tbuckley/cabot-search huggingface dataset:
Immunotherapy efficacy and safety in elderly cutaneous malignancy patients.
Authors: Nicole Carreau, Rajni Kannan, Kathleen M. Madden, Sylvia Crispino, Melissa Wilson, Jeffrey S. Weber, Anna C. Pavlick
Journal: Journal of Clinical Oncology (2018)

e21524 Background: Immunotherapy (IT) has become the mainstay treatment for advanced cutaneous malignancies (ACM), with superior efficacy and tolerability than chemotherapy. Use in elderly patients (pts) is not well investigated. Methods: We conducted an IRB-approved, single institution, retrospective chart review of 53 pts, ages 75-96, with ACM treated with IT to assess for best response (BR) and immune related adverse events (IRAE). Results: 38 men and 15 women were included, with KPS 0-2. At therapy initiation 17 pts had multifocal disease (2 with brain metastases), while 33 had limited sites. 3 adjuvant pts without measurable disease were excluded from response analysis but were included in safety investigation. 78.3% pts responded to IT: 41.3% complete responses and 37% partial responses. 8.7% had stable disease (SD), and 13% progressed. Half of pts (50.9%) tolerated IT without IRAE. In pts with toxicity (tox), 35.8% experienced only grade 1-2 tox. 11.3% had grade 3 tox (1 requiring infliximab for colitis) and none had grade 4. The most common tox was fatigue, followed by pruritis, rash, and arthritis. 33% pts receiving dual agents developed grade 3 tox. Endocrinopathies occurred in 17%, 2 with insulin-dependent diabetes. 2 pts discontinued IT: 1 due to fatigue, the other colitis. At present, 55% have not progressed after BR; time from BR ranges from 3-54 months (mo), with mean 21.4 and median 15.5 mo. Of those who have progressed, time to progression (TTP) from BR ranged from 4-68 mo, with mean 17.4 and median 11 mo. 39.6% pts received multiple lines of IT, several of whom have sustained SD for longer than TTP from BR. In total, 8 pts had brain metastases (mets), all received gamma knife, and 4 are still alive. There were 6 deaths: 3 brain mets, 1 pneumonia (4th with brain mets), 1 refractory angiosarcoma, 1 emphysema. Conclusions: IT is safe and effective in elderly pts with ACM. Combination IT should be carefully considered, given increased toxicity. Multiple lines of therapy are tolerable, controlling disease long enough that cancer may not be their ultimate cause of death.
Treatment of EBV+ nasopharyngeal carcinoma with banked EBV-specific cytotoxic T cells.
Authors: Susan Prockop, Ekatarina Doubrovina, Shrujal S. Baxi, Virginia Escobedo, Stephanie Suser, Victoria Szenes, David G. Pfister, Richard J. O'Reilly
Journal: Journal of Clinical Oncology (2016)

3012 Background: The expression of EBV antigens in Nasopharyngeal Carcinoma (NPC) makes EBV+NPC a candidate for cellular therapy. Prior reports demonstrate the potential of autologous EBV directed T cell therapy for EBV+NPC. However, it is not possible to generate autologous EBV specific cytotoxic T cells (EBV CTLs) from all patients (pts). Methods: We treated 14 pts with metastatic EBV+NPC with adoptive transfer of EBV CTLs selected from a bank of > 300 GMP grade lines generated from EBV seropositive hematopoietic transplant donors by sensitization of T cells with irradiated B-cell lines transformed by EBV strain 95.8. EBV CTLs were selected based on matching for at least 2/8 HLA alleles and exhibiting EBV-specific cytotoxicity restricted by an HLA allele shared by the pt. Cells were administered in cycles of 3 weekly doses of 1-2 x 10e6/kg for a median of 2 cycles (range of 1-4 cycles). Results: Fourteen pts with a median age of 42 years (range 13-64) and median KPS of 90% (range 80-100%) with metastatic NPC were screened. Despite the fact that 9 pts were Asian, 3 Black and 1 Hispanic, an appropriate line was available for all 14 pts. Pts were treated for disease progression after first (N = 6) second (N = 7) or third (N = 1) line therapy. EBV CTLs infusions were well tolerated without toxicities. One pt achieved a complete response (documented by biopsy) lasting 21.2 months, two achieved partial responses lasting 3.5 and 6.7 months and one pt had stable disease lasting 7.4 months. All 4 pts who achieved CR, PR or SD are alive at 20.4 - 48.3 months post therapy. Time to initiation of subsequent therapy in the 10 pts who progressed ranged from 15 to 195 days. Of the 14 pts, two died of disease at 107 and 147 days after the start of therapy and one of toxicity due to subsequent therapy for progressive disease 43 months after the start of EBV CTL therapy. Eleven pts remain alive at a median of 18.1 months (3.0 -48.4 months) after start of therapy. Conclusions: Our findings show that the bank of EBV CTLs has sufficient diversity to treat non-Caucasian pts with NPC. We show that adoptive immunotherapy with banked EBV CTLs is well tolerated. EBV directed adoptive cellular therapy using banked 3rd party EBV CTLs may offer clinical benefit to some pts with metastatic NPC. Clinical trial information: NCT01498484.
Females versus males: Clinical features and outcome differences in large molecularly selected cohort of mCRC patients.
Authors: Marta Schirripa, Dongyun Yang, Fotios Loupakis, Carlotta Antoniotti, Chiara Cremolini, Shu Cao, Satoshi Okazaki, Martin D. Berger, Yan Ning, Yuji Miyamoto, Mitsukuni Suenaga, Roberto Moretto, Francesca Bergamo, Francesca Battaglin, Sara Lonardi, Roel Gopez, Jordan David West, Wu Zhang, Alfredo Falcone, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2016)

3540 Background: The impact of gender differences in terms of OS and of association with clinical and molecular characteristics remains unclear. Previous analyses were limited by small sample size, significant heterogeneity in stage and poor data. We planned the present analysis to determine the prognostic impact of gender and possible associated clinical features in a molecularly selected mCRC pts population. Methods: Metastatic CRC pts referred to UO Oncologia Medica AOUP from 2000 to 2014 were selected for the inclusion in this analysis based on BRAF and/or RAS mut status availability . The following characteristics were collected: age, ECOG-PS, grade, time to metastases, primary tumour site, resection of primary tumour, pT, pN status, mucinous histology, number and sites of mts (peritoneum, lung, or distant lymph nodes), at the time of diagnosis. Chi-square tests were used to compare clinical characteristics between males (M) and females (F). Stepwise Cox regression analysis was performed to identify the prognostic factors affecting OS in m and F separately. The impact of each significant prognostic factor in affecting outcome according to gender was estimated by interaction test. Results: 1045 pts were included. Main pts’ characteristics were the following: F/M = 41/59%; median age = 63 (range 24-92); ECOG-PS 0/1-2 = 76/24%; synchronous/metachronous = 71/29%; RAS-BRAF mutational status (wt-wt/mut-wt/wt-mut) = 37/54/9%. F presented more frequently with younger age ( ≤ 65) (p < 0.001), peritoneal metastasis (p = 0.009), BRAF mutant tumor (p = 0.033) and locoregional node involvement (p = 0.040) compared to M. Among all RAS wild-type, F had worse OS compared to m (median OS 31.7 vs 39.5 months, HR = 1.33 [95%CI: 1.04 1.71] p for interaction = 0.011). This outcome difference was confirmed after adjustment for BRAF status (HR = 1.22 [95%CI:0.95-1.57], p for interaction = 0.044), but not in the multivariate model (HR = 0.99 [95%: 0.76-1.28], p for interaction = 0.90). Conclusions: In the present analyses we confirmed an association of female gender with negative prognostic factors such as BRAFmutation, peritoneal metastases, N status. No significant differences were observed in terms of outcome.
Vaccination targeting insulin-like growth factor binding protein-2 (IGFBP-2) in advanced ovarian cancer: Safety and immunogenicity.
Authors: John Ben Liao, Denise Cecil, Yushe Dang, Kelsey K. Baker, Kelsie J Ovenell, Jessica Reichow, Stephanie Parker, Doreen Higgins, Jennifer Childs, Elizabeth Kyungsun Broussard, Andrew L. Coveler, Lupe G. Salazar, Barbara Ann Goff, Mary Weber Redman, Mary L. Disis
Journal: Journal of Clinical Oncology (2016)

5542 Background: Immunization against self-antigens can induce regulatory responses that inhibit the development of desirable Type I antitumor immune responses. Removing epitopes that bias toward a regulatory phenotype may enhance vaccine efficacy. We developed a novel IGFBP-2 targeting DNA plasmid vaccine capable of selectively inducing Type I immunity. IGFBP-2 is an important regulator of ovarian cancer invasiveness and metastases. Eradication of cancer cells expressing IGFBP-2 through effective immunization could prevent disease relapse or metastatic spread. Methods: In a single-arm non-randomized study of advanced stage (III/IV) or recurrent ovarian cancer patients treated to complete remission after primary or salvage therapy, 25 patients received 3 monthly doses of an IGFBP-2 DNA vaccine by intradermal injection. All adverse events (AE) were reported using the Common Terminology Criteria for Adverse Events Version 4.0. Overall survival (OS) was analyzed using the Kaplan-Meier method. ELISPOT and flow cytometry were used to characterize antigen specific T-cell responses and T-cell populations. Serum antibodies recognizing IGFBP-2 were measured by ELISA and Western blot against recombinant protein. Results: To date, there have been 206 AE in the enrolled patients. Fatigue (12%) and injection site reactions (12%) were the most common. 97% of AE were grades 1-2, 3% grade 3, and there were no grade 4 or 5 AE. In preliminary immune analysis (16 patients), IGFBP-2 specific T-cell precursor frequencies are significantly elevated over baseline levels at 4 (p < 0.01) and 6 (p < 0.001) months. T-regulatory cells were not increased over the levels measured in a control reference population. No patients developed new IGFBP-2 specific antibody responses after immunization suggesting a lack of Th2 augmentation. IGFBP-2 vaccinated patients have yet to reach median OS over a median follow-up period of 23.5 months. The OS rate at 2 years was 82%. Conclusions: IGFBP-2 Th1 selective immunization has a well tolerated safety profile and generates significant Type I immunity. Clinical trial information: NCT01322802.
Patient and provider variables associated with variation in the systemic treatment of advanced prostate cancer.
Authors: Megan Veresh Caram, Shikun Wang, Phoebe A. Cheng, Jennifer J. Griggs, Paul Lin, Bhramar Mukherjee
Journal: Journal of Clinical Oncology (2018)

e17019 Background: Six treatments have demonstrated an improvement in overall survival in men with metastatic castration-resistant prostate cancer (mCRPC), each differing in toxicities and cost. We sought to determine which factors, such as patient race, income, geographic region, and provider specialty are associated with variation in the treatment of men with mCRPC. Methods: A claims database of commercially insured patients was used to identify patients with prostate cancer treated with abiraterone, enzalutamide, docetaxel, cabazitaxel, sipuleucel-T, or radium-223 between 2010 and 2016. Multinomial and binomial logistic regressions using multivariable analyses were conducted to determine patient and provider factors associated with different treatment patterns. Results: Among the 5,200 patients identified, household income > 99 versus < 50 thousand dollars was associated with lower odds of receiving more expensive oral oncolytic therapy (abiraterone or enzalutamide) as first-line treatment versus docetaxel (odds ratio, OR, 0.63, confidence interval, CI, 0.45-0.87). Black race versus white (OR 1.38, CI 1.01-1.91), living in the Pacific region versus South Atlantic (OR 2.68, CI 1.77-4.05), receiving treatment from a urologist versus a medical oncologist (OR 14.72, CI 6.41-33.80), or having pre-existing cardiac arrhythmia (OR 1.91, CI 1.34-2.73) or congestive heart failure (OR 1.61, CI 1.09-2.43) versus none were associated with higher odds of receiving first-line oral oncolytics versus docetaxel. These findings were independent of year therapy was received. Conclusions: Race, income, provider specialty, and region all significantly affected receipt of oral oncolytics versus docetaxel as first-line therapy, suggesting a substantial degree of variation not attributable to clinical factors. The income paradox we observed among patients of higher income, who were significantly more likely to receive docetaxel, a less expensive therapy, may be a consequence of patient assistance programs, which are available to patients with lower incomes.
Human-Specific Abnormal Alternative Splicing of Wild-Type PKD1 Induces Premature Termination of Polycystin-1
Authors: Wendy A. Lea, Stephen C. Parnell, Darren P. Wallace, James P. Calvet, Lesya V. Zelenchuk, Nehemiah S. Alvarez, Christopher J. Ward
Journal: Journal of the American Society of Nephrology (2018)

Background The major form of autosomal dominant polycystic kidney disease is caused by heterozygous mutations in PKD1 , the gene that encodes polycystin-1 (PC1). Unlike PKD1 genes in the mouse and most other mammals, human PKD1 is unusual in that it contains two long polypyrimidine tracts in introns 21 and 22 (2.5 kbp and 602 bp, respectively; 97% cytosine and thymine). Although these polypyrimidine tracts have been shown to form thermodynamically stable segments of triplex DNA that can cause DNA polymerase stalling and enhance the local mutation rate, the efficiency of transcription and splicing across these cytosine- and thymine-rich introns has been unexplored. Methods We used RT-PCR and Western blotting (using an mAb to the N terminus) to probe splicing events over exons 20–24 in the mouse and human PKD1 genes as well as Nanopore sequencing to confirm the presence of multiple splice forms. Results Analysis of PC1 indicates that humans, but not mice, have a smaller than expected protein product, which we call Trunc_PC1. The findings show that Trunc_PC1 is the protein product of abnormal differential splicing across introns 21 and 22 and that 28.8%–61.5% of PKD1 transcripts terminate early. Conclusions The presence of polypyrimidine tracts decreases levels of full-length PKD1 mRNA from normal alleles. In heterozygous individuals, low levels of full-length PC1 may reduce polycystin signaling below a critical “cystogenic” threshold.
Patient centered outcomes for skin cancer treatment: A single day Delphi process to assess the importance of treatment themes to a representative panel of skin cancer patients.
Authors: Ian Maher, Murad Alam, Jeremy S Bordeaux, Todd Cartee, Christian Baum, Anthoy Rossi, Naomi Lawrence, Anit Behera, Eric S. Armbrecht
Journal: Journal of Clinical Oncology (2017)

e21079 Background: Increased emphasis is being placed on patient centered outcomes. There is little existing literature on the patient population's prioritization of outcomes in skin cancer care. A PCORI-supported Patient Outcomes Summit was organized to address this. Methods: Patients were recruited from patient support groups, solicitation of ASDS member practices, as well as personal recruitment of patients from the practices of the investigators. A one-day Patient Outcome Summit was convened in Arlington, VA in August 2016. Patients attendees were given orientation to existing outcomes for skin cancer as well as the Delphi process. They then participated in a two round Delphi process by run non-physician facilitators (AB and EA). Group discussion was used to solicit outcomes for inclusion in the rating rounds. Outcomes were then rated anonymously on a 1 (lowest relevance) to 9 (highest relevance) scale. Patients were then able to view the anonymous feedback of the group and rerate the items as they deemed fit based on the group feedback. Results: 21 patients participated in the Delphi process (5 men and 21 women). 10 were melanoma and 11 were non-melanoma patients. 56 treatment related outcomes and themes were identified. The ten most highly rated themes are shown in the table. Conclusions: The first ever skin cancer patient outcome summit was convened to address the lack of patient-centered data in the skin cancer literature and guide measure development. Some traditional outcomes (recurrence) were identifiend. However, the majority of the themes rated most important by the patient attendees center around inclusion of the patient in the decision making process and the physician-patient communication. Increased emphasis and education in these domains may drive increased patient satisfaction in skin cancer care. [Table: see text]
Efficacy and safety of defibrotide (DF) to treat hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) after primary chemotherapy (CT): A post hoc analysis of final data.
Authors: Nancy A. Kernan, Paul G. Richardson, Brandon Triplett, Stephan A. Grupp, Joseph Harry Antin, Yoav H. Messinger, Wei Liang, Robin Hume, William Tappe, Robert Soiffer
Journal: Journal of Clinical Oncology (2017)

10513 Background: VOD/SOS, which may be unpredictable and potentially life-threatening, is typically considered a complication of hematopoietic stem cell transplantation (HSCT); VOD/SOS with multi-organ dysfunction (MOD) may be associated with &gt;80% mortality. DF is approved to treat hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT in the US and to treat severe hepatic VOD/SOS post-HSCT in the EU. However, VOD/SOS can occur after CT without HSCT. Methods: In an expanded-access protocol for patients (pts) with VOD/SOS post-HSCT or CT, with/without MOD (renal/pulmonary), DF 25 mg/kg/d (6.25 mg/kg q6h) was given a recommended ≥21 days. Post-CT subgroup survival was analyzed post hoc from the day DF was started (days 0–30 after start of CT) for 70 days (ie, up to 100 days, as follow-up was collected for 100 days post-CT). Results: Of 1154 VOD/SOS pts receiving DF, 137 (12%) developed VOD/SOS post-CT without HSCT. Among 82 pts (38 with MOD) treated by day 30 after start of CT, median age was 7.5 yrs (range, 0–68 years) and 66 (81%) were ≤16 yrs. Most common primary diseases were acute leukemias (65%). Kaplan-Meier estimated survival at day +70 was 74% overall (95% CI, 63–82%); 66% (49–79%) and 81% (66–90%) in pts with/without MOD, respectively. In the pediatric pts, estimated survival at day +70 was 80% (68–88%); in adult pts, 50% (25–71%). Adverse events (AEs) were reported in 54/82 pts (66%); 22 (27%) had AEs assessed as possibly related to DF, most commonly (≥2%) pulmonary or mouth hemorrhage (4% each) and hematochezia, nausea, encephalopathy, epistaxis, or hypotension (2% each). Hemorrhagic AEs of any relatedness (≥2%) were pulmonary (6%), epistaxis or mouth (4%), and hematochezia (2%). Related AEs led to discontinuation in 6 pts and were associated with 1 death (pulmonary hemorrhage, hypotension). Conclusions: The 74% survival rate at day +70 in pts with VOD/SOS receiving DF within 30 days of starting CT (80% in pts ≤16 yrs) is clinically encouraging. Of note is the 66% survival rate in pts with MOD. The safety profile was consistent with that previously reported in the overall population of this protocol. Support: Jazz Pharmaceuticals Clinical trial information: NCT00628498.
Effect of liver metastasis from primary rectal adenocarcinoma on activity of tissue plasminogen activators and α2-macroglobulin.
Authors: Elena Alekseevna Dzhenkova, Oleg I. Kit, Elena M. Frantsiyants, Alexander Vasilievich Shaposhnikov, Valeria A. Bandovkina, Larisa S. Kozlova, Evgeniy N. Kolesnikov, Aleksandr V. Snezhko, Vladimir Trifanov, Mikhail A. Averkin, Sergey V. Sanamyants, Roman E. Myagkov, Leonid V. Kharin, Roman E. Tolmakh
Journal: Journal of Clinical Oncology (2018)

e15552 Background: Plasminogen activators play a key role in the cascade fibrinolytic system as they catalyze plasmin (P) formation from plasminogen (PG). Plasminogen activators together with plasmin are directly or indirectly involved in tumor growth. The purpose of the study was to compare the plasminogen activation system in primary adenocarcinomas (РА) of the rectum (R) with and without liver metastases (LM). Methods: Tissues of tumors (РА, st. III, G2, 38-74 years), their perifocal zone (PZ) and resection line tissues with LM (T2-3NхM1, n = 34) and without them (T2-3N0M0, n = 42) were studied by ELISA. Results: The studied parameters did not differ in intact R tissues in the resection line (RL) with and without LM. Plasmin-α2-antiplasmin complex (PAP) was 1.4 times higher in PA with LM than without LM (p < 0.01). Prourokinase and urokinase levels (pro-uPA and uPA) were 12.4 and 3.7 higher than in RL. Pro-uPA and uPA in PA+LM were higher than without LM by 1.4 and 1.6 times. PG levels and α2-macroglobulin (α2M) activity in PA+LM were lower by 1.5 and 2.7 times than in PA without LM and lower than in RL (p < 0.001). Most parameters in PZ+LM were between the levels in PA and RL being significantly different from both and significantly exceeding the values in PZ of PA without LM. α2М was an exception being 1.8 times lower in PZ of PA+LM than in PZ of PA without LM. The results demonstrated higher uPA and РАР levels in PA and its PZ with LM than without them, with increased PG consumption and decreased α2M activity in these parts of the rectum. Activation of the plasminogen system in tissues of PA+LM and in PA without LM was unidirectional. However, all studied parameters, except α2M, in PA+LM were activated more than in PA without LM. Low α2M content supposed realization of effects of uPA and plasmin in insufficient inhibitory control. Conclusions: Levels of uPA and PAP, as well as low α2M content in PA and PZ with LM can be used as an indicator of tumor metastatic activity.
Abstract 16419: Epigenetic Readers: An Attractive Way to Tackle PAH and the Associated Vascular Comorbidities
Authors: Jolyane Meloche, Francois Potus, Mylene Vaillancourt, Alice Bourgeois, Sandra Breuils-Bonnet, Steeve Provencher, Sebastien Bonnet
Journal: Circulation (2015)

Introduction: Pulmonary arterial hypertension (PAH) is a devastating vasculopathy. Recent progress in understanding its pathogenesis led to an increase in patients’ quality of life. With ageing, PAH patients now develop comorbidities including coronary artery diseases (CAD), further challenging their therapeutic management. We previously reported that CAD and PAH share many similarities, including vascular smooth muscle cells (VSMCs) pro-proliferative/anti-apoptotic and metabolic abnormalities. We could speculate that PAH and CAD development share many pathophysiological pathways. In cancer, the epigenetic reader Bromodomain-containing protein 4 (BRD4) increases transcription of many oncogenes contributing to the proliferative/apoptosis imbalance. Interestingly, BRD4 was shown to interact with miR-204 and NFAT, both critical players in PAH and CAD. We hypothesized that BRD4 is a central actor of VSMCs impairment contributing to vascular remodeling observed in PAH and CAD. Method/Results: We demonstrated that remodeled distal pulmonary arteries from PAH patients exhibit a miR-204-dependent increase in BRD4 expression compared to controls (qRT-PCR, western blot, n=10-15, p&lt;0.01). This phenotype is also observed in VSMC of remodeled coronary arteries from both PAH patients with CAD and non-PAH CAD patients compared to non-CAD patients (n=10, p&lt;0.05). In vitro, we showed that BRD4 increases NFAT, Bcl-2 and Survivin (n=6, p&lt;0.01) expression, triggering both proliferation (Ki67, p&lt;0.05) and resistance to apoptosis (AnnexinV, p&lt;0.05) while decreasing spare respiratory capacity (Seahorse XF, n=4, p&lt;0.05) and hyperpolarizing mitochondrial membranes (TMRM, p&lt;0.05). All these abnormalities were reversed upon BRD4 inhibition (JQ1 or siBRD4). In vivo, JQ1/siBRD4 reverses established PAH and prevents carotid stenosis in Sugen/hypoxia and carotid injury rat models respectively (n=8-10/group). Conclusion: Comorbidities in PAH such as CAD has become a major clinical problem. Thus, targeting mechanisms implicated in both PAH and subsequent comorbidities is warranted. To this aim, we propose that BRD4 might represent an attractive target and since BRD4 inhibitors are presently in clinical trials further potentiates its uses in PAH.