tbuckley/cabot-search huggingface dataset:
Is a delay in ALK inhibitor initiation associated with poorer survival? A retrospective analysis based on real-world data.
Authors: Daniel Sheinson, William Bruce Wong, Ning Wu, Aaron Scott Mansfield
Journal: Journal of Clinical Oncology (2019)

e18240 Background: The time between a patient’s positive biomarker test result and initiation of targeted therapy may vary due to a number of factors, including the use of chemotherapy prior to or after the biomarker test result. The objective of this study was two-fold: first, to investigate the impact of delayed ALK inhibitor (ALKi) therapy on overall survival (OS) and second, to examine the association between the use of chemotherapy prior to or after biomarker testing and OS. Methods: The Flatiron Health EHR-derived database was used to identify patients with ALK-positive (ALK+) advanced NSCLC diagnosed between 1/1/2011 - 9/30/2018. The median time from ALK+ test result to ALKi start was used to separate patients into early versus delayed treatment cohorts. To account for potential immortal time bias, times from ALK+ test result to ALKi start from the delayed cohort were sampled with replacement and used to create modified index dates among the early cohort. Cox proportional hazards models adjusting for baseline characteristics (i.e. ECOG) were used to assess the association between delayed ALKi start and OS and the use of chemotherapy with OS. Results: 422 patients with ALK+ aNSCLC were included in this analysis with a median time from test result to ALKi start of 3 weeks. 88 patients (20.9%) received chemotherapy prior to starting their ALKi. Delayed ALKi use was associated with a 2.3 fold increase in risk of mortality (HR [95% CI]: 2.30 [1.28, 4.15], p &lt; 0.01). There was no difference in survival observed between those who had received chemotherapy prior to initiating their ALKi and those who did not receive chemotherapy (HR [95% CI]: 0.99 [0.62, 1.58]). Among those who initiated chemotherapy prior to their ALK+ test result, the continued use of chemotherapy prior to initiating an ALKi did not result in differences in OS compared to those who switched to an ALKi without continuing chemotherapy (HR [95% CI]: 1.03 [0.44, 2.41]). Conclusions: Delayed initiation of ALKi may result in poor outcomes in patients with ALK+ NSCLC. Receipt of chemotherapy prior to ALKi or the duration of chemotherapy did not impact survival. Future strategies to improve the time to therapy initiation may be useful in improving patient outcomes.
Abstract 17934: Bevacizumab for Plaque Stabilization: Evaluation of its Effect on Vasa Vasorum, Lipid Pool, and Atheroma Volume by Multimodality Imaging Techniques in an Atherosclerotic Rabbit Model
Authors: Sining Hu, Jinwei Tian, Nana Dong, Yanli Sun, Xue Han, Wen Cheng, Yongxing Jiang, Liang Chang, Xiang Ban, Qi Huang, Haibo Jia, Lei Xing, Lingbo Meng, Jingbo Hou, Shaosong Zhang, Bo Yu, Ik-Kyung Jang
Journal: Circulation (2012)

Background: Adventitial vasa vasorum may play an important role in plaque progression and rupture by allowing inflammatory cells and red blood cells to penetrate into the plaque through the channel...
Image-guided surgery for tumor agnostic detection of solid tumors using the pH-activated micellar imaging agent ONM-100.
Authors: Floris Jan Voskuil, Pieter Jan Steinkamp, Marjory Koller, Bert van der Vegt, Jan Johannes Doff, Tian Zhao, Jeffrey P. Hartung, Yalia Jayalakshmi, Baran D. Sumer, Jinming Gao, Max J.H. Witjes, Gooitzen Michell Van Dam
Journal: Journal of Clinical Oncology (2019)

3068 Background: ONM-100, a micelle-based polymer imaging agent conjugated to indocyanine green (ICG) and with an exquisitely pH-sensitive binary activation mechanism, may be used for tumor detection. ONM-100 micelles dissociate in acidic environments resulting in activation of the fluorescent ICG tag. As nearly all solid cancer types are acidotic, ONM-100 has the potential to act as a broadly indicated tumor agnostic imaging agent. This first-in-human study investigates the safety and feasibility of ONM-100 as a tumor agnostic imaging agent for intra-operative fluorescent imaging of various solid tumors. Methods: ONM-100 was IV administered 24±8h prior to surgery in a dose escalation scheme (0.1-1.2mg/kg). Patients with histopathologically confirmed breast cancer (BC), head and neck squamous cell carcinoma (HNSCC), colorectal cancer (CRC) and esophageal cancer (EC) were included. Blood was drawn to assess safety and pharmacokinetic data. Intra-operative fluorescence images were collected before and after tumor excision. Post-excision fluorescence images were obtained from serially sliced specimens and correlated with standard histopathological assessment. Results: 30 patients (11 BC, 13 HNSCC, 3 EC, 3 CRC) were enrolled. No ONM-100 related serious adverse events were observed and the agent was well-tolerated. A strong and sharply demarcated fluorescent signal was observed in all patients with vital tumor tissue (median CNR ranging 1.85-14.05) which correlated with tumor on final histopathology. HNSCC and superficially located BC as well as peritoneal metastasis could be clearly visualized in vivo during surgery. In four patients (BC and HNSCC), perioperatively, tumors otherwise unnoticed by the surgeons were detected on the margin or wound bed using fluorescence imaging. Additionally, two BC tumor lesions were detected that were missed by conventional pre-operative imaging and pathological assessment. Conclusions: ONM-100 appears to be safe and enables fluorescent visualization of tumors both in vivo and ex vivo. The first-in-human data demonstrate the feasibility for potential use of ONM-100 for image guided surgery, margin assessment and detection of occult disease. Clinical trial information: NTR 7085.
PD-L1/PD-1 expression as a predictor of response to BCG in patients with high-risk non–muscle invasive bladder cancer.
Authors: Mathieu Roumiguie, Eva Comperat, Yann Neuzillet, Francois-Xavier Nouhaud, Vivien Graffeille, Alexandra Masson-Lecomte, Pierre Colin, Francois Audenet, Nadine Houede, Stephane Larre, Evanguelos Xylinas, Jeanne PIana Thomassin, Juliette Cotte, Geraldine Pignot, Leonor Chaltiel, Morgan Roupret
Journal: Journal of Clinical Oncology (2019)

4550 Background: Intravesical BCG instillation (IBI) is the gold standard adjuvant treatment after transurethral resection of the bladder in high risk non muscle invasive bladder cancer (HR-NMIBC). IBI induce a type of Th1 immune response requiring a recruitment of cytotoxic cells. This response is downregulated by the PD-1/PD-L1 checkpoint inhibitors through an inhibition of the action of CD8+ T cells against their target. Our purpose was to assess whether PD-1/PD-L1 expression was associated with IBI response in HR-NMIBC. Methods: Histologically confirmed HR-NMBC from 5 academic French institutions which underwent maintenance IBI were retrospectively included. The following data were collected: pathological stage, grade, concomitant carcinoma in situ, number of lesions and size. From a paraffin embedded samples of initial resection, a unique dedicated uropathologist quantified immunochemistry expression of CD3, CD8, PD-L1 (antibody SP263/ SP142, E1L3N, 28 8) in both tumour cells and tumoral microenvironment. Univariate and multivariate analyses were performed using Cox proportional hazards model. Results: Overall 140 patients (median age 66.5 years, range:35-87; sex ratio male vs female:6:1) were included. The distribution of NMIBC tumour for stage and grade was: Ta 37.2% (n = 52), T1 62.8% (n = 88) and high grade 100% (n = 140) respectively. The median number of IBI which were delivered was 12 (range 7-36). The median length of follow-up was 54.24 mo (95% CI = 49.91-58.68). Overall, 25 patients (17.9%) had a recurrence/or progression. The 72mo Disease free survival (DFS) rate was 81.11% (95% CI = 72.20-87.41). Using univariate analysis, we found that Age (HR = 1.07; [1.02-1.12] p = 0.005), CD3/CD8 ratio (HR per 10 units = 3.43 [1.62-7.23] p = 0.014) and PD-L1(HR per 10 units = 1.65 [1.15-2.38] p = 0.046) were associated with DFS. In multivariate analysis, Age (HR = 1.07 [1.02-1.13] p = 0.009), CD3/CD8 ratio (HR per 10 units = 1.96 [1.28-3.00] p = 0.02) and PD-L1 expression in tumour cells (HR per 10 units = 3.38 [1.61-7.11] p = 0.01) remained significantly associated with DFS. Conclusions: PD-L1 expression in tumour cells and the T cells population in tumour microenvironment were both predictive factors of BCG response in HR-NMIBC. These results build a scientific rationale for pharmacological intervention on a molecular target using immuno-oncology.
NATALEE: Phase III study of ribociclib (RIBO) + endocrine therapy (ET) as adjuvant treatment in hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) early breast cancer (EBC).
Authors: Dennis J. Slamon, Peter A. Fasching, Ravindranath Patel, Sunil Verma, Sara A. Hurvitz, Stephen K. L. Chia, John Crown, Miguel Martin, Carlos H. Barrios, Gonzalo Spera, Céline Lopez, Inès Hor, Diana Pelov, Gareth Hughes, Moditha Nawinne, Gabriel N. Hortobagyi
Journal: Journal of Clinical Oncology (2019)

TPS597 Background: RIBO is a selective inhibitor of CDK4/6 with demonstrated efficacy and is well tolerated when combined with ET in pre-/peri- and postmenopausal women with HR+, HER2– advanced breast cancer. Given these findings and considering the role of CDK4/6–Rb–E2F pathway dysregulation in ET resistance, there is a rationale for evaluating whether RIBO + ET prevents, or delays acquired resistance to ET in the adjuvant setting, to improve invasive disease-free survival (iDFS). Methods: The phase 3 multicenter, randomized, open-label NATALEE trial will evaluate the efficacy and safety of RIBO + ET as adjuvant treatment in patients with HR+, HER2– EBC. Eligible women (any menopausal status) and men aged ≥ 18 years will be randomized to RIBO 400 mg/day (3 weeks on/1 week off) + ET or ET alone. In both arms, ET will comprise daily continuous letrozole 2.5 mg/day or anastrozole 1 mg/day; men and premenopausal women will also receive goserelin 3.6 mg once every 28 days. Treatment with RIBO will last 36 months whereas treatment with ET (in both arms) will last 60 months. Patients must have had American Joint Committee on Cancer (8 th ed.) Anatomic Stage II (either N0 with grade 2-3 and/or Ki67 ≥ 20% or N1) or III EBC, with an initial diagnosis ≤ 18 months prior to randomization, and completed chemotherapy and radiotherapy (if indicated). Patients receiving standard (neo)adjuvant ET are eligible only if this treatment was initiated within 12 months of randomization. Key exclusion criteria include previous CDK4/6 inhibitor treatment and clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality. The primary endpoint is iDFS using STEEP (Standardized Definitions for Efficacy End Points) criteria as assessed by the investigator; secondary endpoints include recurrence-free survival, distant DFS, overall survival, patient-reported outcomes, and RIBO pharmacokinetics. Safety and tolerability will also be evaluated. Estimated enrollment is 4000 patients from 425 sites in 21 countries. Recruitment is ongoing. Clinical trial information: NCT03701334.
Burden of thrombocytopenia in adult cancer patients receiving chemotherapy.
Authors: Gerald A. Soff, Jaime Shaw, Karynsa Kilpatrick, Andrea Marongiu, Joseph Park
Journal: Journal of Clinical Oncology (2019)

1555 Background: Thrombocytopenia is a common toxicity of chemotherapy, yet there are limited data on its occurrence in routine clinical practice. Methods: Using structured patient-level data from the Flatiron Health EHR-derived database, we assessed risk (3-month cumulative incidence) of chemotherapy-induced thrombocytopenia (CIT) in adult patients (2012-2017) based on platelet counts, overall and by each grade of CIT, cancer type, and chemotherapy regimen (Table); and the co-occurrence of other hematologic abnormalities. Results: Of 15,521 solid tumor patients who initiated chemotherapy, 13% had evidence of CIT within 3 months (platelet count &lt;100x10 9 /L), 4% had grade 3 (25 to &lt;50x10 9 /L) and 2% had grade 4 (&lt;25x10 9 /L) CIT. Of the solid tumors examined, incidence was highest in melanoma patients. In hematologic malignancies (N = 2,537), 3-month risk was even higher with nearly 30%, 16%, and 12% having any grade, grade 3 and 4 CIT, respectively; and the greatest risk being in multiple myeloma patients. Anthracycline-based regimens were associated with the highest risk of CIT (7% grade 3; 4% grade 4), followed by gemcitabine- and platinum-based regimens. Anemia often accompanied first evidence of CIT (49%); isolated thrombocytopenia occurred in 15%. Conclusions: This study provides a current snapshot of CIT risk in a large sample of adult patients undergoing chemotherapy in routine clinical practice, highlighting patients at highest risk for CIT and underscoring the complexity of managing cancer treatment. [Table: see text]
Case 17-1988
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, John Shillito, Anna C. McKee
Journal: New England Journal of Medicine (1988)

Presentation of CaseA 40-year-old man was admitted to the hospital because of a question of a brain abscess.He was in excellent health until several months earlier, when he began to have pain in the region of a left upper tooth that was treated with aspirin. One month before entry the pain became more severe, with local tenderness. A dentist reported evidence of an apical abscess and prescribed penicillin, with resolution of his symptoms. A dental extraction was advised, but the patient declined it. Two weeks before admission headache developed and persisted. Two days before entry he was awakened . . .
Metastatic penile (mPSCC), uterine cervical (mCSCC), and skin (mSSCC) squamous cell carcinomas: A comparative genomic profiling (CGP) study.
Authors: Joseph Jacob, Gennady Bratslavsky, Oleg Shapiro, Nick Liu, Julia Andrea Elvin, Jo-Anne Vergilio, Jonathan Keith Killian, Nhu Ngo, Douglas I. Lin, Shakti Ramkissoon, Eric Allan Severson, Siraj Mahamed Ali, Jon Chung, Alexa Betzig Schrock, Prasanth Reddy, Brian Alexander, Kimberly McGregor, Vincent A. Miller, Andrea Necchi, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2019)

4585 Background: We compared the genomic alteration (GA) profiles of mCSCC, mPSCC and mSSCC to study impact on the targeted and immunotherapy options for the men and women suffering from these refractory cancers. Methods: 78 mPSCC, 604 mCSCC and 338 mSSCC underwent CGP using a hybrid-capture based assay. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and and microsatellite instability (MSI) was determined on 114 loci. Results: The HPV+/CDKN2A- status was significantly more frequent in the mCSCC than mPSCC or mSSCC (P &lt; 0.0001). The GA/tumor frequencies were similar for mCSCC and mPSCC, but significantly higher in mSSCC (P &lt; 0.0001). TP53 mutations were more common in mSSCC (UV light exposure) and mPSCC (likely due to loss of an original HPV+ status). TERT, NOTCH1 and FAT1 GA were more frequent in mPSCC and mSSCC whereas PIK3CA GA were more common in mCSCC. MTOR pathway targets (GA in STK11, FBXW7 and PTEN) were more common in mCSCC than mPSCC or mSSCC. MSI high status was extremely rare in all cases. TMB ≥ 10/20 mut/Mb frequencies were noteworthy in mPSCC and mCSCC but extraordinarily high in mSSCC. Examples of patients with mCSCC, mPSCC and mSSCC responding to targeted and immunotherapies will be presented. Conclusions: Although mCSCC, mPSCC and mSSCC share a variety of clinicopathologic features, the 3 tumor types can be sharply differentiated on CGP. The TP53, CDKN2A and HPV status of the tumor types differ significantly with HPV+ higher in the mCSCC group. There are opportunities for targeted therapies in all groups predominantly identified in the MTOR pathway. The relatively high numbers of cases with significantly elevated TMB in all 3 tumor types suggest that immunotherapies would be beneficial in a large subset of patients. [Table: see text]
Association between tumor biology and occult lymph node metastases before and after primary neoadjuvant therapy (NAT) for patients with early breast cancer.
Authors: Hans-Christian Kolberg, Cornelia Kolberg-Liedtke, Maja Krajewska, Ingo Bauerfeind, Tanja N. Fehm, Barbara Fleige, Gisela Helms, Annette Lebeau, Annette Staebler, Sibylle Loibl, Michael Untch, Thorsten Kuehn
Journal: Journal of Clinical Oncology (2019)

518 Background: Scientific efforts aim at a reduction of axillary morbidity through reduced axillary intervention among patients with early breast cancer. However, it is still unclear if this approach is feasible in all subtypes based on their risk of axillary involvement. We analyzed the association of tumor biology and occult axillary involvement with data from arms A and B of the SENTINA trial (Kühn T et al., Lancet Oncol 2013). Methods: Patients were included if they presented with a clinically negative axilla before NAT (arms A and B) and stratified according to tumor biology. All patients received SLNB before NAT, in cases of negative SLNB without further axillary surgery (Arm A) and in cases of positive SLNB (Arm B) with SLNB and axillary dissection after NAT. Logistic and linear regression analyses were carried out to evaluate the association between tumor biology and axillary involvement before and after NAT. Results: Of the 1022 patients in arms A and B of the SENTINA trial 926 were evaluable for this analysis. Of these, 27.9% had triple negative (TN), 16.3% hormone receptor (HR) and HER2 positive (triple positive = TP), 47.6% HR positive and HER2 negative (luminal) and 8.2% HR negative and HER2 positive (HER2) tumors. 39.7% of the luminal, 28.9% of the HER2, 19% of the TN and 47% of the TP tumors had involved SLN before NAT. Subgroup comparisons showed a significant difference between luminal and TN (p &lt; 0.0001), whereas the differences between luminal and TP (p = 0.115) and HER2 (p = 0.077) were not statistically significant. The 317 patients with involved SLN prior to NAT received SLNB and axillary dissection after completion of NAT. The analysis after NAT showed trends for lower rates of involved lymph nodes for the high-risk groups (TN 20% / TP 14.3% / HER2 8.7%) compared to luminal tumors (27.6%) without reaching statistical significance. Conclusions: Our analysis demonstrates that among patients enrolled in the SENTINA trial, patients with triple negative disease have the lowest risk for occult lymph node metastases at initial presentation. Our results do not justify more intense local intervention among patients with triple negative breast cancer.
ALK resistance mutations (muts) developed in different ALK fusion types.
Authors: Jun Zhao, Caixia Liu, Jianhua Chen, Likun Chen, Xinghao Ai, Zaiwen Fan, Yifen Wu, Rongrong Chen, Xuefeng Xia
Journal: Journal of Clinical Oncology (2019)

e14741 Background: Patients (pts) treated with ALK inhibitors (ALKi) inevitably develops resistance. Diverse mutations (muts) confer resistance to ALKis, which may be related to the diverse types of ALK fusion. The objective of this study is to see whether the resistance mechanisms developed during ALKi therapy are ALK fusion types dependent. Methods: The mutation profiles of 38 pts with known ALK fusion partners and positions, who ordered NGS test in our institution after progressed on ≥ 1 ALKis, were analyzed. Results: Resistant muts in ALK kinase domain ( ALK resistant muts) were detected in 53% (20/38) of the resistant pts. 100% (1/1) of the EML4-ALK V5’ variant (V5’), 81% (13/16) of the EML4-ALK V3 variant (V3), 60% (3/5) of the non- EML4-ALK, 23% (3/13) of EML4-ALK V1 variant (V1), and 0% (0/3) of the EML4-ALK V2 variant (V2) had ALK resistant muts. ALK G1202R was detected in 29% of the pts. 100% (1/1) of the V5’, 50% (8/16) of the V3, 20% (1/5, HIP1-ALK) of the non- EML4-ALK, and none of the V1 (0/13) and V2 (0/3) had G1202R. Amplification and gain of function muts in oncogenes and loss of function muts in tumor suppressor gene were detected in 16% (6/38) of the pts, namely 4 V1, 1 V2, and 1 V3. On average, pts treated with 3 rd generation ALKis had significantly more muts in ALK (7.5 vs. 3.6, p = 0.0008) and in all targeted regions (9.1 vs. 4.3, p = 0.0005) than pts treated with only 1 st and 2 nd generation ALKis. Conclusions: The type of resistance mechanisms developed during ALKi therapy may depend on the ALK fusion type of the pt. ALK resistant muts, especially G1202R, developed most frequently in V3/V5’, followed by non- EML4-ALK, and V1/V2, while amplification and grain of function muts in oncogenes and loss of function muts in tumor suppressor genes developed more often in V1/V2 than in V3/V5’. The 3 rd generation ALKi may increase the genomic alterations in treated pts.
AB0180 VALIDATION OF COMPLEX IMMUNOPHENOTYPING STRATIFICATION OF PATIENTSWITH LUPUS AND SJÖGREN’S SYNDROME WITH THERAPEUTIC POTENTIAL
Authors: Lucia Martin-Gutierrez, Hannah Peckham, George Robinson, Giulia Varnier, Elizabeth Jury, Coziana Ciurtin
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> There is a current paucity in effective treatments for patients with primary Sjögren's syndrome (pSS) and systemic lupus erythematosus (SLE). Their overlapping symptoms mean that they are often treated with similar biologic therapeutics, despite being distinct diagnoses. Our pilot research sought to stratify patients by novel, complex immune signatures, to potentially facilitate a more personalised approach to prescribing medication, irrespective of clinical diagnosis. From a cohort of 40 patient patients with SLE, pSS or combined SS/SLE, and 33 healthy controls; five distinct clusters were originally identified. <h3>Objectives:</h3> Here we aimed to validate the original patient endotypes from our pilot data with a new patient cohort, and refine the identified clusters to be of more realistic clinical benefit. <h3>Methods:</h3> A new cohort of patients with SLE (n=32), pSS (n=31) and SS/SLE (n=15) donated peripheral blood samples while attending appointments at UCLH clinics. None had received B-cell depletion therapy in the preceding 48 months. Complex phenotyping of peripheral T and B-cell subsets was performed by flow cytometry. Unsupervised clustering, statistical comparison to healthies and Receiver Operator Characteristic (ROC) analysis, as per our previous work, were used to stratify patients using immune signatures into distinct endotypes considering only those markers where sensitivity and specificity were above 80% (AUC&gt; 0.80). Characteristics of new clusters were compared with previous findings to refine the number of markers and unique groups. <h3>Results:</h3> Five distinct endotypes across the three disease groups were identified after unsupervised clustering of CD19+ B-cell, CD4+ and CD8+ T-cell subsets. Two of these clusters serve to validate groupings from our original data- one with a distinct B cell fingerprint (Bm1, lBm5 and Total CD19+) with AUC=0.87, AUC=0.81 and AUC=0.83 respectively, and another with a T cell fingerprint (Total CD4+, Total CD8+, CD8+ naïve, CD8+ effector memory T cell subsets) with AUC&gt;0.80 for all of them. Clinical diagnoses and symptoms treatment did not differ significantly between clusters. <h3>Conclusion:</h3> Our results demonstrate a novel method to re-classify patients using clustered immune phenotype abnormalities. Two distinct groups demonstrated either B or T-cell immunophenotypes, likely reflective of their underlying immunopathogenesis. Stratification by patient endotype has the potential to facilitate a better-informed selection of biologic therapeutics for individual patients; and highlights pathways for further mechanistic research. <h3>Acknowledgement:</h3> British Sjögren's syndrome Association and Versus Arthritis <h3>Disclosure of Interests:</h3> None declared