tbuckley/cabot-search huggingface dataset:
Outcomes of G-CSF alone vs G-CSF with upfront plerixafor vs G-CSF/chemotherapy for collection of autologous stem cells in patients with multiple myeloma.
Authors: Giampaolo Talamo, Melissa George, W. Christopher Ehmann, Joseph J. Drabick, Shin Mineishi
Journal: Journal of Clinical Oncology (2017)

e19504 Background: Strategies for optimizing the collection of peripheral blood stem cells (PBSC) for autologous stem cell transplant (ASCT) in patients with multiple myeloma (MM) vary among transplant centers, and include the use of G-CSF alone or in combination with plerixafor, or mobilization chemotherapy + G-CSF. In 2010, we started using “upfront” plerixafor, given on the day before the PBSC collection. Methods:We retrospectively analyzed the outcomes of 423 consecutive MM patients who underwent PBSC collections at the Penn State Hershey Cancer Institute. PBSC were collected after mobilization chemotherapy + G-CSF 5 mcg/Kg/day (group A, 91 pts), G-CSF alone, 10-16 mcg/Kg/day (group B, 72 pts), and G-CSF with “upfront” plerixafor 0.16-0.24 mg/Kg on the day before the stem cell collection (group C, 245 pts). Fifteen patients were excluded from the analysis because they collected with chemotherapy + plerixafor, received pegylated G-CSF, or plerixafor “on demand”, i.e., after failure to achieve an adequate number of stem cells on the first day of collection. We compared yields, number of days required for apheresis, clinical outcomes, and adverse events among these groups. Results: The median number of PBSC collected was 16.4 (range, 0.1-134), 4.2 (range, 0-12), and 6.2 (range, 0.2-41.2) million CD34 + cells/Kg in group A, B, and C, respectively (p&lt;0.001). The mean number of days to collect PBSC was 1.5, 1.5, and 1.3 in group A, B, and C, respectively (p=0.033). Collection failure, defined as a yield &lt;2 million CD34 + cells/Kg, was observed in 5 (5.5%), 9 (12.5%), and 15 (6.1%) patients of group A, B, and C, respectively (p&lt;0.001). Twenty patients in group A developed neutropenic fever requiring hospital admission, and 1 of them died of septic shock, whereas no mortality was observed in groups B or C. No difference in the rapidity of PBSC engraftment, progression-free survival, and overall survival was observed among the 3 groups. Conclusions:In patients with MM, the upfront use of plerixafor with G-CSF provided the best collection strategy: it avoided the morbidity and mortality associated with the mobilization chemotherapy, and it provided higher yields than G-CSF alone.
The Mayo Clinic experience in patients with metastatic melanoma who have failed previous pembrolizumab treatment.
Authors: Yiyi Yan, Jarrett Failing, Alexey A Leontovich, Matthew Stephen Block, Robert R. McWilliams, Lisa A. Kottschade, Roxana Stefania Dronca, Svetomir Markovic
Journal: Journal of Clinical Oncology (2016)

e21014 Background: Blockade of programmed death (PD-1) receptor has shown unprecedented rates of durable clinical responses in patients with metastatic melanoma. However, the majority of patients eventually progress on anti-PD-1 therapy. Currently, there is no standard strategy guiding the treatment in this setting, partly due to the lack of knowledge of the clinical course after PD-1 blockade failure. Methods: We retrospectively reviewed 140 patients with metastatic melanoma treated with pembrolizumab at Mayo Clinic, Rochester, between January 1, 2012 and November 1, 2015, identifying 70 patients who failed pembrolizumab treatment (due to disease progression or toxicity). The clinical outcomes and RECIST objective response rates (ORR) to treatments received after pembrolizumab were assessed. Results: Of the 70 patients who failed pembrolizumab therapy, 48 received further systemic therapies. Of these, 43 had complete follow-up data and were included in our analysis. Thirty patients received 1 line of subsequent therapy; while 13 patients received multiple subsequent treatments (average 2.5). Eighteen patients with a BRAF mutation received targeted therapy, 9 of whom received targeted therapy alone, with an ORR of 55.6% and 0% stable disease (SD). Nine of these 18 BRAF mutant patients received targeted therapy combined with chemotherapy and/or immunotherapy, with an ORR of 22.2% and 33.3% SD. Twenty two of the 43 patients received immunotherapy (nivolumab and/or ipilimumab or pembrolizumab)-based treatment (alone or in combination with chemotherapy), with an ORR of 31.8%, and 13.6% SD. Nineteen of the 43 patients received chemotherapy alone with an ORR of 26.3% and 0% SD. Conclusions: Patients with metastatic melanoma who failed previous pembrolizumab therapy appear to benefit from further systemic treatments, including additional immunotherapy. Combination therapies show favorable clinical outcomes. The biological mechanism of combining PD-1 blockade with other therapy modalities is currently being studied and will further improve patient outcomes.
Function and expression of checkpoint inhibitors and immune agonists on immune cells in monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM) and MM and tumor-specific T lymphocytes.
Authors: Jooeun Bae, Brandon Nguyen, Yu-Tzu Tai, Teru Hideshima, Dharminder Chauhan, Nikhil C. Munshi, Kenneth Carl Anderson
Journal: Journal of Clinical Oncology (2017)

11577 Background: Characterization of expression and function of immune regulatory molecules in tumor microenvironment will provide the framework for developing novel therapeutic strategies. Methods: We evaluated the expression and functional impact of various immuno-regulatory molecules, PD-1, PDL-1, PDL-2, LAG3, TIM3, OX40 and GITR, on the CD138 + tumor cells, myeloid derived suppressor cells (MDSC), and T cell subsets from patients with MGUS, SMM and active MM (newly diagnosed, relapsed, relapsed/refractory), and the myeloma-specific cytotoxic T lymphocytes (CTL) induced with XBP1/CD138/CS1 peptides. Results: PDL-1/PDL-2 was more highly expressed on CD138 + myeloma cells in active MM than SMM or MGUS. G-type MDSC (CD11b + CD33 + HLA-DR low CD15 + ). Treg cells (CD3 + CD4 + /CD25 + FOXP3 + ) numbers were increased and expressed higher levels of PD1/PD-L1 in active MM than in MGUS, SMM or healthy donors. Among the checkpoint molecules (PD-1, PDL-1, PDL-2, LAG3, OX40, GITR) evaluated, PD-1 showed the highest expression on CD3 + CD4 + and CD3 + CD8 + T cells in BMMC and PBMC from patients with active MM. Functionally, T cells from MM patients showed increased proliferation upon treatment with an individual immune agonist ( &gt; 150%) or checkpoint inhibitor ( &gt; 100%). Interestingly, each individual anti-checkpoint molecule induced proliferation of T cells expressing other checkpoint molecules. In addition, the blockade of PD1, LAG3 or TIM3 enhanced MM antigen-specific cytotoxicity, assessed by parameters including CD107a, granzyme B and IFN-g production, which was most prominent within the memory CTL subset of MM antigen-specific T cells. Conclusions: These results demonstrate an increased frequency of immune regulatory cells, which highly express checkpoint inhibitors in active MM. Direct stimulation with an immune agonist or blockade of a checkpoint inhibitor increased MM patients’ T cell proliferation and myeloma-specific CTL function, supporting development of combination immune regulatory therapies to improve patient outcome in MM.
Natural progression of symptoms after diagnosis of pancreatic cancer.
Authors: Katherine Elaine Fero, Daniel M Seible, Nicholas Cardillo, James Don Murphy
Journal: Journal of Clinical Oncology (2016)

e15748 Background: Numerous symptoms impact patient quality of life during and after a diagnosis of cancer. Among pancreatic cancer patients, common symptoms include pain, nausea and/or vomiting and depression. The goal of this study was to describe the incidence, timing and severity of cancer-related symptoms that negatively impact quality of life. Methods: We retrospectively reviewed records of all patients treated for pancreatic cancer at a single academic institution from 2004-2014. First report of cancer related pain was noted, as was first report of nausea and/or vomiting and depression after cancer diagnosis. For each patient we identified whether pain or nausea and/or vomiting was the primary diagnosis for any hospitalization after diagnosis. Additional demographic and clinical variables including stage and treatment details were recorded. Results: Two hundred and ninety eight consecutive patients with pancreatic adenocarcinoma were included in this study. Forty-three patients (14.4%) experienced nausea and/or vomiting at presentation. The majority of patients experienced nausea and/or vomiting at some time after diagnosis (207/298, 69.8%), including 24 patients (8.0%) who had symptoms severe enough to require hospitalization. At presentation 170 patients (57%) experienced pain; nearly every patient experienced cancer-related pain over the course of their disease after diagnosis (261/298, 88.2%). Most patients who experienced pain were treated with opioid analgesia (240/261, 92%) and 13 (4.9%) underwent radiotherapy for treatment of pain. Fifty patients (16.8%) had depressive symptoms at some point throughout their disease course and every patient who experienced depressive symptoms experienced cancer related pain (50/50, 100%). There was a small but significant difference in the proportion of patients experiencing cancer pain between patient groups (metastatic [96%] vs unresectable [97%] vs resectable [87%], p = 0.006). Conclusions: Pancreatic cancer carries a large symptom burden starting at diagnosis and extending throughout the patient’s disease course. These findings can help with patient communication and anticipatory planning to help optimize patient quality of life.
Delays in initial breast cancer treatment among black and white women in Boston.
Authors: Sharon Bak, Rachel A. Freedman, Erica T. Warner, Susan T Gershman, Karen M Freund, Beverly Moy, Eric A Jones, Tracy Ann Battaglia
Journal: Journal of Clinical Oncology (2018)

e18620 Background: The Boston Breast Cancer Equity Coalition was founded in 2014 to address the persistent mortality gap between black and white women with breast cancer living in Boston. Since delays in breast cancer care are known to impact outcomes, the Coalition evaluated the time to initiation of breast cancer treatment as a potential contributing factor in the breast cancer mortality gap, and to understand whether future interventions based on time to initial treatment are warranted in Boston. Methods: Using Massachusetts Cancer Registry data, we identified 1716 black and white non-Hispanic female Boston residents with stage 0-III breast cancer diagnosed between 2010 and 2014. The outcome of ‘delayed treatment’ was defined as receipt of first cancer treatment (surgery, chemotherapy, hormonal therapy or radiation) > 60 days from diagnosis. We performed multivariate logistic regression to examine delays, adjusting for age, stage, tumor subtype and insurance. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were calculated. Results: Of 1716 women, 33% were black with mean age of 60 years. For insurance, 49% had private, 28% Medicare, 16% Medicaid and 7% other. Black women were twice as likely to have delayed treatment when compared to white women (aOR 2.09, 95% CI 1.57, 2.78), as were women on Medicaid when compared to women with private insurance (aOR 2.25, 95% CI 1.56, 3.27). Women with Stage I (aOR 0.65, 95% CI 0.43,0.97), Stage II (aOR 0.59, 95% CI 0.37, 0.92) or Stage III (aOR 0.43, 95% CI 0.22, 0.83) disease were less likely to have delays in initial treatment (all vs. stage 0). Conclusions: In the city of Boston, we observed significant treatment delays for black women and those on Medicaid compared to white and privately-insured women. Our results suggest that interventions targeting women at risk for delayed initial treatment are necessary to address breast cancer disparities in Boston.
Real world experience with pembrolizumab and nivolumab for treatment of non-small cell lung cancer (NSCLC) in an Irish Regional Cancer Center.
Authors: Colum Dennehy, Will Mullally, Caitriona Goggin, Jack Patrick Gleeson, John Patrick Greene, Derek Gerard Power, Seamus O'Reilly, Dearbhaile Catherine Collins, Deirdre O'Mahony, Richard Martin Bambury
Journal: Journal of Clinical Oncology (2018)

e21196 Background: Immunotherapy (IO) has improved outcomes of advanced NSCLC patients in randomized clinical trials. Data on outcomes for these agents outside of a clinical trial setting in Ireland is lacking and is of importance to confirm the generalizability of trial data to real world patients. Prior retrospective studies have suggested that antibiotic use around the time of initiating IO can adversely affect outcomes due to alteration of the gut microbiome. Here we report outcomes for a cohort of patients treated outside of clinical trials and explore the association between antibiotic use and treatment outcomes. Methods: A retrospective review of all patients treated with IO (N = 39) for NSCLC from June 2015 and January 2018 was carried out. Baseline clinical factors (age, ECOG score, stage, presence of brain metastases, smoking status) and laboratory factors (histopathology, EGFR/ALK status, complete blood count, LDH) were collected. Patients were defined as Abx+ if they received therapeutic antibiotics within 2 months before and 1 month after starting IO. Treatment outcomes were analysed by measuring objective response rate (ORR), progression free (PFS) and overall survival (OS). Results: Median age at diagnosis was 63 years (range 46-78). The majority of patients were male (61%), had de novo metastatic disease (60%) and adenocarcinoma histology (58%). ORR was 18% and the median duration of response was 9 months (95% CI 5-14 months). The median PFS was 3.4 months (95% CI 2.2-4 months) and median OS was 7.3 months (95% CI 0-15 months). Abx+ patients had numerically inferior PFS (median 2.1 vs 3.4 months, p = 0.16) and OS (4.0 vs 11.1 months, p = 0.30) when compared to non-exposed patients (Abx-). Conclusions: These results using immune checkpoint inhibitors in the community show comparable treatment outcomes to those seen in published literature. The results also suggest worse treatment outcomes in Abx+ patients, although these findings did not reach statistical significance and we are expanding our cohort to further validate this. Multivariate analyses examining clinical and laboratory factors are needed to ultimately identify those patients who will benefit most from IO.
Clonality patterns of driver mutations (mut) to reveal spatial-temporal genomic heterogeneity in colorectal cancer (CRC).
Authors: Rodrigo Dienstmann, Elena Elez, Ignacio Matos, Enrique Sanz-Garcia, Carolina Ortiz, Guillem Argiles, Teresa Mercade Macarulla, Jaume Capdevila, Maria Alsina, Tamara Sauri, Julieta Graselli, Helena Verdaguer, Marta Vilaro, Fiorella Ruiz, Ariadna Garcia, Stefania Landolfi, Hector G. Palmer, Paolo Nuciforo, Ana Vivancos, Josep Tabernero
Journal: Journal of Clinical Oncology (2016)

3509 Background: The mutant allele fractions (MAFs) of a driver gene may influence response to matched targeted therapies, such as KRAS and anti-EGFR antibodies in CRC. We performed a comprehensive analysis of clonal-subclonal frequencies of driver alterations in unpaired prim (prim) vs metastatic (met) CRC and studied their potential clinical implications. Methods: 642 CRC samples with targeted mut analysis from 2010-2015 (Sequenom in 469, MiSeq in 173; prim in 496, met in 110). MAFs of each variant were normalized for tumor purity in the sample. Non-parametric statistics and Cox models are described. Results: APC mut were found in 50% (median MAF 0.5; reference group for comparisons), TP53 mut in 65% (0.67; p = .035), KRAS mut in 46% (0.56; p = .2), NRAS mut in 4% (0.51; p = .9), BRAF mut in 8% (0.28; p < .001) and PIK3CA mut in 16% (0.39; p < .001). Half of samples with KRAS/PIK3CA coexisting mut had significantly lower PIK3CA than KRAS MAFs (0.27 [n = 34] vs 0.46 [n = 39]; p < .001). We only found higher MAFs in met vs prim after chemo +/- anti-EGFR for TP53 (0.77 [n = 70] vs 0.56 [n = 32]; p = .004) and BRAF (0.44 [n = 8] vs 0.26 [n = 42]; p = .04). BRAF MAFs were higher in non-V600 than V600 (0.45 [n = 5] vs 0.27 [n = 48]; p = .02). In 31 patients (pts) treated with 41 anti-BRAF regimens, no correlation between BRAF V600 MAFs and time to treatment failure was found (p = .36). Pts with any RAS mut tumors, irrespective of MAFs, had worse time from recurrence to death (TRD) as compared to RAS/BRAF/PIK3CA wild-type (43 vs 34 months [m], HR 1.39; p = .004), but coexisting PIK3CA mut, either clonal or subclonal, did not further impact survival (31 m and 35 m, HR 1.07; p = .7). Pts with BRAF V600 mut had worse TRD (21 m, HR 2.2; p < .001), but not those with BRAF non-V600 mut (46 m, HR 1.35; p = .55). Conclusions: Our results indicate clonality of RAS mut and subclonality of BRAF V600 mut and a subset of PIK3CA mut. Differences in prim vs met sites for TP53 and BRAF V600 MAFs suggest acquired copy number events and clonal selection after therapy. BRAF V600 MAFs in prim tissue did not predict benefit with targeted drugs in met setting. Despite significant differences in prognosis according to mut in driver oncogenes, their clonality patterns did not influence survival.
Abstract 14677: Oxidative Damage in Failed Clinical Bioprosthetic Heart Valve Explants
Authors: Suengwon Lee, Giovanni Ferrari, Robert J Levy
Journal: Circulation (2015)

Introduction: Bioprosthetic heart valves (BHVs), fabricated from glutaraldehyde-fixed bovine pericardium or porcine aortic valves, have been widely used in valve replacement surgery. However, BHVs fail over time due to structural degeneration. Despite frequent observations of calcification-associated BHV failure, more than 25% of BHV structural failures occur without calcification. Previously, we reported that oxidative stress may have a pivotal role in noncalcific BHV failure. Moreover, oxidation-induced formation of dityrosine (DT) crosslinks via hydroxyl- and tyrosyl-radical mediated pathways was only detected in clinical BHV explants. Yet the mechanism of DT formation and its role in structural degeneration of clinical BHV is incompletely understood. Hypothesis: Oxidative damage to BHV is due to a specific spatial localization of DT crosslink formation mediated by myeloperoxidase (MPO) and/or iron (Fe) deposition in clinical BHV explants Method &amp; Results: BHVs from 7 human subjects were collected and subjected to mass spectrometry to measure DT in paraffin sections of BHV. 4 different regions of each BHV leaflet (free edge, sewing cushion, commissure, and middle region) were sampled as well as entire cross-sections of each cusp. DT was only detected in the mid–cusp (137.37±49.96 μmol/mol) and was not significantly different from DT quantitated in the cross-sections (191.29±65.98 μmol/mol). DT was not detected in other regions, implying a specific spatial localization of oxidative stress in BHV. MPO, a neutrophil derived enzyme, is responsible for reactive oxygen species (ROS) generation. Immunofluoresence microscopy demonstrated significant presence of MPO in the BHV, implying that MPO may be responsible for the DT formation in BHV. Fe deposition due to intracuspal hematomas and/or Fe-association with calcific deposits can also be responsible for ROS and DT formation. Fe was shown to be present in histology sections in failed BHV by Prussian Blue staining, indicating that Fe deposits may also in part be responsible for the observed DT formation. Conclusion: These results demonstrated a mid-leaflet localization of DT formation in clinically failed BHV explants. This may in part be mediated by MPO and/or Fe-deposits in clinical BHV.
The accuracy of pre-operative MRI in predicting the rectal cancer tumour stage, node status and complete clinical response in patients who have undergone neoadjuvant chemoradiotherapy using histopathologic analysis as the reference standard.
Authors: Killian Nugent, Emily Harrold, Gavin Sugrue, Ronan McDermott, Lisa Mary Prior, Geoffrey Alan Watson, Jack Patrick Gleeson, Connor Gerard O'Leary, Deirdre Kelly, Marvin Chang Jui Lim
Journal: Journal of Clinical Oncology (2016)

e15142 Background: Neoadjuvant chemoradiotherpy (CRT) has become standard in the treatment of rectal cancer patients with stage 3 disease. This approach has shown to reduce both local recurrence rates and increase the rate of sphincter preservation procedures.Up to 20% of patients 6 weeks post neoadjuvant CRT have a complete histological response (pCR). PCR has shown to correlate with better and sustained oncological outcomes. The feasibility of the emerging watch and wait management strategy for patients with pCR will depend on the reliability of restaging assessments post CRT. Methods: We retrospectively identified all patients who underwent neoadjuvant CRT (50.4 Gy, 1.8 Gy/fraction, in 5.5 weeks, with continuous infusional fluorouracil 225 mg/m2daily) for rectal cancer and proceeded to standard TME at our institution over a 16 month period. Their initial cTNM staging was collected as was their restaging ycTNM post CRT (based on diffusion weighted MRI pelvis). The sensitivity and specificity of the latter at predicting tumour, nodal and complete clinical response compared to surgical histology was analysed. Results: 38 patients underwent CRT and subsequent TME over the time period at our institution. Overall histopathological response rate was 93% with a pCR rate of 11%. MRI had a sensitivity of 51% and specificity of 94% at assessing compete clinical response, 95 CI 40-93%, 80-99% respectively. At predicting tumour response MRI had sensitivity of 43% and specificity of 85%, 95 CI 62-80%, 74-94% respectively. Accuracy of predicting nodal response were lower with a sensitivity of 43% and specificity of 40% , 95 CI 30-88%. The average modal time interval between CRT and MRI was 5 weeks while the average modal time between CRT and surgery was 8 weeks Conclusions: Our study suggests that MRI alone may not be accurate enough in assessing clinical stage post neoadjuvant CRT, and particularly the clinical node status. Imaging alone will likely be needed to be combined with clinical, biochemical and endoscopic assessments in order to improve reliability of post treatment rectal staging.