: Comparison of health-related quality of life between clinical trial participants and decliners. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-11-09.

Abstract P5-18-01: A randomized clinical trial of postoperative adjuvant therapy for elderly breast cancer patients: Conditions of obtaining informed consent and reasons for declining participation

Abstract Background: There are few randomized clinical trials examining adjuvant treatment in elderly breast cancer patients. While obtaining informed consent is essential for participation in clinical studies, there is little information on the frequency of agreement to participate among elderly patients. Furthermore, elderly patients might have specific reasons to decline participation. Patients and Method: The National Surgical Adjuvant Study of Breast Cancer 07 (N-SAS BC 07) is a randomized clinical trial in women over 70 years with HER2-positive primary breast cancer. The primary aim was to investigate the benefit of trastuzumab monotherapy compared with the combination of trastuzumab and chemotherapy. Key inclusion criteria were as follows: women between 70 and 80 years old with HER2-positive breast cancer; underwent curative operation; stage I to IIIA; with sufficient organ function. Patients were randomized to receive either trastuzumab plus chemotherapy or trastuzumab monotherapy. The primary endpoint was disease-free survival, and the secondary endpoints were overall survival, relapse-free survival, safety, health-related quality of life, and cost effectiveness (NCT01104935). It was not possible to predict the number of patients who would agree to participate. In order to comprehensively assess the effect of postoperative adjuvant therapy, we evaluated the reasons why eligible patients declined to participate. The patients were registered in a cohort study to prospectively evaluate the subsequent treatment options and prognosis (07-Cohort). This study examined the obtaining of informed consent for N-SAS BC 07 and the reasons for declining participation, and compared the clinicopathological backgrounds between the N-SAS BC 07 and 07-Cohort groups. Results: 398 eligible patients have been recruited. Informed consent to participate in N-SAS BC 07 has been obtained from 275 patients (69%) and 123 patients (31%) who declined to participate in the RCT have been registered in the 07-Cohort. The common reasons to decline participation in the RCT were "cannot choose the treatment option (55%)", "refused chemotherapy (16%)", "wanted chemotherapy (9%)", "anxious about clinical studies (9%)" and "family opposition (8%)". The mean ages of the patients in N-SAS BC 07 and 07-Cohort were 73.9 and 74.6 years old, respectively. There were no differences in stage, surgical procedure, lymph node metastasis, or co-morbidities between the groups. ER-positive rate was higher in 07-Cohort group compared with N-SAS BC 07 group (53% vs. 37%, p=0.017, χ2 test). Conclusion: While we expected the number of registrants to be small, since N-SAS BC 07 investigated whether elderly patients with HER2-positive breast cancer should undergo chemotherapy, almost 70% of the patients accepted informed consent. The most common reason to decline participation in N-SAS BC 07 was "cannot choose the treatment option" and the majority refused chemotherapy. Furthermore, ER-positivity was higher in the 07-Cohort group, which suggested that ER expression in the patients with HER2-positive breast cancer might influence their decision to participate in the study or to choose the treatment option. Citation Format: Sagara Y, Sawaki M, Taira N, Saito T, Kashiwaba M, Iwata H, Kobayashi K, Nakayama T, Bando H, Mizuno T, Yamamoto Y, Tsuneizumi M, Takahashi M, Yamaguchi M, Kawashima H, Takashima T, Uemura Y, Hozumi Y, Sagawa N, Mukai H, Ohashi Y. A randomized clinical trial of postoperative adjuvant therapy for elderly breast cancer patients: Conditions of obtaining informed consent and reasons for declining participation. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-18-01.

Addition of clonidine to bupivacaine in transversus abdominis plane block prolongs postoperative analgesia after cesarean section.

Background and Aims:The aim was to compare duration of postoperative analgesia with addition of clonidine to bupivacaine in bilateral transversus abdominis plane (TAP) block after lower segment cesarean section (LSCS).Material and Methods:One hundred American Society of Anesthesiologists (ASA) grade I and II pregnant patients undergoing LSCS under spinal anesthesia were randomly divided to receive either 20 ml bupivacaine 0.25% (Group B; n = 50) or 20 ml bupivacaine+1ug/kg clonidine bilaterally (Group BC; n = 50) in TAP block in a double-blind fashion. The total duration of analgesia, patient satisfaction score, total requirement of analgesics in the first 24 h, and the side effects of clonidine such as sedation, dryness of mouth, hypotension, and bradycardia were observed. P < 0.05 was taken as significant.Results:In 99 patients analyzed, TAP block failed in five patients. Duration of analgesia was significantly longer in Group BC (17.8 ± 3.7 h) compared to Group B (7.3 ± 1.2 h; P < 0.01). Mean consumption of diclofenac was 150 mg and 65.4 mg in Groups B and BC (P < 0.01), respectively. All patients in Group BC were extremely satisfied (P < 0.01) while those in Group B were satisfied. Thirteen patients (28%) in Group BC were sedated but arousable (P = 0.01) compared to none in Group B. In Group BC, 19 patients complained of dry mouth compared to 13 in Group B (P = 0.121). None of the patients experienced hypotension or bradycardia.Conclusion:Addition of clonidine 1 μg/kg to 20 ml bupivacaine 0.25% in TAP block bilaterally for cesarean section significantly increases the duration of postoperative analgesia, decreases postoperative analgesic requirement, and increases maternal comfort compared to 20 ml of bupivacaine 0.25% alone.

Abstract PR10: Use of random peptide array to discover cancer neo-antigens for vaccines and diagnostics

Abstract The humoral response to tumors could reveal tumor antigens recognized by immunosurveillance. We have developed the immunosignatures diagnostic technology to detect this tumor specific response. The technology profiles reactivity of sera antibodies on the HT330K chip with 330K addressable random peptides. We have shown that subjects with specific cancers have specific immunosignatures that are distinguished from health people and other cancers. Here we demonstrate that the signatures can be deciphered to indicate specific neo-antigens for any cancer. Neo-antigens caused by mistranscription in tumors can be the sources of tumor antigens. We have set up a database of predicted chimeric tumor antigens encoded by trans-splicing transcripts analyzed from EST databases. These transcripts encode the neo-epitopes by producing frame shift (FS) peptides from shifted reading frames of the downstream genes. We hypothesize that these predicted neo-antigens are frequently expressed in cancers and recognized by the immune system. We predict that these neo-antigens can be deciphered by their immunosignatures. To test the hypothesis, we assayed the sera from glioblastoma patients (GBM, n=16) and normal controls (NC, n=16) on the HT330K chip. The 1,000 most significantly different peptides between GBM and NC were selected. Recurrent motifs in these peptides were across searched in the neo-antigen database. The seven most frequently matched antigens were selected for further study: 2 of them were encoded by the in-frame fusion transcripts and others were encoded by the FS fusion transcripts. To validate the antibody reactivity of 7 deciphered neo-antigens, three overlapping peptides encompassing each of the antigens were synthesized and printed with unrelated peptides on the CIM10K array, which contains total 10,000 peptides. We analyzed NC (n=69) and GBM (n=19) with the CIM10K array. The positive cut off value of each peptide is the average plus two fold standard deviations of the NC. A positive sample was indicated as positive to at least one peptide of the antigen. The highest positive rates of 7 antigens is 11.6% in NC and 57.9% in GBM. 34.8% NC were positive to at least one antigen, 15.9% to more than one and only 4.3% positive to more than two antigens. No NC was positive to more than three antigens. This indicated the reactivity to these antigens is random in NC. The positive percentage in GBM were 89.5%, 73.7% and 47.4% respectively. 26.3% GBM was positive to more than three antigens. The implication is that cancer patients had much higher reactivity to these putative neo-antigens. To test if other cancers elicited reactions to these neo-antigens, we analyzed breast cancer sera (BC, n=95) with the CIM10K. Similar to GBM, 83.15% BC were positive to at least one antigen and 34.7% were positive to more than 3 antigens. Five of seven antigens had positive reactivity in more than 25% of patients in both GBM and BC. To further characterize these neo-antigens, we designed primers for RT-PCR analysis. We detected and sequence confirmed five fusion transcripts in GBM cDNAs. Two of the FS transcripts were also detected in multiple BC cDNAs and several normal tissues with lower level. Our interpretation is that the processing of the FS variants is primarily post-transcriptional in normal tissue but this processing is defective in tumors. Here we showed that the neo-antigens from predicted fusion transcripts are the targets of the cancer humoral immune response. The specific antibody response was only in cancer patients indicating that the expression of these antigens in normal tissues was below the sensitivity of the immune system. Most importantly, this work indicates that we can efficiently decipher neo-antigens from the immunosignatures of cancer subjects. This may be a new source of antigens for diagnosis and cancer vaccines. This abstract is also presented as Poster B35. Citation Format: Phillip Stafford, Josh Richer, Stephen Albert Johnston, Luhui Shen. Use of random peptide array to discover cancer neo-antigens for vaccines and diagnostics. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr PR10.

Comparison of Effect of Epidural Bupivacaine, Epidural Bupivacaine Plus Fentanyl and Epidural Bupivacaine Plus Clonidine on Postoperative Analgesia after Hip Surgery

Background: Management of postoperative pain is one of the most challenging and gratifying domains of anaesthesia. Search for an ideal adjuvant for post operative epidural analgesia still continues. Methods: A total of 75 healthy patients of both sexes in age group 50-80 years belonging to ASA status I and II posted for elective hip surgeries were enrolled and randomly divided into three groups of 25 each - Group B, Group BF and Group BC All the patients in the three groups received 3.5 ml Bupivacaine heavy (0.5%) intrathecally before surgery, followed by epidural bolus postoperatively, at ‘two segment sensory regression’ in following manner: initial bolus made to 10 ml with each group given - 7 ml of 0.125% Bupivacaine and 3 ml distilled water with adjuvant as 50 μg Fentanyl in group BF and 100 μg Clonidine in group BC. Top up of 7 ml was given to each group with 5 ml of 0.125% Bupivacaine and 2 ml distilled water with adjuvant as 50 μg Fentanyl in group BF and 75 μg Clonidine in group BC. Results: There was no statistically significant difference between the demographic profile. VAS scores were found to be better in Group BF and BC at most of the times and these scores were significantly lower than Group B. Rescue analgesia was required in 12% patients in Group B while none of the patients in Group BF or Group BC required rescue analgesia. Nausea, vomiting and pruritus were observed in 52% of the patients in Group BF and in none of the patients in Group BC and Group B.Degree of sedation was significantly more in Group BC when compared with Group BF and Group B. Conclusion: Combination of Bupivacaine-Clonidine was found to be a better option than Bupivacaine-Fentanyl for postoperative epidural analgesia in hip surgery patients.

A comparison of intrathecal dexmedetomidine, clonidine, and fentanyl as adjuvants to hyperbaric bupivacaine for lower limb surgery: A double blind controlled study

Background:Various adjuvants are being used with local anesthetics for prolongation of intraoperative and postoperative analgesia. Dexmedetomidine, the highly selective 2 adrenergic agonist is a new neuraxial adjuvant gaining popularity.Settings and Design:The study was conducted in prospective, double blind manner. It included 120 American Society of Anesthesiology (ASA) class I and II patients undergoing lower limb surgery under spinal anesthesia after approval from hospital ethics committee with written and informed consent of patients.Materials and Methods:The patients were randomly allocated into four groups (30 patients each). Group BS received 12.5 mg hyperbaric bupivacaine with normal saline, group BF received 12.5 mg bupivacaine with 25 g fentanyl, group BC received 12.5 mg of bupivacaine supplemented 30 g clonidine, and group BD received 12.5 mg bupivacaine plus 5 g dexmedetomidine. The onset time to reach peak sensory and motor level, the regression time of sensory and motor block, hemodynamic changes, and side effects were recorded.Results:Patients in Group BD had significantly longer sensory and motor block times than patients in Groups BC, BF, and BS with Groups BC and BF having comparable duration of sensory and motor block. The mean time of two segment sensory block regression was 147 ± 21 min in Group BD, 117 ± 22 in Group BC, 119 ± 23 in Group BF, and 102 ± 17 in Group BS (P > 0.0001). The regression time of motor block to reach modified Bromage zero (0) was 275 ± 25, 199 ± 26, 196 ± 27, 161 ± 20 in Group BD, BC, BF, and BS, respectively (P > 0.0001). The onset times to reach T8 dermatome and modified Bromage 3 motor block were not significantly different between the groups. Dexmedetomidine group showed significantly less and delayed requirement of rescue analgesic.Conclusions:Intrathecal dexmedetomidine is associated with prolonged motor and sensory block, hemodynamic stability, and reduced demand of rescue analgesics in 24 h as compared to clonidine, fentanyl, or lone bupivacaine.

Prognostic Factors in the Blastic and Accelerated Phase of Patients with Chronic Myeloid Leukemia (CML) in the Tyrosine Kinase Inhibitor (TKI) Era

AbstractAbstract 3786With the advent of TKIs, significant improvement has been made in the survival outcome of CML patients. Many prognostic factors have in identified in chronic phase CML patients. However, prognostic factors in blastic phase (BP) and accelerated phase (AP) of CML patients have not been previously investigated, especially in the era of TKIs.We have analyzed CML patients either been diagnosed in or progressed into BP or AP from 2000 to 2010 enrolled into the clinical trials with different TKIs such as imatinib, nilotinib, dasatinib, and bosutinib at MD Anderson Cancer Center. All demographic, clinicopathologic variables and medication data including TKIs and other medication were collected at the time of the diagnosis of BP or AP. Primary outcomes; progression free survival (PFS) and overall survival (OS) were defined as time from diagnosis of either BP or AP to treatment failure and death, respectively.Among a total of 260 CML patients, mean age was 51.4 (SD 14.1). Males were 59%. Caucasians were 72%; African-Americans, 12%; and Hispanics, 14%. Only 17% reached complete hematologic remission and 62% eventually died during the follow up (mean 4.1 yrs, SD 4.0 yrs). 26% were in BP and 74% in AP. 38 patients were in BP (n=9) or AP (n=29) at initial diagnosis. Mean time from initial diagnosis in chronic phase to BP or AP was 4.1 yrs (0 to 23 yrs). Among BP, 17% had lymphoid BP and 84% myeloid BP. Cytogenetic analysis at diagnosis demonstrated 38% had only Philadelphia chromosome (Ph) present while 62% had other chromosomal abnormalities besides Ph. 30% had received one or more prior TKI by the time of transformation. 64% started on monotherapy imatinib (no prior TKI), 15% nilotinib (86% prior TKI), 14% dasatinib (93% prior TKI), and 3% bosutinib (100% prior TKI); 3.5% received imatinib combined with other agents (57% prior monotherapy with imatinib). Median PFS was 0.7 yr and median OS, 2.4 yrs.Factors linked with worse PFS were higher bone marrow (BM) blast % (HR=1.01, p<0.001), higher peripheral blood (PB) blast % (HR=1.01, p<0.001), higher PB basophil % (HR=1.01, p=0.02), lower PB polymononuclear cells (HR=0.98, p<0.001), lower hemoglobin (HR=0.91, p=0.02), lower platelet counts (HR=0.99, p=0.045), and higher number of prior TKI treatments (HR=1.52, p<0.001). In AP, compared to other TKIs, imatinib was associated with superior PFS (HR=0.63, p=0.03) while nilotinib was linked with inferior PFS (HR=1.81, p=0.04). Dasatinib (HR=1.17, p=0.57) and bosutinib (HR=1.85, p=0.18) did not show difference in PFS. In BP, there was no difference in OS by TKIs. Concurrent use of ACE inhibitors, ARBs, statins, aspirin, or metformin with TKIs was not associated with change in PFS. In multivariate analysis adjusting for the above variables, only prior TKI use was associated with worse PFS (adjusted HR [AHR]=1.57, p=0.001). Imatinib (AHR=0.70, p=0.36) nor dasatinib (AHR=0.67, p=0.11) were no longer associated with favorable or unfavorable PFS.Factors associated with inferior OS were old age (HR=1.02, p<0.001), bigger spleen size (HR=1.03, p=0.001), higher BM blast % (HR=1.02, p<0.001), higher PB blast % (HR=1.02, p<0.001), lower PB polymononuclear cells (HR=0.98, p<0.001), lower hemoglobin (HR=0.80, p<0.001), lower platelet counts (HR=0.99, p=0.008), higher LDH (HR=1.0002, p<0.001), presence of other cytogenetic abnormality besides Ph (HR=1.45, p=0.03),and higher number of prior TKI treatments (HR=1.64, p<0.001). In AP, imatinib was associated with more favorable OS (HR=0.65, p=0.07) compared to others (nilotinib: HR=1.28, p=0.47; dasatinib: HR=1.70, p=0.077; bosutinib: HR=1.09, p=0.88). In BP, there was no difference in OS by TKIs. Concurrent use of ACE inhibitors, ARBs, statins, aspirin, or metformin with TKIs was not associated with change in OS. In multivariate analysis adjusting for the above variables, only age (AHR=1.01, p=0.002) and BM blast% (AHR=1.02, p=0.005) were associated with worse OS. Imatinib was no longer associated with favorable outcome (AHR=1.27, p=0.57).In conclusion, we identified spleen size, blast counts, and number of prior TKI use as major prognostic factors in CML patients in BC or AP. Imatinib was associated with favorable outcome. This is likely due to the fact that patients treated with imatinib had received no prior TKIs while most patients treated with 2nd generation TKI had. Further studies are required to validate our findings in a larger and prospective cohort. [Display omitted] [Display omitted] Disclosures:Kantarjian:Novartis: Research Funding; Bristol Myers Squibb: Research Funding; Ariad: Research Funding; Pfizer: Research Funding. Jabbour:Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Cortes:Pfizer: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding.

Molecular Response to Nilotinib 600 Mg Bid for Imatinib Resistance in a Patient with CML AP with Multiple Mutations Including G250E and E255K.

Abstract 4287Resistance to imatinib has emerged as a common management problem that has been addressed first by dose escalation and later by the use of second generation tyrosine kinase inhibitors (2TKI). In about half the cases the basis for acquired resistance to imatinib is the emergence of mutant bcr-abl whose “in vitro” sensitivity to 2TKIs has been reported. In theory, mutations with intermediate “in vitro” sensitivity to nilotinib could be overcome by the use of higher doses (600mg bid).Higher doses of nilotinib have been administered safely in phase I and II clinical trials involving patients in CP, AP and BC of CML. Total steady-state drug levels were reported in 18 patients receiving the 600mg bid and a dose-proportional increase in exposure was observed between the 400mg and 600mg bid schedules. The mean serum trough level at the steady-state was 1.7(mu)M at 400mg bid and 2.3(mu)M at 600mg bid.We present and discuss the successful use of 600mg bid of nilotinib in a patient with Chronic Myeloid Leukemia (CML) resistant to imatinib 800mg qd and to nilotinib 400mg bid in whom G250E and E255K mutations were sequentially detected. Previous publications have suggested that E255K is unresponsive to nilotinib.A 44 years old male was diagnosed with chronic phase CML with intermediate risk Sokal score and no histocompatible siblings; six months after diagnosis imatinib 600mg qd was started due to progression to AP. The patient achieved hematologic and cytogenetic remissions in 2 and 12 months respectively. Nineteen months later, loss of hematologic response was detected. Trials of imatinib 800mg qd and low dose Ara-C were not effective. Mutational analysis of bcr-abl revealed G250E, a p-loop mutation, with in vitro sensitivity to nilotinib. Within six months the patient had symptomatic transfusion-dependent anemia (Hb < 7 g/dL), bone pain, hepatomegaly and painful lymphadenopathy. Nilotinib 400mg bid was initiated with significant clinical improvement (becoming asymptomatic and transfusion independent in a few weeks). Within 18 months a complete cytogenetic response and a 2 log reduction of the bcr-abl transcripts by quantitative PCR was demonstrated (IS: 1,48%). Loss of hematologic response was observed six months later. There was quick deterioration of clinical status. A second mutation analysis demonstrated G250E and E255K.Nilotinib was then increased to 600mg bid with rapid clinical improvement, followed by CHR in four weeks. Weekly CBC and chemistry profile as well as monthly EKG's were performed for safety. Due to marrow fibrosis cytogenetics was not available, but a major molecular response could be demonstrated after 3-months with 4 log reduction of bcr-abl transcripts (IS: 0,026%). The depth of molecular response has continued to improve with 5 log reduction after seven months (IS: 0,0026%). No serious side effects was seen on the higher dose schedule. Mild indirect hyperbilirrubinemia has remained stable on serial measurements. There was no significant change in the QTc interval (baseline QTc: 0,33).Due to a favourable toxicity profile, nilotinib 600mg bid may be an option for refractory patients with mutations of intermediate sensitivity to nilotinib and who have progressed, especially when a suitable bone marrow donor is not identified. Disclosures:No relevant conflicts of interest to declare.

HBV superinfection in HCV chronic carriers: A disease that is frequently severe but associated with the eradication of HCV #

The impact of hepatitis B virus (HBV) superinfection in hepatitis C virus (HCV) chronic carriers was evaluated in a long-term follow-up study on 29 chronic anti-HCV carriers with acute hepatitis B (AVH-B) (Case group BC) and 29 anti-HCV negative patients with AVH-B (Control group B), pair-matched for age (+/-5 years), sex, and risk factors for the acquisition of HBV infection. Patients in Case group BC and those in Control group B showed similar initial HBV viral load and a similar trend of becoming negative for HBV-DNA. AVH-B showed a severe course more frequently in Case group BC than in Control group B (34.5% versus 6.9%, P < 0.05). Of the 28 patients in Case group BC alive at the end of the acute illness (one death from liver failure), 24 were followed up for 2-6 years, median 5 years: 22 patients became HBsAg-negative and two progressed to HBsAg-positive chronic hepatitis. HCV-RNA was undetectable in all patients during AVH-B; in the 24 patients with a long-term follow-up, HCV-RNA was detected in seven (29.2%) after 1 year, in 14 (58.3%) after 2 years, and in 18 (75%) after 3-6 years. The six patients who eradicated chronic HCV infection, compared with 18 showing reactivation of HCV replication, had higher values of aspartate aminotransferase and alanine aminotransferase and a higher prevalence of cases with severe AVH-B (83.3% versus 22.2%, P < 0.05). Although it can be life-threatening, HBV superinfection in HCV chronic carriers may lead to clearance of chronic HCV infection, especially in patients with severe AVH-B.

Survival analysis of sequential use of first-line tamoxifen versus aromatase inhibitors for estrogen-positive metastatic breast cancer in postmenopausal women

1093 Background: Tamoxifen has been the gold standard of treatment in postmenopausal women with estrogen receptor-positive (ER+) metastatic breast cancer (MBC). Over the past decade, new aromatase inhibitors (AIs)—anastrozole, letrozole, exemestane—have emerged as equally efficacious alternatives to tamoxifen. Recent data suggest that first-line AI therapy may even confer a moderate but statistically significant increase in overall survival compared to tamoxifen (∼4 months). Traditionally, patients with disease progression after tamoxifen are often treated with second-line AI. Similarly, tamoxifen may be used as second-line for disease progression after AI therapy. It is unclear if the sequence of use of tamoxifen vs. AI would confer any difference in benefits. We performed a population-based analysis of survival associated with sequential use of first-line tamoxifen versus AIs for ER+ MBC to examine whether there is any difference in overall survival for patients in BC. Methods: This is a population-based retrospective analysis. Patients were identified from the BC Cancer Agency Information System (CAIS), systemic therapy drug database, and the provincial registry (Breast Cancer Outcomes Unit). Data was analyzed for all postmenopausal women treated with the sequential use of tamoxifen to AIs and from AIs to tamoxifen for ER+ MBC (stage IV disease) from January 1998 through December 2003 in BC. Patients treated with other first-line hormonal agents were excluded. The primary outcome is overall survival, defined as the time to death by any cause from the date of first-line tamoxifen or AI therapy. Overall survival was compared between patients treated with tamoxifen versus AI. Results: We found that there is an overall survival benefit with the use of sequential first line tamoxifen to AI therapy in comparison to AI to tamoxifen in our patient population. Conclusions: This analysis will provide pertinent information regarding the survival benefit between the sequential use of first-line treatment with tamoxifen and AI. The preliminary data provided by this analysis will assist in decision making regarding appropriate sequential use of hormonal therapy for ER+ MBC. No significant financial relationships to disclose.