tbuckley/cabot-search huggingface dataset:
Human papillomavirus (HPV) induced malignancies and markers of immunogenicity.
Authors: Nooshin Hashemi Sadraei, Robert Koncar, Kelsey Poorman, El Mustapha Bahassi
Journal: Journal of Clinical Oncology (2017)

e23083 Background: Approximately 5% of all cancers result from HPV, commonly leading to head and neck (HN) and anogenital (AG) cancers. Immune therapy is used in many cancers including HN. Positive PDL1 and high tumor mutation load (TML) have been proposed as potential markers of immunogenicity among many tumors, but little is known specifically among HPV driven cancers. Methods: A retrospective analysis of patients with HPV related cancers was performed based on tissue availability. TP53 wild type status was used as a surrogate for HPV positivity. Among oropharynx cases with TP53 wt, p16 testing was performed for confirmation. Next generation Sequencing (NGS Sanger) was used for tumor mutation load (TML) calculation. High TML cut off was defined as ≥17 mutations/megabase based on prior publications. PDL1 status was reported based on IHC ≥5%. A 2-tail Fisher’s exact test was utilized for statistical analysis. Results: A total of 737 patients with HN and AG (cervical, anal, vulvar, penile) squamous cell carcinoma were identified. Of these, 251 had complete 592 gene panel NGS data. HPV + TP53 Wt disease was detected in oropharynx (70%), cervical (88%), and anal (82%) cancer. HPV+ HNSCC had a trend to a higher PDL1 compared to HPV neg (50% vs 31%, p = 0.16) but there were no significant differences among PDL1 between HPV+ and neg patients across the entire combined disease cohorts (41% vs 36%, p = 0.56). TML-high patients showed a trend to increased PDL1 positivity (60% vs 38%, p = 0.09). However, high TML was less common in HPV+ HNSCC vs HPV neg (2.2 vs. % 9.7% p = 0.19). Unlike some other malignancies, high TML was uncommon across HPV+ tumors in general (8%). Conclusions: Despite fewer TML high cases among HPV + patients, there was no difference among PDL1 expression. It is possible that a lower threshold may need to be used when determining TML high vs. low in viral-driven cancers. It is also possible that in view of viral immunogenicity, certain genomic alterations contribute more to higher PDL1 expression rather than the sum of total genomic alterations. We are currently pursuing both lines of investigation. These findings are hypothesis generating for future trial design rather than treatment decision-making, and need to be confirmed in large prospective cohorts.
Safety and efficacy of docetaxel + b-701, a selective inhibitor of FGFR3, in subjects with advanced or metastatic urothelial carcinoma.
Authors: Joaquim Bellmunt, Sumanta K. Pal, Joel Picus, Manish Kohli, Yull Edwin Arriaga, Matthew I. Milowsky, Jocelyn Holash, David Albert Ramies, Jesse S. McGreivy
Journal: Journal of Clinical Oncology (2017)

4540 Background: Patients w/ locally advanced or metastatic urothelial carcinoma (UCC) have a poor prognosis. Prior to atezolizumab’s approval, there were no approved treatments (txs) for pts who progressed after chemotherapy. Even w/ immune checkpoint inhibitors, most pts require additional txs. FGFR3 is frequently overexpressed in UCC and 15-20% of pts w/ advanced disease have tumors w/ FGFR3 gene mutations or fusions. B-701 (formerly R3Mab) is a fully human monoclonal antibody against FGFR3 that blocks activation of the wildtype and genetically activated receptor. NCT02401542 is a phase (ph) 1b/2 study designed to evaluate the safety and efficacy of B-701 plus docetaxel (D) in advanced UCC pts. Methods: The study has a lead-in (n=20 pts) and a randomized ph (n=201). Eligible pts: Stage IV UCC, relapsed/refractory to 1 or 2 prior chemotherapy regimens not including taxanes with ECOG 0-1. Txs: B-701 at 25 mg/kg q3w (+ loading dose on C1D8) and D at 75 mg/m 2 q3w. Efficacy assessed by RECIST 1.1. Primary obj: PFS and safety. Secondary obj: overall response rate (ORR); duration of response (DOR); disease control rate (DCR); overall survival (OS). Exploratory obj: association of FGFR3 status w/ efficacy and AEs. Results: As of 20 Jan 2017, 19 pts enrolled to lead-in ph w/median age 66 yrs, ECOG 1 58%, Hgb &lt;10 gm/dL 5%, liver mets 26% and ≥ 2 prior regimens 63%. 17 evaluable for PFS/ORR. 5 pts w/ FGFR3 mut or TACC3-fus. Gr ≥3 AEs occurring in ≥2 pts: decreased neutrophils (26.3%), neutropenia (10.5%), decreased WBCs (10.5%). 2 pts had D dose reductions and 1 pt discontinued tx due to AE (disseminated intravascular coagulation). Conclusions: Preliminary results show that B-701 combines safely and effectively with D in UCC, with the combination being well tolerated and showing promising ORR and PFS in pts w/ FGFR3 mut/fus. The protocol has been amended to add Cohorts 2 (B-701+D) and 3 (B-701) (n=20 pts/cohort) for pts w/ FGFR3 mut/fus+ tumors only. Clinical trial information: NCT02401542. [Table: see text]
TCT-260 Outcomes of Transcatheter Aortic Valve Replacement In Patients Undergoing Conscious Sedation Compared To General Anesthesia
Authors: Brett Hiendlmayr, Jeff Mather, Lauren Curtis, Kerry McGuire, None nichole hoover, Mohiuddin Cheema, Robert Hagberg, None david underhill, Jennifer Jantz, None sean McMahon, William Duvall, Talhat Azemi, Immad Sadiq, Francis Kiernan, Raymond Mckay
Journal: Journal of the American College of Cardiology (2018)
Efficiency and safety of regorafenib in metastatic colorectal cancer (mCRC): Real life experience from Turkey.
Authors: Guliz Zengin, Neslihan Özyurt, Ismail Beypınar, Havva Yesil Cinkir, Burak Bilgin, Ozge Gumusay, Ismail Erturk, Mehmet Ali Nahit Sendur, Mukremin Uysal, Yuksel Urun, Umut Demirci
Journal: Journal of Clinical Oncology (2018)

e15551 Background: In this study, we aimed to investigate the efficiency and safety of initiation of regorafenib at different doses in mCRC Methods: Between January 2013 and January 2018, this study retrospectively reviewed mCRC patients (pts) who treated with regorafenib after failure of fluoropyrimidine, irinotecan and oxaliplatin +/- biologic agent from 7 centers in Turkey Results: The median age of 112 pts was 54.85 years (range, 28-78) and 63 (56.3%) pts was male. At the time of diagnosis; there were 12 pts (10.7%) with ECOG PS 0, 68 pts (60.7%) with ECOG PS 1, and 32 pts (28.6%) with ECOG PS 2. The disease was localized to the right colon in 20.5% of the pts. RAS mutation was detected in 56.8% of the pts. All of the pts had a history of using one or two biological agents. Median 3 lines (range, 2-7) of treatment was given before regorafenib. The median regorafenib cycle was 3 (1-24). Regorafenib was continued in 14 (12.5%) pts during the analysis. Regorafenib was started with 80 mg in 14 pts (14.3%), 120 mg in 17 pts (15.2%) and 160 mg in 79 pts (70.5%). Regorafenib dose was increased in 21 pts (%18.8) after initial dose. The maintenance dosage was 160 mg in 71 pts, 120 mg in 29 pts, and 80 mg in 12 pts. In the follow-up, dose reduction was performed in 32 pts (28.6%). Median progression-free survival (PFS) and median overall survival (OS) were 12 weeks (11.6-17.3w) and 72 weeks (64.9-77.3w) respectively. PFS was longer (15 weeks versus 12 weeks) in the low-dose started group (p < 0.05). OS was longer in the groups that started with standard dose treatment and dose reduction performed in the follow up (p < 0.05). The clinical benefit rate was 31.8% (partial response 11.8%). The reason for discontinuation of treatment was toxicity in 33 pts (29.5%) and progression in 64 pts (57.1%). 75.9% of the patients had any degree of toxicity. The most frequent serious (grade 3-4, 41.9%) adverse events complaints were fatigue (n = 26), hypertension (n = 5), rash (n = 5), diarrhea (n = 4) and hand foot syndrome (n = 7). Conclusions: Initiation of regorafenib at the standard 160 mg dose and appropriate dose reduction according to toxicity should be the standard approach.
Outcomes with lower intensity therapy in TP53-mutated AML.
Authors: Tapan M. Kadia, Prajwal C. Boddu, Farhad Ravandi, Guillermo Garcia-Manero, Gautam Borthakur, Michael Andreeff, Elias Jabbour, Courtney Denton Dinardo, Marina Konopleva, Naval Guastad Daver, Koichi Takahashi, Keyur Patel, Rashmi Kanagal-Shamanna, Jorge E. Cortes, Hagop M. Kantarjian
Journal: Journal of Clinical Oncology (2017)

7017 Background: TP53 mutations confer an adverse prognosis in patients (pts) with AML treated with standard chemotherapy. A recent study reported high response rates using a 10-day regimen of decitabine (DAC10) in pts with TP53-mutated ( TP53-MUT) AML. The question remains whether this benefit is unique to DAC10 or whether the same benefit among TP53-MUT AML applies to other low intensity therapy (Rx). Methods: We reviewed our own experience of pts treated with low intensity Rx from 2012 - 2016. Mutation testing was performed using a whole-exome sequencing panel. We reviewed the clinico-pathologic characteristics of these pts, and compared their outcomes based on the presence/absence of a TP53mutation and by the type of Rx they received. Results: There were 131 pts in our cohort of which 33 (25%) had TP53-MUT. Pt characteristics are outlined in Table 1A. All pts were treated with low intensity Rx and were divided into the following groups: DAC10 [n=34, 26%]; 5-day decitabine, or 7-day azacytidine (DAC5) [n=39, 30%]; or cladribine+low dose araC (CLAD/LDAC) [n=58, 44%]. Response rates and OS by Rx and TP53-MUT status are summarized in Table 1B. While there was no significant difference in response rates or OS by TP53-MUT status within any of the treatment approaches, there was a trend for inferior response rates and OS among pts with TP53-MUT who received either DAC-5 or CLAD/LDAC ; this was not seen in pts receiving DAC10. Conclusions: The presence of a TP53-MUT was associated with a nonsignificant trend towards inferior outcomes among pts receiving DAC5 or CLAD/LDAC, but not among those receiving DAC10. Comparing across groups, the CLAD/LDAC combination was associated with the longest OS, and DAC10 was associated with superior outcomes compared to DAC5, in TP53-MUT cohort. [Table: see text]
Multimodal Structural Neuroimaging Markers of Brain Development and ADHD Symptoms
Authors: Gareth Ball, Charles B. Malpas, Sila Genc, Daryl Efron, Emma Sciberras, Vicki Anderson, Jan M. Nicholson, Timothy J. Silk
Journal: American Journal of Psychiatry (2018)

Objective: Attention deficit hyperactivity disorder (ADHD) is a multifactorial disorder with diverse associated risk factors and comorbidities. In this study, the authors sought to understand ADHD from a dimensional perspective and to identify neuroanatomical correlates of traits and behaviors that span diagnostic criteria. Methods: Multimodal neuroimaging data and multi-informant cognitive and clinical data were collected in a densely phenotyped pediatric cohort (N=160; 70 with ADHD; age range, 9–12 years). Multivariate analysis identified associations between clinical and cognitive factors and multimodal neuroimaging markers (across tissue volume, cortical thickness, cortical area, and white matter microstructure). The resulting imaging markers were validated in an independent cohort (N=231; 132 with ADHD; age range, 7–18 years). Results: Four novel patterns of neuroanatomical variation that related to phenotypic variation were identified. The first imaging pattern captured association of head size with sex, socioeconomic status, and mathematics and reading performance. The second pattern captured variation associated with development and showed that individuals with delayed development were more likely to be receiving ADHD medication. The third pattern was associated with hyperactivity, greater comorbidities, poorer cognition, lower parental education, and lower quality of life. The fourth pattern was associated with a particular profile of poorer cognition and irritability independent of ADHD. The authors further demonstrated that these imaging patterns could predict variation in age and ADHD symptoms in an independent cohort. Conclusions: The findings suggest that ADHD presentation may arise from a summation of several clinical, developmental, or cognitive factors, each with a distinct neuroanatomical foundation. This informs the neurobiological foundations of ADHD and highlights the value of detailed phenotypic data in understanding the neurobiology underlying neurodevelopmental disorders.
Therapeutically Active RIG-I Agonist Induces Immunogenic Tumor Cell Killing in Breast Cancers
Authors: David L. Elion, Max E. Jacobson, Donna J. Hicks, Bushra Rahman, Violeta Sanchez, Paula I. Gonzales-Ericsson, Olga Fedorova, Anna M. Pyle, John T. Wilson, Rebecca S. Cook
Journal: Cancer Research (2018)

Cancer immunotherapies that remove checkpoint restraints on adaptive immunity are gaining clinical momentum but have not achieved widespread success in breast cancers, a tumor type considered poorly immunogenic and which harbors a decreased presence of tumor-infiltrating lymphocytes. Approaches that activate innate immunity in breast cancer cells and the tumor microenvironment are of increasing interest, based on their ability to induce immunogenic tumor cell death, type I IFNs, and lymphocyte-recruiting chemokines. In agreement with reports in other cancers, we observe loss, downregulation, or mutation of the innate viral nucleotide sensor retinoic acid-inducible gene I (RIG-I/DDX58) in only 1% of clinical breast cancers, suggesting potentially widespread applicability for therapeutic RIG-I agonists that activate innate immunity. This was tested using an engineered RIG-I agonist in a breast cancer cell panel representing each of three major clinical breast cancer subtypes. Treatment with RIG-I agonist resulted in upregulation and mitochondrial localization of RIG-I and activation of proinflammatory transcription factors STAT1 and NF-κB. RIG-I agonist triggered the extrinsic apoptosis pathway and pyroptosis, a highly immunogenic form of cell death in breast cancer cells. RIG-I agonist also induced expression of lymphocyte-recruiting chemokines and type I IFN, confirming that cell death and cytokine modulation occur in a tumor cell-intrinsic manner. Importantly, RIG-I activation in breast tumors increased tumor lymphocytes and decreased tumor growth and metastasis. Overall, these findings demonstrate successful therapeutic delivery of a synthetic RIG-I agonist to induce tumor cell killing and to modulate the tumor microenvironment in vivoSignificance: These findings describe the first in vivo delivery of RIG-I mimetics to tumors, demonstrating a potent immunogenic and therapeutic effect in the context of otherwise poorly immunogenic breast cancers. Cancer Res; 78(21); 6183-95. ©2018 AACR.
Reasons for urban-rural differences in colon cancer outcomes: A population-based analysis.
Authors: Nicholas Adam Bosma, Derek Tilley, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2018)

3609 Background: Previous studies showed that rural patients with colon cancer tend to have worse overall survival (OS). In the US, this disparity is due in part to poorer healthcare access or lack of insurance in rural populations. It is unclear what drives this disparity in single payer healthcare systems. Methods: Patients diagnosed with stage II and III colon cancer from 2004 to 2015 in a large Canadian province were identified. Demographics, disease, treatment, and outcome data were collected. Using residential postal codes, we classified patients as living in urban, regional, or rural areas. OS was measured from the time of diagnosis to death and analyzed using the Kaplan-Meier method. Multivariate Cox regression models were used to assess the impact of residence on outcomes, while adjusting for measured confounders. Results: We included 6,163 patients: 3,691 in urban, 693 in regional, and 1,779 in rural areas. Median age at diagnosis was 71 years, with 52% men, 51% stage II disease, 54% left-sided colon cancer, and 59% Charlson score 0. In comparison, there were more younger patients (p = 0.033) and more right-sided colon cancers (p = 0.042) in urban areas. In addition, urban patients experienced shorter times from diagnosis to surgery (p < 0.001), but longer delays from surgery to adjuvant chemotherapy (p = 0.002) (see Table). In survival analysis, median OS among urban, regional, and rural populations was 104, 83, and 94 months, respectively (log-rank p < 0.001). After adjusting for measured confounders and observed variations in baseline characteristics across patient populations, residence continued to predict for OS (HR 1.3, 95% CI 1.1-1.4, p < 0.001) for regional and HR 1.1, 95% CI 1.0-1.2, p = 0.040) for rural, when compared to urban. Conclusions: Urban-rural differences in colon cancer survival persist, even in settings with universal healthcare coverage. These findings may be partly driven by a younger population and more expedited surgical intervention in urban populations, but they do not fully explain the disparities. Median time to surgery and adjuvant chemotherapy. Urban Rural Regional Time to Surgery 12 days 16 days 15 days Time to Adjuvant Chemotherapy 61 days 60 days 55 days
The volume-outcome relationship in Medicare beneficiaries aged 65 and older with acute myeloid leukemia and acute lymphocytic leukemia.
Authors: Teresa M Waters, Michael P Thompson, Erin Kaplan, Caitlin N McKillop, Michael Gary Martin
Journal: Journal of Clinical Oncology (2016)

e18110 Background: Although relatively rare, acute myeloid (AML) and lymphocytic (ALL) leukemia are highly fatal in older populations. The purpose of this study was to examine whether hospitals treating AML and ALL more frequently had better post-discharge outcomes in Medicare beneficiaries aged 65 and older. Methods: We used 2013 fee-for-service claims data from 10,101 Medicare beneficiaries aged 65 and older receiving acute leukemia care in 2,045 hospitals to rank-order facilities by increasing annual case volume. Hospitals were then categorized as very high volume (N = 38, 1.9%), high (N = 109, 5.4%), and low volume (N = 1,898, 92.8%). We used hierarchical logistic regression models to estimate 30-day mortality rates and odds ratios comparing mortality for patients treated in very high and high hospital volume to patients treated in low volume hospitals for AML and ALL separately, adjusting for patient factors. Results: The median (IQR) case volume for very high, high, and low volume hospitals was 46.5 (35-53), 17 (14-22), and 2 (1-4), respectively. The proportion of AML (n = 9,020) vs. ALL (n = 1,081) patients was not significantly different between hospital volume categories (p = 0.86): very high – 89.2% vs. 10.8%, high – 86.8% vs. 13.2%, and low – 86.5% vs 13.5%. Adjusted 30-day mortality rates for very high, high, and low volume hospitals were 38.8%, 41.3%, and 41.8% for AML patients, and 33.0%, 33.6%, and 33.5% for ALL patients, respectively. Compared to low volume hospitals, both AML (OR = 0.66; 95% CI: 0.57, 0.76; p < 0.001) and ALL (OR = 0.63; 95% CI: 0.41, 0.95; p < 0.05) patients treated in very high volume hospitals had significantly reduced likelihood of mortality. But, only AML patients treated in high volume hospitals had significantly reduced mortality compared to low volume hospitals (OR = 0.85; 95% CI: 0.75, 0.97; p < 0.05), while ALL patients did not (OR = 1.06; 95% CI: 0.73, 1.52; p > 0.05). Conclusions: Very high volume hospitals treating both AML and ALL Medicare beneficiaries aged 65 and older had better outcomes compared to low volume hospitals. Further research should seek to understand the clinical benefit observed in very high volume hospitals in AML and ALL.
Replacement of ixazomib for relapsed/refractory multiple myeloma patients refractory to a bortezomib or carfilzomib-containing combination therapy.
Authors: James R. Berenson, Alexa Cohen, Tanya M. Spektor, Jacob D. Bitran, Gigi Qiqi Chen, Mehdi M. Moezi, Alberto Bessudo, Joseph Z. Ye, Steven Jeffrey Hager, Robert A. Moss, Alan D. Cartmell, Teresa A. Coleman, John Stewart Hrom, Shahrooz Eshaghian, Tina Maluso, Regina A. Swift, Stephen Lim
Journal: Journal of Clinical Oncology (2017)

8013 Background: The proteasome inhibitor (PI) ixazomib (Ixz) is the first orally administered PI approved for treating multiple myeloma (MM). It has shown clinical activity as a single agent and when used in other combinations. In this phase 1/2 trial, we evaluated Ixz as a replacement therapy for bortezomib or carfilzomib for MM patients who were refractory to a bortezomib- or carfilzomib-containing combination regimen. Methods: This was a phase 1/2, intra-patient, multicenter, open-label trial evaluating the replacement of ixazomib for bortezomib or carfilzomib for MM patients who were refractory in combination with the other agents that the patients had received and failed. Patients received Ixz on days 1, 8 and 15 on a 28-day schedule and the other drugs were administered using the same doses and schedules as they were receiving during their prior regimen. If the Ixz maximum tolerated dose (MTD) for a particular combination regimen was previously determined, then patients were enrolled directly into Phase 2 (PhII). If not, MTD was determined during the Phase 1 (PhI) portion of the trial. Results: To date, a total of 40 patients have been enrolled; 37 patients (21 were enrolled in PhI and 16 in PhII) had completed at least one cycle of this treatment. Patients received a median of 5 prior treatments (range, 1-22). The median follow-up time for all patients was 1.6 months (range, 0.1-10.7 months), whereas that of PhII was 2.2 months (range, 0.2-10.7 months). There was no clinical benefit (CBR; 0%) nor any overall response rate (ORR; 0%) for patients receiving Ixz 3 mg (PhI). Nine patients (43%) showed stable disease (SD) while 12 (57%) exhibited disease progression (PD). In PhII (4mg Ixz) portion of the trial, ORR and CBR were both 18.7% with 16 (43.2%) patients showing SD, and 18 (48.6%) patients displaying PD. Common ≥ Gr3 adverse events were anemia (11%), thrombocytopenia (5.4%), hyponatremia (5.4%), dehydration (5.4%) and neutropenia (2.7%). Conclusions: Replacement of bortezomib or carfilzomib with Ixz infrequently leads to responses among RRMM patient who have progressed while on proteasome inhibitor -containing combination regimens. Clinical trial information: NCT02206425.