tbuckley/cabot-search huggingface dataset:
Role of the inflammasome of tumor cells in modulating the biology of Tumor Infiltrating T lymphocytes (TILs) in colorectal cancer.
Authors: Celine Bossard, Delphine Dansette, Adrien Ouairy, Nicolas Jouand, Romain Oger, Chantal Bou-Hanna, Christian Laboisse, Jean-François Mosnier, Nadine Gervois, Anne Jarry
Journal: Journal of Clinical Oncology (2017)

640 Background: In colorectal cancer (CRC), little is known about mechanisms by which tumor cells can influence the phenotype and biology of Tumor Infiltrating T lymphocytes (TILs) of the tumor microenvironment. One of these mechanisms could be the inflammasome, a molecular platform present in normal intestinal epithelial cells, whose effector protein, caspase-1, can rapidly mature IL18 and generate a mucosal Th1/Tc1 (IFNg) response. However, the inflammasome status of tumor cells in CRC and its potential role on TILs are unknown yet. Methods: Prospective and retrospective cohort studies aimed to determine in CRC patients: the status of the inflammasome in tumor cells (IL18 immunostaining on tissue microarrays (TMA) and in situ detection of active caspase-1 on frozen sections) and the density of TILs (CD8+, T-bet+) in relation with the microsatellite stable (MSS) or unstable (MSI) status of CRC, and the levels of cytokines (IL18, IFNg) secreted in an ex vivo explant culture model of CRC. Finally, we assessed the effect of recombinant human IL18 (rhIL18) on the IFNg response of isolated TILs. Results: TMA analysis of the retrospective cohort showed that IL18 was significantly expressed (in more than 50% of tumor cells) in 80% of CRC, especially in MSI CRC, and correlated with a high density of T-bet+ and CD8+ intraepithelial TILs (IEL-TILs). Active caspase-1 was detected in tumor cells in 60% of CRC. In the prospective cohort, the presence of active caspase-1 in tumor cells was associated with high levels of mature IL18 secreted in explant cultures, with high density of T-bet+ TILs and with IFNg release in most cases. In addition, isolated TILs expressing IL18 receptors (IL18Ra), cultured with rhIL18, were able to secrete IFNg either unstimulated or stimulated with OKT3. Conclusions: The inflammasome of tumor cells, when maintained and active, can contribute to a Th1/Tc1 antitumor immune response elicited by TILs, that can modulate tumor growth. The inflammasome of tumor cells can thus be considered as a potential new therapeutic target to strengthen the antitumor immune response in CRC, in association with other immunotherapies.
Open-Label, Multicenter, Dose Escalation Phase 1b Study to Assess the Subcutaneous Delivery of Daratumumab in Patients (pts) with Relapsed or Refractory Multiple Myeloma (PAVO)
Authors: Saad Z Usmani, Hareth Nahi, Maria-Victoria Mateos, Henk M. Lokhorst, Ajai Chari, Jonathan L. Kaufman, Philippe Moreau, Albert Oriol, Torben Plesner, Lotfi Benboubker, Peter Hellemans, Tara Masterson, Pamela L Clemens, Tahamtan Ahmadi, Kevin Liu, Jesús San-Miguel
Journal: Blood (2016)
A pilot laboratory study comparing the 21-gene assay and PAM50-ROR.
Authors: Che Prasad, Megan Rothney, Diana B. Cherbavaz, Amy P. Sing, Frederick L. Baehner, Christer Svedman, Christos Markopoulos
Journal: Journal of Clinical Oncology (2014)

11003 Background: The Oncotype DX 21-gene Recurrence Score assay was developed in endocrine-treated patients (pts) and validated as a predictor of 10-yr distant recurrence risk and chemotherapy benefit in ER+ early-stage invasive breast cancer. The Prosigna assay (ROR) which uses 46 of the PAM50 genes, was validated on centrally processed samples as a prognostic assay only in endocrine treated, post-menopausal pts. To date no direct comparison data on paired samples from the same patients for these two assays has been reported and yet it’s frequently believed that these assays are interchangeable. We performed a pilot study comparing test results from the two assays obtained from the same tumor blocks. Methods: Sequential breast cancer tumors from Marin Medical Laboratories with sufficient tumor material were tested with the standard 21-gene Recurrence Score assay. 40 cases stratified by the Recurrence Score (20 low, 10 intermediate and 10 high) were sent to an independent laboratory where the Prosigna assay for ROR and intrinsic subtype was performed with the operators blinded to the Recurrence Score results. Descriptive statistics were calculated for the results obtained from the two assays. Results: Of the 40 pts, 3 were excluded due to low RNA signal in the Prosigna assay and 4 were ER(-) by RT-PCR. Of the 33 remaining cases, 24 were ductal, 7 lobular and 2 other; 27 were N- and 6 were N+. The Spearman rank correlation between Recurrence Score and ROR was 0.40 (95% CI 0.06 – 0.65). Risk group assignment (low/intermediate/high) between Recurrence Score and ROR was in agreement in 56% (15/27) of N(-) pts. Prosigna classified 19 as luminal A, 12 as luminal B, 2 as HER2 enriched and 0 as basal. In both the luminal A and B groups there was a wide range of Recurrence Score results. Conclusions: Consistent with other comparisons between expression-based assays, it should not be assumed that these assays are interchangeable. While additional data from a larger independent analysis is needed, this pilot suggests that there is only a modest agreement between the Recurrence Score and ROR, with almost half of N(-), ER+ pts classified differently.
Exploring decision making about neoadjuvant chemotherapy for early breast cancer.
Authors: Nicholas Zdenkowski, Phyllis Noemi Butow, Sheryl Fewster, Corinna Beckmore, Kathryn Wells, John F. Forbes, Frances M. Boyle
Journal: Journal of Clinical Oncology (2014)

e20578 Background: For women who have been diagnosed with early stage breast cancer, the option of receiving neoadjuvant chemotherapy (NACT) adds complexity to the decision-making process. A high level of involvement in decisions about breast cancer management is associated with improved decisional outcomes. Little is known about how women make the decision about whether to have NACT. We aimed to explore women’s information needs, decision control preference, reasons for and against the approach, and satisfaction with the decision. Methods: An email invitation was sent to members of the Breast Cancer Network Australia Review and Survey Group who had been diagnosed with early stage breast cancer. Women who had previously been offered neoadjuvant or adjuvant chemotherapy for early breast cancer took part in a semi-structured interview about their experience with NACT. Data were analysed thematically using qualitative methodology. Results: Twenty-two consecutive women were interviewed, at which point no new major themes were identified, and no further interviews took place. Thirteen women had received NACT, 6 had declined an offer of NACT, and 3 were not offered it. Clinicians were the major source of information about NACT. Participants endorsed the neoadjuvant approach for the following reasons: aiming to downstage from mastectomy to breast conserving surgery; as part of a clinical trial protocol; to delay surgery; for prognostic purposes; and to avoid any delays to chemotherapy. Barriers included a lack of written consumer information and unawareness of neoadjuvant chemotherapy as a valid treatment. Women trusted their clinicians’ recommendations, which led to allowed high levels of satisfaction with the decision and subsequent treatment they received. Conclusions: Women were unable to become fully informed about NACT, in order to participate in the decision. In order to derive decisional satisfaction, women put a high level of trust in their treating clinician. Based on these results, a patient decision aid is under development for women considering NACT.
Phase I/IIa, randomized, open-label, drug-drug interaction study of trabectedin and rifampin in patients with advanced cancer.
Authors: Arthur P. Staddon, Trilok V. Parekh, Roland Elmar Knoblauch, Chi Keung, Apexa Bernard, Ana L. Aymes, Charles Phelps, Sunil Sharma
Journal: Journal of Clinical Oncology (2013)

e13512 Background: Trabectedin (Yondelis ; T) is a tetrahydroisoquinoline compound initially isolated from the marine tunicate, Ecteinascidia turbinata, and currently produced synthetically. It is primarily metabolized by the cytochrome P450 (CYP)3A4 enzyme. Thus, potent inducers or inhibitors of this enzyme may alter the plasma concentrations of T. This study assessed the effects of rifampin (R), a strong CYP3A4 inducer, on the pharmacokinetics (PK) and safety of T. Methods: In this 2-way crossover study, patients (≥18 years of age) with locally advanced or metastatic disease were randomized (1:1) to receive one of the 2 treatment sequences: sequence 1: R plus T followed 28 days later by T; sequence 2: T followed 28 days later by R plus T. During each sequence, R (600 mg/day) was administered for 6 consecutive days and T (1.3 mg/m 2 , IV) was administered over a 3 hour infusion. Dexamethasone (20 mg, IV) was administered before T administration. PK and safety of T were evaluated with and without coadministration of R. Results: Of the 11 enrolled patients, 8 were PK evaluable. Coadministration of R with T decreased mean maximum plasma concentration (C max ) by approximately 22% and mean area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUC last ) by approximately 31% (Table 1). Coadministration of R with T also resulted in 23% shorter elimination half-life. Overall, the safety profile of T was comparable when administered alone or with R. Conclusions: In comparison with T alone, coadministration of R resulted in reduced systemic exposure of T in these 8 patients, as measured by C max and AUC last . The coadministration of potent inducers of CYP3A4 with T may increase the metabolic clearance of T. Clinical trial information: NCT01273480. [Table: see text]
Birth Outcomes Among Adolescent and Young Adult Cancer Survivors
Authors: Chelsea Anderson, Stephanie M. Engel, Jennifer E. Mersereau, Kristin Z. Black, William A. Wood, Carey K. Anders, Hazel B. Nichols
Journal: JAMA Oncology (2017)

Cancer diagnosis and treatment may adversely affect reproductive outcomes among female cancer survivors.To compare the birth outcomes of adolescent and young adult cancer survivors (AYA [diagnosed at ages 15-39 years]) with those of women without a cancer diagnosis.The North Carolina Central Cancer Registry (CCR) was used to identify female AYA cancer survivors diagnosed from January 2000 to December 2013; CCR records were linked to statewide birth certificate files from January 2000 to December 2014 to identify postdiagnosis live births to AYA survivors (n = 2598). A comparison cohort of births to women without a recorded cancer diagnosis was randomly selected from birth certificate files (n = 12 990) with frequency matching on maternal age and year of delivery.Prevalence of preterm birth, low birth weight, small-for-gestational-age births, cesarean delivery, and low Apgar score.Overall, 2598 births to AYA cancer survivors (mean [SD] maternal age, 31 [5] years) were included. Births to AYA cancer survivors had a significantly increased prevalence of preterm birth (prevalence ratio [PR], 1.52; 95% CI, 1.34-1.71), low birth weight (PR, 1.59; 95% CI, 1.38-1.83), and cesarean delivery (PR, 1.08; 95% CI, 1.01-1.14) relative to the comparison cohort of 1299. The higher prevalence of these outcomes was most concentrated among births to women diagnosed during pregnancy. Other factors associated with preterm birth and low birth weight included treatment with chemotherapy and a diagnosis of breast cancer, non-Hodgkin lymphoma, or gynecologic cancers. The prevalence of small-for-gestational-age births and low Apgar score (<7) did not differ significantly between groups.Live births to AYA cancer survivors may have an increased risk of preterm birth and low birth weight, suggesting that additional surveillance of pregnancies in this population is warranted. Our findings may inform the reproductive counseling of female AYA cancer survivors.
A phase I study of gemcitabine, carboplatin, and lenalidomide for treatment of patients with advanced/metastatic urothelial carcinoma (UC) and other solid tumors.
Authors: Andrea Borghese Apolo, Howard L. Parnes, Ravi Amrit Madan, James L. Gulley, Jane B. Trepel, Min-Jung Lee, Sunmin Lee, Seth M. Steinberg, Simone JOHN, Sylvia Vania Alarcon Velasco, William Douglas Figg, William L. Dahut
Journal: Journal of Clinical Oncology (2014)

e15527 Background: Gemcitabine plus carboplatin is an accepted first-line chemotherapy regimen for patients with either metastatic UC unfit for cisplatin or other solid tumors. Lenalidomide has both anti-angiogenic and potent immunomodulatory properties, enhances the antiproliferative properties of standard chemotherapy in preclinical studies (Apolo, ASCO 2011), and has been safely co-administered with cytotoxic therapy. Methods: Previously untreated patients with UC unfit for cisplatin or with other advanced solid tumors and no more than 1 prior regimen were eligible. Patients received gemcitabine 1000 mg/m2 IV days 1 and 8, carboplatin AUC 5 IV day 1 and lenalidomide PO days 1-14 at three dose levels (5, 10, and 20 mg) for 6 21-day cycles. Patients with stable disease (SD), partial response (PR), or complete response (CR) after 6 cycles received lenalidomide alone as maintenance until disease progression. Restaging evaluations were performed every 3 cycles. The primary objective was to establish the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of the combination of gemcitabine, carboplatin and lenalidomide (GCL). Results: Sixteen patients were enrolled: urothelial carcinoma (n=8), non-small cell lung adenocarcinoma (n=3), unknown primary (n=2), pancreatic cancer (n=1), mesothelioma (n-1), and penile cancer (n=1). DLTs included ALT elevation and infection. Grade 3/4 adverse events included thrombocytopenia (75%), neutropenia (67%), anemia (58%), transaminitis (25%), hypokalemia (17%), hyponatremia (17%), hypophosphatemia (8%), hypomagnesemia (8%), rash (8%) and infection (8%). Tumor responses included: 7 PRs (44%), 5 SD (31%), 1 PD (6%), and 3 unevaluable (19%). Conclusions: GCL is active in patients with advanced urothelial carcinoma and other solid tumors. It was generally well tolerated, despite a high rate of myelosuppression, especially thrombocytopenia. The recommended phase II dosing is gemcitabine 1000 mg/m2 on days 1 and 8, carboplatin AUC 5 on day 1 and lenalidomide10mg on days 1-14 every 21days. An expansion cohort of only bladder cancer patients is ongoing at this dose and schedule. Clinical trial information: NCT01352962.
Metastatic NSCLC: Can molecular biology guide surgical decision making?
Authors: Paola Ulivi, Sandro Mattioli, Maurizio Puccetti, Laura Capelli, Wainer Zoli, Marianna Ricci, Daniele Calistri, Dino Amadori, Carlo Milandri
Journal: Journal of Clinical Oncology (2012)

e18045 Background: Guidelines do not recommend surgical resection of metastatic non-small cell lung cancer (NSCLC), with the exception of single brain or adrenal gland lesions, and further resection in the event of a new lung metastasis is generally not indicated. A different therapeutic approach is used in patients with multiple primary lesions. Can molecular alterations help to distinguish between independent primary tumors and metastatic lesions? Methods: A 74-year old woman underwent bilateral inferior lobectomy in May 2008 for two different synchronous NSCLC (adenocarcinoma and adenocarcinoma in situ, formally known as “bronchioloalveolar carcinoma” – J Thorac Oncol 2011;6:244–285). Three months after surgery the patient developed a single symptomatic brain metastasis. A CT scan also highlighted a suspect lingular lesion of the lung. Stereotaxic brain radiotherapy was carried out followed by systemic platinum-based chemotherapy. The brain metastasis showed very good radiological partial remission (PR) while the lung lesion remained stable after 4 cycles of chemotherapy. After two years’ follow-up the brain metastasis remained in PR whereas the lung lesion had progressed, and fine needle aspirate revealed adenocarcinoma. Results: Molecular analysis showed that EGFR gene status was wild type in all three tumors, whereas K-ras gene status differed. With regard to the two synchronous tumors, a barely visible G12C K-ras gene mutation was found in the bronchioloalveolar carcinoma, while a G12D K-ras mutation was detected in the adenocarcinoma. Moreover, K-ras gene status in the lingular node revealed a G12A mutation. On the basis of these results we hypothesized the presence of a third lung cancer and it was decided to proceed with surgery. The patient underwent laparoscopic lingulectomy which confirmed the diagnosis of adenocarcinoma with the same G12A K-ras mutation. Conclusions: This case highlights the importance of the molecular characterization of tumors in patients with multiple lesions. Different alterations within a single gene in different lesions are indicative of an independent clonal origin and suggestive of separate primary tumors rather than secondary lesions, thus facilitating treatment decision making.
Histone Deacetylase Inhibitor Valproic Acid Has Differential Effects on Trafficking of Normal Hematopoietic Stem/Progenitor Cells and Leukemic Blasts.
Authors: Hilal Gul, Leah A. Marquez-Curtis, Ashraf Kharrat, Jencet Montano, A. Robert Turner, Anna Janowska-Wieczorek
Journal: Blood (2007)
Disparities in patient portal messaging by hematology and oncology patients.
Authors: Matthew J. Rioth, Robert M Cronin, Sharon E Davis, Gretchen Purcell Jackson
Journal: Journal of Clinical Oncology (2015)

e17608 Background: Patient portals are online applications that patients utilize to interact with their healthcare information and organizations. Patient portal adoption is increasing, and secure patient-provider messaging is one of the most popular functions. Portal research, predominately in primary care, has demonstrated disparities in use of messaging. Adoption of messaging by hematology and oncology patients and providers has not been studied. Methods: This retrospective cohort study examined utilization of patient-initiated secure messages versus clinic visits by hematology and oncology patients between January 1, 2008 and December 31, 2010. Clinic visits and messages were assigned to hematology, oncology, or stem cell transplant subspecialties. Patient demographics and the percentage of outpatient interactions done through messaging were determined. Hypothesis testing used χ2and Wilcox signed rank tests; multivariable analysis used logistic regression. Results: Hematology and oncology patients participated in 59192 clinic visits and initiated 15,089 messages during the study period. Caucasian patients initiated the most messages and had the highest percentage of outpatient interaction through messaging (n=19211; 20.3%) while African American patients had the lowest proportion (n = 858; 6.8%). Messages increased from 3271 (7.81%) in 2008 to 11093 (28.4%) in 2010 (p < 0.001). Conclusions: Patient portal messaging and percentage of outpatient interaction delivered by hematology and oncology providers through messaging increased significantly during the study period. There were racial disparities in messaging, with non-Caucasian patients sending significantly fewer messages and receiving less care online. As more care is delivered online, additional research is needed to determine if disparities in technology use exacerbate or create disparities in healthcare. Message n % outpatient interaction OR 95% CI Age (per 5 year) 0.96 0.95-0.96 Oncology 15089 25.4% Ref Hematology 1359 4.2% 0.21 0.18-0.24 Stem cell transplant 4945 18.6% 0.50 0.46-0.55 Sex=M 0.99 0.96-1.03 Caucasian 19211 20.3% Ref African American 858 6.8% 0.40 0.38-0.43 Hispanic/Latino 94 8.8% 0.42 0.33-0.52 Race=Other 105 10.2% 0.44 0.36-0.54
Frailty: A major consideration for short- and long-term outcomes in resected pancreatic cancer.
Authors: Ioannis Konstantinidis, Aaron G Lewis, Federrico Tozzi, Philip HG Ituarte, Susanne Warner, Yanghee Woo, Gapandeep Singh, Yuman Fong, Laleh Golkar Melstrom
Journal: Journal of Clinical Oncology (2017)

418 Background: Frailty has been associated with adverse postoperative outcomes. However, little is known about its correlation with survival in resected pancreatic cancer. This study examined the correlation of frailty with postoperative outcomes and survival after pancreatectomy for cancer. Methods: Data from National Surgical Quality Improvement Program (NSQIP) patients (n = 7400) who underwent pancreatectomy between 2011 to 2013. A modified frailty index (mFI) validated for use in NSQIP was used to examine correlations between frailty and postoperative outcomes. California Cancer Registry (CCR) data for patients (n = 4959) who underwent pancreatectomy for cancer between 2000 to 2012 was used to assess the association between the Charlson Comorbidity Index (CCI), as a surrogate for frailty, and overall survival. Results: The distribution of NSQIP patients according to the mFI was 0, 1, 2, 3, 4 in 2797 (37.8%), 3422 (46.2), 1074 (14.5), 104 (1.4) and 3 (0.04) respectively. The patients were divided to non frail (mFI = 0), mildly frail (mFI = 1-2), or severely frail (mFI3 ≥ 3). Overall, 8.7% of patients experienced a grade 4 Clavien complication and 3.1% experienced postoperative mortality. Worsening frailty correlated with an increase in grade 4 Clavien complications (non-frail: 6.3% vs. mildly frail: 9.7% vs. severely frail: 26.2%; p &lt; 0.001) and mortality (1.9% vs. 3.8% vs. 4.7% respectively; p &lt; 0.001). The majority of CCR patients had similarly few comorbidities: CCI: 0, 1, ≥ 2 in 3869 (77.8%), 861 (17.31%) and 243 (4.89%) respectively. Median survival decreased as CCI increased (for CCI 0, 1 and ≥ 2 was 23 vs. 19 vs. 15 months respectively; p &lt; 0.001). Conclusions: Frailty is a powerful correlate of postoperative outcome and survival for resected pancreatic cancer patients and is an important consideration in planning for surgical intervention.