tbuckley/cabot-search huggingface dataset:
Abstract TMIM-074: IGF2 IN HUMAN FOLLICULAR FLUID PROMOTES LYMPHOMAGENESIS IN MAMMARY FAT PAD OF TRP53-NULL MICE, DEPENDING ON ESTROGEN IN MICROENVIRONMENT
Authors: Hsuan-Shun Huang, Sung-Chao Chu, Tang-Yuan Chu
Journal: Clinical Cancer Research (2019)

Abstract Ovulation overdrive is the most important risk factor of ovarian cancer. In previous study we discovered that preovulatory follicular fluid (FF) collected from IVF women, upon weekly injections into the mammary fat pad of Trp53-null mice for 7 weeks, could induce early onset of B cell lymphomas. In subsequent studies (Abstract by Chu TY et al.), we disclosed the IGF-axis signaling conferred by FFs is responsible for the stemness, clonal expansion and transformation of fallopian tube fimbrial epithelial cells where IGF2 in FF bound IGF-1R on secretory cells to activate the downstream PI3K/Akt/mTOR and PI3K/Akt/NANOG signaling pathways for the transformation. In this study, we identified the same IGF2 is also responsible for the FF-induced lymphomagenesis in Trp53-null mice. When IGF2 was depleted from FF, the tumorigenesis rate reduced from 10/18 (56%) to 1/6 (17%). On the other hand, injections with pure IGF2 (100 mg/ml) grew tumors in 33% (2/6) of mice. The same injection to Trp53 wild type did not grow tumor. We also found a microenvironment of adipose tissue seemed to be important for the FF-induced lymphomagenesis. The same injections of FF into the subcutis and other sites did not grow tumor. Additionally, tumor development depends not only on the injection site but also on the female sex hormone and ER function. No tumor growth was observed in castrated female mice and in male mice. Adding fulvastrant to the injections resulted in complete shrinkage of tumor. Meanwhile, extended injection of FF from 7 weeks to 13 weeks promoted tumor progression but did not increase tumor incidence. The findings suggest a transformation activity of human preovulatory FF largely conferred by IGF2. In the context of germline Trp53 loss, this activity likely promotes expansion of the lymphocytic progenitors that have already been transformed. Meanwhile, we found ER is expressed in the tumor adjacent adipocytes but not in the lymphoma cells. Also, ER antagonist, although largely confined tumor growth, did not decrease the tumor incidence. In this tumorigenesis model conferred by Trp53 loss and FF-IGF2, estrogen seems to play an essential role in tumor progression but not in tumor initiation, and this promotion effect is through the adipocyte microenvironment. Citation Format: Hsuan-Shun Huang, Sung-Chao Chu, Tang-Yuan Chu. IGF2 IN HUMAN FOLLICULAR FLUID PROMOTES LYMPHOMAGENESIS IN MAMMARY FAT PAD OF TRP53-NULL MICE, DEPENDING ON ESTROGEN IN MICROENVIRONMENT [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr TMIM-074.
Baseline neutrophil-to-eosinophil ratio (NER) and its association with clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (CPI).
Authors: Deepak Ravindranathan, Yuan Liu, Dylan J. Martini, Jacqueline T Brown, Bassel Nazha, Greta Russler, Lauren Beth Yantorni, Sarah Caulfield, Bradley Curtis Carthon, Omer Kucuk, Viraj A. Master, Mehmet Asim Bilen
Journal: Journal of Clinical Oncology (2021)

e16569 Background: Inflammatory markers have been studied as prognostic markers in patients with mRCC treated with CPIs. Recently, eosinophilia has been found to be associated with improved survival of patients with melanoma treated with CPIs. We reported baseline NER in patients with mRCC treated with CPIs and its association with clinical outcomes. Methods: We conducted a retrospective analysis of patients with mRCC treated with CPIs at Winship Cancer Institute from 2015-2018. Clinical outcomes were measured as overall survival (OS), progression-free survival (PFS), and clinical benefit (CB). OS and PFS were calculated from CPI-initiation to date of death and radiographic or clinical progression, respectively. Patients with baseline NER were categorized into high or low; high defined as NER &gt; 49.2 and low defined as NER &lt; 49.2. Univariate (UVA) and multivariate (MVA) analyses were carried out for OS and PFS using Cox proportional hazard model. Results: A total of 184 patients were studied with a median follow up of 25.4 months. Median age was 63 years old with 72% male and 20% black. About 25% were in high NER group. The high NER patients had significantly shorter OS in both UVA (HR: 0.58, p-value=0.017) and MVA (HR: 0.62, p-value=0.046) (Table). There was no significant difference between groups for PFS. Clinical benefit was seen in 47.3% of patients with low baseline NER and 40% with high NER. Conclusions: High baseline NER was associated with worse OS in patients with mRCC treated with CPIs. Larger, prospective studies are warranted to validate this hypothesis generating data.[Table: see text]
Solitary Contralateral Adrenal Metastasis of Renal Cell Carcinoma
Authors: Nuh Filizoglu, Salih Ozguven
Journal: Clinical Nuclear Medicine (2021)

68Ga-DOTATATE PET/CT is an imaging technique used in the diagnosis of neuroendocrine tumors. Since renal cell carcinoma (RCC) expresses the somatostatin receptors, 68Ga-DOTATATE PET/CT could be used in the surveillance of RCC. However, limited cases showing 68Ga-DOTATATE uptake in the metastases of RCC have been reported before. Herein, we report a case of a 55-year-old woman with a history of left nephrectomy for clear cell renal cell carcinoma 2 years before, and referred to 68Ga-DOTATATE PET/CT for the evaluation of adrenal mass. 68Ga-DOTATATE PET/CT showed intense 68Ga-DOTATATE uptake on the adrenal mass. Histopathology of the adrenal mass confirmed the diagnosis of clear cell renal cell carcinoma metastasis.
A national survey on cancer pain management among medical oncologists in the Philippines.
Authors: Marvin Jonne Limbo Mendoza, Alfredo Viray Chua, Patricia Grace Chua Tan, Carla Bonifacio Dofitas, Emmanuell Villano, Maria Dolma Gudez Santos, Heinrik Martin Jude Sampedro Strebel
Journal: Journal of Clinical Oncology (2021)

e24071 Background: Pain is one of the most burdensome symptoms of cancer. Although cancer pain management is an integral component in the practice of oncology, many patients still complain of insufficient pain control. Therefore, there is a need to pursue and strengthen strategies on how to adequately and effectively manage cancer pain. This study aimed to determine the knowledge and attitudes of Filipino medical oncologists regarding cancer pain management. It also examined the practices and perceived barriers in managing cancer pain. Methods: This was a cross-sectional study which utilized a validated questionnaire designed to assess a physician’s knowledge on pain management and opioid therapy, perceptions of the adequacy of cancer pain management, and significance of various potential barriers in optimal cancer pain management. Results: Out of the 280 PSMO members practicing in the Philippines, 85 responded to the survey. Using numeric rating scales of 0 to 10, medical oncologists appeared to agree on their knowledge about opioid therapy as well as in their perceptions of pain management. Respondents have rated themselves highly (Med: 8; IQR 6-8) in their ability to manage cancer pain. There were similar responses to ascribing all potential barriers as significant in rendering optimal cancer pain management, with cost as the most considerable factor (Med: 8, IQR: 7-10). However, given two challenging clinical scenarios, 66% and 90%, respectively endorsed treatment decisions that were unacceptable to pain experts. Conclusions: In this study, Filipino medical oncologists have shown agreement on their knowledge but perceived significant barriers in cancer pain management, with cost as the most considerable factor. Educational strategies, positive attitudinal change, and multidisciplinary collaboration with pain or palliative care specialists should be strengthened to improve patient care.
First results of a head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia.
Authors: John C. Byrd, Peter Hillmen, Paolo Ghia, Arnon P. Kater, Asher Alban Akmal Chanan-Khan, Richard R. Furman, Susan M. O'Brien, Mustafa Nuri Yenerel, Árpád Illés, Neil E. Kay, Jose Antonio Garcia Marco, Anthony R. Mato, John Francis Seymour, Stephane Leprêtre, Stephan Stilgenbauer, Tadeusz Robak, Priti Patel, Kara Higgins, Sophia Sohoni, Wojciech Jurczak
Journal: Journal of Clinical Oncology (2021)

7500 Background: Increased selectivity of the Bruton tyrosine kinase inhibitor (BTKi) acalabrutinib (Aca) vs ibrutinib (Ib) may improve tolerability. We conducted an open-label, randomized, noninferiority, phase 3 trial to compare Aca vs Ib in patients (pts) with chronic lymphocytic leukemia (CLL). Methods: Previously treated CLL pts with del(17p) or del(11q) by central lab were randomized to receive oral Aca 100 mg BID or Ib 420 mg QD (stratified by del(17p) status, ECOG PS [2 vs ≤1], and number of prior therapies [1–3 vs ≥4]) until progression or unacceptable toxicity. Primary endpoint was progression-free survival (PFS) as assessed by IRC; secondary endpoints of all grade atrial fibrillation (AF), grade ≥3 infection, Richter transformation, and overall survival (OS) were assessed in hierarchical order. Results: 533 pts (Aca, n=268; Ib, n=265) were randomized (median age 66 y; median 2 prior therapies; del(17p) 45.2%; del(11q) 64.2%). At a median follow-up of 40.9 mo (range 0.0–59.1), Aca was noninferior to Ib with a median PFS of 38.4 mo in both arms (HR 1.00; 95% CI 0.79–1.27). Aca was statistically superior to Ib in all-grade AF incidence (9.4% vs 16.0%; P=0.023). Among the other secondary endpoints, incidences of grade ≥3 infection (Aca: 30.8%, Ib: 30.0%) and Richter transformation (Aca: 3.8%, Ib: 4.9%) were comparable between arms. Median OS was not reached in either arm (HR 0.82 [95% CI 0.59–1.15]), with 63 (23.5%) deaths in the Aca arm and 73 (27.5%) in the Ib arm. Among any-grade AEs in ≥20% of pts in either arm, Aca was associated with a lower incidence of hypertension (9.4%, 23.2%), arthralgia (15.8%, 22.8%), and diarrhea (34.6%, 46.0%) but a higher incidence of headache (34.6%, 20.2%) and cough (28.9%, 21.3%). AEs led to treatment discontinuation in 14.7% of Aca- vs 21.3% of Ib-treated pts. Among any-grade events of clinical interest, cardiac, hypertension, and bleeding events were less frequent with Aca (Table). Conclusions: In this first head-to-head trial of BTKis in CLL, Aca demonstrated non-inferior PFS with less cardiotoxicity and fewer discontinuations due to AEs vs Ib. Clinical trial information: NCT02477696. [Table: see text]
Impact of using volumetric dosimetry to screen childhood cancer survivors for radiation-related late effects.
Authors: Sally Cohen-Cutler, Cameron Kaplan, Arthur Olch, Kenneth Wong, Jemily Malvar, Louis S. Constine, David R. Freyer
Journal: Journal of Clinical Oncology (2021)

12066 Background: Late effects screening guidelines for survivors of childhood cancer treated with radiation therapy currently use irradiated regions (IR) rather than volumetric dosimetry (VD), which more precisely identifies organs-at-risk (OAR). We recently showed that VD reduced mean number of recommended screening diagnostic imaging studies and procedures by 37.0% per patient (p&lt;0.001). 1 Here we have incorporated chemotherapy and refined volumetric dosimetry dose thresholds. Methods: This was a cross-sectional cohort study of patients (n=132) treated for cancer using computerized tomography-planned irradiation at Children’s Hospital Los Angeles from 2000-2016. For each patient, both VD and IR methods were used to determine radiation exposure to the cochlea, heart, lung, breast, and colon. Dose thresholds for VD were based on those supplied in the Children’s Oncology Group (COG) Long-Term Follow-Up Guidelines. Relevant chemotherapy exposures were recorded. Under each method, COG Long-Term Follow-Up Guidelines were applied to determine potential chemotherapy- and radiation-related late effects and their correlative screening practices (complete audiologic evaluation, pure tone audiometry, mammogram, breast MRI, echocardiogram, pulmonary functions test, and/or colonoscopy). Identified OAR were compared using Exact McNemar’s test. Total numbers of screening practices were computed using VD and IR and compared. Results: Median age at end of treatment was 10.6 years (range 1.4-20.4). The most frequent cancer type was brain tumor (45%), followed by bone and soft tissue tumor (39%) and leukemia/lymphoma (16%). Head/brain was the most commonly irradiated region (61%), followed by abdomen (22%). Anthracyclines were received by 25% of patients at &lt; 250 mg/m 2 and by 16% at ≥ 250 mg/m 2 . With use of VD, fewer patients were flagged for screening for each organ of interest: cochlea (-21.3%, p&lt;0.001), heart (-22.5%, p&lt;0.001), lung (-13.8%, p=0.219), breast (-25%, p=0.625), colon (-51.9%, p&lt;0.001). Over the lifetime of this cohort, use of VD resulted in recommendations for 1,333 fewer pure tone audiometric tests (-21.5%), 9 fewer complete audiologic evaluations (-16.1%), 4 fewer pulmonary function tests (-13.8%), 112 fewer mammograms (-25.0%) and breast MRIs (-25.0%), 349 fewer echocardiograms (-16.1%), and 275 fewer colonoscopies (-51.9%). Conclusions: Use of VD rather than IR significantly reduces guideline-based screening for radiation-related late effects in long-term childhood cancer survivors. This work forms the basis for a comparative cost-effectiveness analysis of these two approaches. (1) Cohen-Cutler et al, Cancer Medicine, 2020.
Association between body mass index, dosing strategy, and efficacy of immune checkpoint inhibitors
Authors: Murtaza Ahmed, Mitchell S von Itzstein, Thomas Sheffield, Shaheen Khan, Farjana Fattah, Jason Y Park, Vinita Popat, Jessica M Saltarski, Yvonne Gloria-McCutchen, David Hsiehchen, Jared Ostmeyer, Saad A Khan, Nazima Sultana, Yang Xie, Quan-Zhen Li, Edward K Wakeland, David E Gerber
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Increased body mass index (BMI) has been associated with improved response to immune checkpoint inhibitors (ICIs) in multiple cancer types. We evaluated associations between BMI, ICI dosing strategy, and clinical outcomes. Methods We abstracted clinical data on patients with cancer treated with ICI, including age, sex, cancer type, BMI, ICI type, dosing strategy (weight-based or fixed), radiographic response, overall survival (OS), and progression-free survival (PFS). We compared clinical outcomes between low-BMI and high-BMI populations using Kaplan-Meier curves, Cox regressions, and Pearson product-moment correlation coefficients. Results A total of 297 patients were enrolled, of whom 40% were women and 59% were overweight (BMI≥25). Of these, 204 (69%) received fixed and 93 (31%) received weight-based ICI dosing. In the overall cohort, overweight BMI was associated with improved PFS (HR 0.69; 95% CI 0.51 to 0.94; p=0.02) and had a trend toward improved OS (HR 0.77; 95% CI 0.57 to 1.04; p=0.08). For both endpoints, improved outcomes in the overweight population were limited to patients who received weight-based ICI dosing (PFS HR 0.53; p=0.04 for weight-based; vs HR 0.79; p=0.2 for fixed dosing) (OS HR 0.56; p=0.03 for weight-based; vs HR 0.89; p=0.54 for fixed dosing). In multivariable analysis, BMI was not associated with PFS or OS. However, the interaction of BMI≥25 and weight-based dosing had a trend toward association with PFS (HR 0.53; 95% CI 0.26 to 1.10; p=0.09) and was associated with OS (HR 0.50; 95% CI 0.25 to 0.99; p=0.05). Patients with BMI&lt;25 tended to have better outcomes with fixed-dose compared with weight-based ICI, while patients with BMI≥25 tended to have better outcomes with weight-based ICI, although these differences did not achieve statistical significance. There was no association between radiographic response and BMI with fixed-dose ICI (p=0.97), but a near-significant trend with weight-based ICI (p=0.1). In subset analyses, the association between BMI, ICI dosing strategy, and clinical outcomes appeared limited to men. Conclusions The clinical benefit of ICI in high-BMI populations appears limited to individuals receiving weight-based ICI dosing. Further research into optimal ICI dosing strategies may be warranted.
A phase I study of a TGF-<b>β</b> receptor I kinase inhibitor YL-13027 in patients with advanced solid tumors.
Authors: Jin Li, Tianshu Liu, Hanying Bao, Zusheng Xu, Yang Shu, Binghua Zheng
Journal: Journal of Clinical Oncology (2021)

3098 Background: Transforming growth factor beta (TGF-β) is upregulated in the majority of tumors, promoting tumor cell proliferation, differentiation, and, modulation of the tumor microenvironment. YL-13027, a small molecule inhibitor of type 1 receptor of TGF-β, is a potent highly selective oral agent that downregulates TGFbR1-dependent pathways in tumor cells. YL-13027 dosed into tumor bearing animals drives tumor growth inhibition and interruption of metastasis. In this first-in-human phase1 study, we characterized the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK) and preliminary efficacy of YL-13027 in patients with advanced solid tumors. Methods: YL-13027 tablets were administered orally, twice daily under fasted conditions for 28 days, for at least two 28 day cycles until disease progression, unacceptable toxicity or withdrawal from the study. Starting with an initial dose of 60 mg, dose escalation in a 3+3 design, and pre-determined PK assessments were applied. Adverse events (AEs) were graded by NCI-CTCAE v5.0. PK analysis was performed using a non-compartmental method. Efficacy was evaluated according to RECIST1.1. Results: As of January 18th 2021, thirteen patients were enrolled sequentially to Cohort-1 (60 mg, n = 2), Cohort-2 (120 mg, n = 1), Cohort-3 (180 mg, n = 3), Cohort-4 (240 mg, n = 4) and Cohort-5 (300 mg, n = 3), having gastrointestinal (n = 9), esophageal (n = 1), gallbladder (n = 1), lung (n = 1) and breast (n = 1) carcinomas. These patients had prior systemic antitumor standard therapies, including multi-line chemotherapy, radiation therapy, molecular targeted therapy, immunotherapy, or surgery. Twelve patients completed the cycle 1 safety observation period, with no cardiovascular toxicities or other DLTs observed. The MTD was not reached. Twelve patients experienced AEs possibly related to YL-13027. The most frequent related TEAEs (all grades/grade ≥3) were gamma-glutamyltransferase increased (38.5%/7.7%), haemoglobin decreased (38.5%/0%), blood alkaline phosphatase increased (23.1%/7.7%), aspartate aminotransferase increased (23.1%/0%) and blood phosphorus decreased (23.1%/0%). A maximum YL-13027 plasma concentration was reached within 2h post dose, and the mean elimination half-life was 4.2h in the steady state. Six subjects were evaluable for efficacy. One triple-negative breast cancer (TNBC) subject (Cohort-4) acquired a Partial Response (38.8% reduction of the target lesion), with the response exceeding 4 cycles, and YL-13027 treatment is continuing. The TNBC patient’s tumor profile indicated genomic mutations of EGFL7p.Q256H(13.50%), TP53p.E51*(10.90%) and NF1p.L21V(8.70%) from the initial tumor specimen at diagnosis. Conclusions: YL-13027 is well tolerated and further clinical investigation is warranted. Clinical trial information: NCT03869632.
Phase I dose-escalation study of desynchronized irinotecan plus bevacizumab, oxaliplatin, 5-fluorouracil, and folinic acid (bFOLFIRINOX-3) administration in chemorefractory metastatic colorectal cancer patients.
Authors: Jean-David Fumet, Alice Hervieu, Audrey Hennequin, Sylvie Zanetta, Aurelie Bertaut, François Ghiringhelli
Journal: Journal of Clinical Oncology (2021)

e15573 Background: Treatment of non-resectable metastatic colorectal cancer (mCRC) involves chemotherapy based on 5-fluorouracil, oxaliplatin and irinotecan and monoclonal antibodies targeting VEGF or EGFR. Rechallenge with oxaliplatin and irinotecan bi fractionation (FOLFIRI3) have previously shown efficacy in chemorefractory patients but desynchronized triplet chemotherapy was never tested. The aim of this study was to evaluate the safety and efficacy of a new regimen so-called: FOLFIRINOX-3 bevacizumab in chemorefractory mCRC. Methods: A phase I study to test bFOLFIRINOX 3 regimen was designed using Standard “3 + 3” design for dose escalation. Patients enrolled, &gt;18years and ECOG 0 or 1, have a pathologically confirmed mCRC and experienced treatment failure after standard chemotherapy that include 5-fluorouracil, oxaliplatin and irinotecan. Absence of residual neuropathy and previous grade 3 irinotecan related toxicity was manditory. Regimen tested consisted of bevacizumab (5mg/kg) plus simplified FOLFOX4 (folinic acid (400mg/m2), 5-fluorouracil (400mg/m2 bolus followed by 2400mg/m2 for 46h), oxaliplatin (85mg/m2) and irinotecan (administered before and after infusional 5-fluorouracil). Three irinotecan levels were planned at 60, 70 and 90 mg/m² (day 1 and day 3). Dose limiting toxicities (DLT) were identified during the first 2 cycles. Primary endpoint was assessment of maximum tolerable dose trough evaluation of acute toxicities (CTCAE v4.03). Secondary endpoints included objective response (RECIST 1.1), progression free survival, overall survival and late toxicity. Results: Thirteen patients received experimental treatment on this study. The RP2D was irinotecan 70mg/m² day 1 and day 3. Two patients experienced DLTs (G3 diarhea ) at dose level 90mg/m² and one DLT occured (G3 diarrhea) at 70mg/m² level. The most common drug-related adverse events (all grades) were fatigue (92.3%), diarrhea (76.9%), nausea (61.5%), peripheral neuropathy (61.5%), thrombopenia (46.1%) and anemia (15.3%). Among 11 response-evaluable patients, we noticed 4 partial responses, 7 stable disease and no progression as best response. Conclusions: The combination of bFOLFIRINOX-3 at the RP2D of 70mg/m² day 1 and day 3. was well tolerated and feseably. The regimen resulted in high response rate in chemorefractory metastatic colorectal cancer. Phase II is ongoing. Clinical trial information: NCT03795311.
The Electrocardiogram in Nonsystemic Ventricular Pacing in a Patient with Congenitally Corrected Transposition of the Great Arteries and Dextrocardia
Authors: Robert Hull
Journal: Clinical Cardiology and Cardiovascular Interventions (2021)

Congenitally corrected transposition of the great arteries (CCTGA) has a high incidence of dextrocardia and complete heart block. We describe a 34 year-old male with CCTGA, dextrocardia, and third degree atrioventricular block status-post dual chamber pacemaker that presented with acute heart failure syndrome. Cardiac CT Angiography confirmed CCTGA with situs solitus and dextrocardia. EKG with standard frontal leads showed a normal P wave axis and right-sided precordial leads showed a right bundle branch block pattern. With situs solitus there is a normal P wave axis on standard frontal leads. With nonsystemic ventricular pacing in CCTGA with dextrocardia left- and right-sided precordial leads show a left bundle branch block pattern and right bundle branch block pattern respectively. This case highlights electrocardiographic patterns seen with dextrocardia and morphologic reversal of ventricles.