tbuckley/cabot-search huggingface dataset:
Role of parathyroid hormone in poor stem cell mobilisers.
Authors: Mansi Haresh Khanderia
Journal: Journal of Clinical Oncology (2016)

e19002 Background: The dose of PBSCs infused is critical to the success and the rate of hematopoietic recovery after auto-SCT. Approximately 20% patients mobilize < 2 x 10^ 6/kg CD34+ cells per kg with GCSF which is insufficient to ensure sustained hematopoietic engraftment. With the advent of plerixafor, about 2/3rd of poor mobilisers with GCSF achieve adequate collection. However 1/3rd of these patients who fail despite plerixafor receive only suboptimal alternative treatments in the absence of sufficient autologous PBSCs. Animal studies have shown Para- thyroid hormone (PTH) affects osteoblasts and the stem cell niche, induces expansion and mobilization of progenitor cells effectively related to an endogenous release of G-CSF and other factors. In a Phase I study of 20 subjects, PTH given s.c for 14 days along with GCSF on the last 4 days, 40-47% patients with 1 or 2 prior mobilization failures had adequate PBSC collection. Methods: This is a prospective study of 4 patients of NHL post 2 lines of chemotherapy and requiring Auto-HSCT but were poor mobilisers with GCSF and Plerixafor. PTH was given at 100mcg s.c OD on day 1 to day 14 with G-CSF 15 mcg /kg s.c on day 10 to day 14 and PBSC collection done on day 15 to day 18 was done. Results: In this study 3 out of 4 patients who failed GCSF and plerixafor mobilization successfully reached a total of > 2x 10^ 6/kg CD 34 + stem cells collection and underwent auto- HSCT. One patient could not undergo apheresis as peripheral blood CD34 + count was not adequate for collection. Hence 3 patients who were not eligible for autologous HSCT due to poor mobilization were benefitted by PTH.The cost of PTH for 14 days was Rs. 14000 (215 US$) and no dose related toxicities with PTH were noted. Conclusions: The role of PTH on the bone marrow niche and mobilization as well as homing and engraftment needs to be studied in phase 2 trials. PTH could be a novel potential and economical last resort in patients who fail mobilization with Plerixafor or those who cannot afford it. CD34 + CELLS CASES GCSF+ PLERIXAFOR PTH TOTAL DLBCL 1.19x10^6/kg 1.65x10^6/kg 2.84x10^6/kg DLBCL 1.09x10^6/kg 1.28x10^6/kg 2.37x10^6/kg ALCL 1 x10^6/kg FAILED 1 x10^6/kg DLBCL 1.4x 10^6/kg 2.17x10^6/kg 3.57x10^6/kg
Treatment related radiation toxicity among cervical cancer patients.
Authors: Lisa A. Rubinsak, Emma Charlotte Fields, Jori S. Carter, William P. McGuire, Sarah Madhu Temkin
Journal: Journal of Clinical Oncology (2018)

e22072 Background: Studies describing patient factors associated with radiation toxicity in cervical cancer (CxCa) treatment predate advancements in the delivery of radiotherapy. This study identifies factors that correlate with severe late gastrointestinal and or genitourinary toxicity (SLT) in women with CxCa treated with radiation using modern techniques. Methods: CxCa patients treated with radiation from 2005 to 2017 in a single academic institution were included. Records were reviewed for demographic information, Charlson comorbidity index (CCI), treatment details, toxicities and outcomes. Characteristics of patients with and without SLT were compared. Results: Of 185 patients identified, 21.6% had SLT; 17.8% had gastrointestinal toxicity and 10.8% had genitourinary toxicity. The mean duration of follow up was 37 (1-146) months. The majority of patients (84.3%) received 3-dimensional conformal therapy (3D), and 21% received intensity-modulated radiation therapy (IMRT). Factors associated with SLT were lower BMI (24.6 vs 28.7, p < 0.001), White race (62.5% vs 43.4%, p = 0.03), and smoking (59.0% vs 39.7%, p = 0.03). SLT was not associated with total dose, 3D versus IMRT planning, or time to complete therapy. Patients with SLT had PFS and OS similar to those without toxicity. Conclusions: In CxCa patients, radiation toxicity correlated with lower BMI, White race and smoking. Even with modern radiotherapy planning and delivery, toxicity rates are high, and interventions to reduce the burden of treatment are needed. Table 1: Characteristics of patients with SLT SLT n = 40 Age (years), mean ± SD 48.4 ± 14.1 BMI (kg/m2), mean ± SD 24.6 ± 8.0* Race, n (%) White 25 (62.5%)* Non-white 15 (37.5%) Smoking status, n (%) Never/former 16 (41%) Current 23 (59%)* CCI quartile, n (%) 0 18 (45%) 1 to 2 13 (32.5%) ≥ 3 9 (22.5%) Tumor stage, n (%) Early (FIGO 1A-1B1) 7 (17.9%) Locally advanced (FIGO IB2 to IVA) 32 (82.1%) Radiation timing, n (%) Primary 32 (80%) Adjuvant 8 (20%) External beam radiation therapy, n (%) 3D conformal therapy 26 (89.7%) IMRT 3 (10.3%) Brachytherapy, n (%) LDR 15 (55.6%) HDR 12 (44.4%) Concurrent chemotherapy, n (%) Yes 35 (87.5%) No 5 (12.5%) Total radiation dose (Gy), mean ± SD 79.7 ± 17.5 Time to complete treatment (days), mean ± SD 56 ± 22.7 *p < 0.05
Microsatellite instability as a prognostic factor in stadium II colon cancer patients. A meta-analysis of published literature.
Authors: Jan Novotny, Ioannis Gkekas, Ladislav Pecen, Karin Strigard, Richard Palmquist, Gilberto Morgan, Ulf Gunnarson
Journal: Journal of Clinical Oncology (2017)

e15075 Background: The prognostic role of microsatellite instability (MSI) in stage II colon cancer patients remains controversial despite it has been investigated in a number of studies. Hazard ratios differ considerably among these studies. We performed a meta-analysis to define the significance of MSI in this group of patients. Methods: Studies indexed in PubMed presenting separate data on MSI status and survival outcomes for stage II colon cancer patients have been analyzed using fixed-effect meta-analysis of hazard ratio according to the method of Peto. Results: Analysis was performed on 19 studies including 5998 patients. 47.2% patients received postoperative chemotherapy, 52.8% were males and 47.2% females. Eight studies included also rectal cancer patients. MSI was detected in 20.8 % of the patients. Hazard ration (HR) for overall survival (OS): MSI vs MSS for the entire population: 0.73 (95% confidence interval (CI): 0.33-1.65); HR for disease free survival (DFS): 0.60 (95% CI: 0.27-1.32). No statistical significant difference was found when comparing studies analyzing MSI with genotyping (MG) and immunohistochemistry (IHC) (MG vs IHC: HR OS 0.45, 95% CI 0.10-2.05 vs. 0.95, 95% CI 0.57–1.58; HR DFS 0.51, 95% CI: 0.14-1.85 vs. 0.67, 95% CI 0.26-1.70). However, numerically MSI determination with genotyping shows remarkably lower hazard ratios (further from HR equal to one) for both OS and DFS. Separate analysis of studies investigating colon cancer patients only showed HR OS 0.72 (95% CI: 0.31-1.71); HR DFS 0.60 (95% CI: 0.27-1.31). Conclusions: This is the first meta-analysis that evaluates the prognostic role of MSI in the well defined population of colon cancer patients with stage II disease. No significant relation was found between MSI status and various survival outcomes. Routine determination of MSI status to guide postoperative management of stage II colon cancer patients cannot be recommended based on the presently included studies. This study was supported from the unrestricted grant of Cancerforskningsfonden i Norrland/Lions Cancerforskningsfond LP 14-2065 and Akademisk Miljö NLL-576531.
Predictors of venous thromboembolism among cancer inpatients: A predictive model.
Authors: Shiva Shrotriya, Prajwal Dhakal, Mukta Sharma, Joseph Gardiner, Alexa Lupi, Supratik Rayamajhi
Journal: Journal of Clinical Oncology (2018)

e18824 Background: There has been an increased risk of venous thromboembolism (VTE) among cancer patients. Cancer associated thrombosis caused increased hospitalizations, increased inpatient/outpatient medical and prescription claims, and increased health care costs. Our objective was to identify risk factors for VTE in cancer inpatients. Also, we identified predictors of VTE and prepared a predictive model. Methods: Ours is a retrospective cohort study of VTE in cancer patients from January 2013 to September 2015. Logistic regression was performed with backward selection to identify potential predictors of VTE. Odds ratio (OR) with 95% confidence interval (CI) was estimated. A preliminary ROC analysis was conducted towards the goal of developing, testing and validating a prediction model for VTE. Results: A total of 3918 cancer inpatients were identified. Mean age was 66±14 years; 53% males; 85% Caucasians, 7% African Americans; and 15.8% were obese. Cancer types were 30% prostate, 16% lung, 11% cervical, 11% breast etc. Common comorbidities were 46% hypertension, 35% pulmonary diseases, 21% renal diseases, 23% diabetes, 11% congestive heart failure, 9% anemia etc. Total of 152 (3.87%) cancer patients had VTE. On univariate analysis, variables associated with increased VTE risk were renal disease (OR = 2.1, 95% CI: 1.43-2.97; p 0.0001), anemia (OR = 1.8, 95% CI: 1.14-2.89; p 0.012), and infection (OR = 1.4, 95% CI: 0.96-2.04; p 0.078). On multivariate analysis, cancer types, anemia, infection and renal disease were associated with increased risk of VTE. Breast and genitourinary cancer, anemia, infection, and renal disease formed the initial predictive model (c-statistic = 0.67), that will be enriched by key baseline laboratory markers such as hemoglobin, WBC, platelet count and creatinine. Conclusions: Anemia, renal diseases and infection increased VTE risk among cancer inpatients, with the highest risk among breast and genitourinary cancers. These variables and laboratory markers will inform our predictive model for VTE.
An Interleukin-1 Signature in Breast Cancer Treated with Interleukin-1 Receptor Blockade: Implications for Treating Cytokine Release Syndrome of Checkpoint Inhibitors
Authors: Charles Anthony Dinarello
Journal: Cancer Research (2018)

Abstract In this issue of Cancer Research, Wu and colleagues show that IL1b orchestrates tumor-promoting inflammation in breast cancer and can be targeted in patients using an IL1 receptor antagonist. Cancer Res; 78(18); 5200–2. ©2018 AACR. See related article by Wu et al., p. 5243
Phase I trial of the triplet M6620 (formerly VX970) + veliparib + cisplatin in patients with advanced solid tumors.
Authors: Geraldine Helen O'Sullivan Coyne, Khanh Tu Do, Shivaani Kummar, Naoko Takebe, Mary Flanagan Quinn, Sarina Anne Piha-Paul, Ashley Bruns, Lamin Juwara, Elad Sharon, Richard Piekarz, Howard Streicher, Larry Rubinstein, Deborah Wilsker, Robert J. Kinders, Ralph E. Parchment, Elliot B Levy, Austin Doyle, James H. Doroshow, Alice P. Chen
Journal: Journal of Clinical Oncology (2018)

2549 Background: Ataxia-telangiectasia-related (ATR) protein kinase is central to the repair of damaged DNA through the homologous recombination (HR) pathway, activating phosphorylation cascades that culminate in cell cycle arrest to allow time for DNA damage repair (DDR). M6620 is an ATR inhibitor with antitumor activity across a range of cell lines. Veliparib (ABT-888), an oral poly (ADP-ribose) polymerase (PARP) 1/2 inhibitor, plays a pivotal role in DDR response through the base excision repair pathway, with clinical evidence of antitumor activity in combination with cisplatin in BRCA mutation carriers. As DNA damage and antitumor activity of platinum results from DNA cross-links that stall replication forks and halt transcription, this trial evaluates if veliparib together with M6620 impair DNA repair by inducing a "BRCA null"-like phenotype that potentiates the antitumor activity of cisplatin. Methods: Open label phase I trial of the M6620+veliparib+cisplatin combination; 3+3 design, 21-day cycle: cisplatin 40mg/m2 intravenously (IV) Day 1 [Day 8 added from dose level (DL)3]; M6620 (M) IV Days 2+9; Veliparib (V) orally twice daily Days 1-3 and 8-10. Prior platinum, PARPi therapy permitted. Response: RECIST 1.1. Results: 23 patients(pts) enrolled, 22pts evaluable for response. 3/22pts confirmed partial responses (PR) lasting > 4cycles (range 4-15): 1pt with BRCA-wildtype ovarian cancer (DL3), 1pt with esophageal cancer/biallelic loss of ATM (DL4); 1pt with NSCL cancer/ATM mutation (DL5); all remain on study. 12/22pts have stable disease: median time on study 5 cycles (range 3-10). DL3+4 expanded for dose limiting toxicity: grade 4 hypophosphatemia and thrombocytopenia respectively (1pt, 4%). Other adverse events: grade 3 thrombocytopenia (6pts, 27%), leucopenia (5pts, 22%), lymphopenia (4pts, 18%). Maximally tolerated dose (MTD) not reached for the combination, currently enrolling DL7: V 200mg, M 210mg/m2. Conclusions: combination is safe and shows anti-tumor activity in HR-compromised tumors. Planned biomarker assessment at MTD includes γH2AX, RAD51, pNbs1, and pATR in tumor biopsies and circulating tumor cells using a validated, quantitative immunofluorescence assay. Clinical trial information: NCT02723864.
Phase 1 dose escalation of XMT-1522, a novel HER2-targeting antibody-drug conjugate (ADC), in patients (pts) with HER2-expressing breast, lung and gastric tumors.
Authors: Erika Paige Hamilton, Minal A. Barve, Aditya Bardia, Muralidhar Beeram, Johanna C. Bendell, Rebecca Mosher, Eric Hailman, Donald Alan Bergstrom, Howard A. Burris, Hatem Hussein Soliman
Journal: Journal of Clinical Oncology (2018)

2546 Background: XMT-1522 is comprised of 10-15 molecules of the payload AF-HPA, an auristatin-derivative with two-step intra-tumor metabolism intended to optimize therapeutic index, conjugated to a novel anti-HER2 monoclonal antibody via the Dolaflexin ADC platform. Methods: In this ongoing Phase 1 study, pts with advanced HER2-expressing (IHC ≥1+) breast cancer (BC), gastric cancer (GC) and non-small cell lung cancer (NSCLC) progressing on standard therapy or for whom no standard therapy exists are treated with XMT-1522 administered intravenously every 3 weeks. Dose escalation uses a 3+3 design with a modified Fibonacci escalation and a 3 week dose limiting toxicity (DLT) evaluation period. Primary objectives in dose escalation are safety and tolerability and determination of maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). (ClinicalTrials.gov NCT02952729) Results: As of February 1, 2018 19 pts have completed the DLT evaluation period across 6 dose levels (2 to 21.3 mg/m2). There have been no DLTs nor serious adverse events (SAEs) attributed to study drug. Treatment-related adverse events (TRAEs) have been Grade 1 or 2; the most common TRAEs included increased liver enzymes, fatigue, nausea, vomiting, headache, and anorexia. 18 patients have had post-treatment restaging scans. Disease control rate (DCR) was 5/6 (83%) for patients dosed at 16 or 21.3 mg/m2 with 1 PR and 4 SD. The ongoing PR occurred at first assessment in a pt with HER2-positive BC previously treated with ado-trastuzumab emtansine. Two SD were seen in HER2-positive BC pts (ongoing 13+ and 12+ wks duration) and SD was seen in two GC pts (12 weeks and ongoing 6+ weeks duration). DCR in patients treated at doses less than 16 mg/m2 was 3/12 (25%) with 3 SD (duration 23, 13 and 9 wks). The systemic exposure of total payload showed approximately dose-proportional increase. Plasma concentration of free drug payload and its active metabolite were low. Conclusions: XMT-1522 has been well-tolerated up to the 21.3 mg/m2 dose level with early signs of anti-tumor activity. Neither MTD nor RP2D has been identified. Dose escalation continues in pts with advanced HER2-expressing BC, GC and NSCLC. Clinical trial information: NCT02952729.
Abstract B004: A combination of two chemically distinct inhibitors of class I HDACs is highly effective to suppress AR signaling and in vivo growth of prostate cancer xenograft
Authors: Guimei Tian, Iqbal Mahmud, Ryan Stowe, Yushan Zhang, Hamsa Thayek Purayil, William Roush, Yehia Daaka, Daiqing Liao
Journal: Cancer Research (2018)

Abstract Class I HDACs 1-3 are critical for the AR-mediated transcriptional program. Thus, targeting class I HDACs is a promising strategy for treating prostate cancer. However, several FDA-approved HDAC inhibitors (HDACi) broadly inhibiting different HDACs have been shown to be ineffective and overtly toxic for treating castration-resistant prostate cancer in clinical trials. These observations suggest that HDACi selective for class I HDACs may be more effective but less toxic for treating prostate cancer than pan HDACi. Notably, we and others have shown that HDACi of different chemical classes individually exhibit nonoverlapping but limited effects on the acetylome in cancer cells. We hypothesize that a combination treatment strategy with class I HDAC-selective HDACi of different chemical classes is more effective to block AR signaling and prostate tumor growth than such HDACi individually. We have recently discovered the novel benzoylhydrazide chemo-type of class I HDAC-selective HDACi with a unique pharmacologic profile. Medicinal chemistry effort led to an optimized analog, SR-4370, with 6 nM potency to HDAC3. In support of our hypothesis, SR-4370 in combination with the clinical class I HDACi entinostat markedly suppressed AR signaling, prostate cancer cell proliferation in vitro, and tumor growth in vivo, and the tumor-suppressive effects by the HDACi combination were more pronounced than by SR-4370 and entinostat individually. Gene expression profiling experiments revealed that the SR-4370/entinostat combination profoundly downregulated AR, AR-V7, and AR target genes, while activating immune and cell death signaling pathways. In a C4-2 xenograft model using athymic nude mice, the SR-4370/entinostat combination was highly effective in suppressing tumor growth. Importantly, these HDACi alone or in combination did not cause observable adverse effects judged by body weight and blood chemistry tests of treated mice. Overall, our data suggest that the SR-4370/entinostat combination may be a translatable treatment for castration-resistant prostate cancer. Citation Format: Guimei Tian, Iqbal Mahmud, Ryan Stowe, Yushan Zhang, Hamsa Thayek Purayil, William Roush, Yehia Daaka, Daiqing Liao. A combination of two chemically distinct inhibitors of class I HDACs is highly effective to suppress AR signaling and in vivo growth of prostate cancer xenograft [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B004.
Final analysis of single-arm confirmatory study of diagnostic endoscopic resection(ER) plus selective chemoradiotherapy (CRT) for stage I esophageal squamous cell carcinoma (ESCC): JCOG0508.
Authors: Keiko Minashi, Keiji Nihei, Gakuto Ogawa, Kohei Takizawa, Tomonori Yano, Yusuke Amanuma, Tomohiro Tsuchida, Hiroyuki Ono, Toshiro Iizuka, Satoki Shichijyo, Ichiro Oda, Yoshinori Morita, Masahiro Tajika, Junko Fujiwara, Yoshinobu Yamamoto, Chikatoshi Katada, Shinichiro Hori, Hisashi Doyama, Haruhiko Fukuda, Manabu Muto
Journal: Journal of Clinical Oncology (2018)

4023 Background: For clinical stage I submucosal (cT1b-SM) ESCC, surgery is the standard treatment and CRT is optional. We conducted a single-arm confirmatory study of diagnostic ER plus selective CRT for cT1bN0M0 ESCC and reported the 3-year survival at 2016 ASCO Annual Meeting. We will report the final data of survival analysis after 5-year follow-up with a cutoff date of Aug 2017. Methods: Clinical stage I ESCC (cSM1-2, N0M0), tumor size ≤ 5 cm and circumference ≤ 3/4 was eligible. After ER, additional treatment was selected based on the histological evaluation: Group A, pT1a with negative resection margin and no lymphovascular invasion (LVI) -no additional treatment; Group B, pT1b with negative resection margin and pT1a with LVI -prophylactic CRT; Group C, pT1b with positive resection margin -definitive CRT. CRT consisted of concurrent 2 courses of chemotherapy (5-fluorouracil and cisplatin with 4-week interval, and radiotherapy of 41.4 Gy/23 fr (Group B) or 50.4Gy/28 fr (Group C). Primary endpoint was 3-year overall survival (OS) of Group B. The sample size was 82 for primary analysis, with one-sided alpha of 0.05 and power of 90%, based on the expected and threshold 3-year OS as 90% and 80%. Final analysis was planned after 5-year follow-up for all pts. Results: Between Dec 2006 and July 2012, 177 pts were enrolled from 23 institutions in Japan. 176 pts underwent ER and Group A/B/C were 74/87/15, respectively. The 3- and 5-year OS of Group B was 90.8% (90% CI; 84.1- 94.8) and 89.7% (95% CI; 81.1-94.5). The 3- and 5-year OS of all pts was 92.6% (90% CI; 88.6-95.3) and 90.9% (95% CI; 85.6-94.3). Twenty pts relapsed (Group A; 1 primary, 1 distant LN, Group B; 4 primaries , 8 regional LNs, 2 distant, Group C; 2 regional LNs, 2 distant), 7 pts underwent salvage esophagectomy. Univariable analysis in 83 pts of Group B showed that vascular invasion , one course of chemotherapy, SM2 with LVI had lower progression-free survival. Conclusions: Five-year survival data was comparable to that of surgery or CRT for c stage I ESCC. Vascular invasion, one course of chemotherapy, SM2 with LVI may be a risk factor of recurrence for prophylactic CRT after ER. Clinical trial information: UMIN000000553.
Pulmonary Sarcomatoid Carcinoma with ALK rearrangement: Frequency, Clinical-Pathological Characteristics, and Response to ALK inhibitor.
Authors: Xinru Chen, Jianzhong Liang, Jiabin Lu, Yu Zhang, Chuan-Miao Xie, Shaohan Yin, Likun Chen, Xuewen Liu
Journal: Journal of Clinical Oncology (2016)

e20055 Background: Pulmonary sarcomatoid carcinoma (PSC) is a poor-differentiated subtype of non-small cell lung cancer (NSCLC) distinguished from other subtypes of NSCLC with higher aggressive courses and far worse survival. ALK rearrangement was thought to be quite rare in PSC. However, ALK rearrangement in PSC was recently reported in few Asian patients. In order to determine the incidence rates in Chinese patients with PSC, we detected ALK rearrangement in a series of 82 cases of PSC at a single institution and evaluated the response to crizotinib in a patient with ALK rearrangement-positive PSC. Methods: Immunohistochemistry (IHC) using Ventana anti-ALK rabbit monoclonal antibody (D5F3 clone) was performed in a total of 82 formalin-fixed paraffin-embedded PSC specimens. IHC-positive cases were then confirmed using ALK fluorescence in situ hybridization (FISH).The incidence rates and clinical-pathological characteristics of ALK rearrangement positive PSC were then analyzed. One paitent with ALK rearrangement-positive PSC was treated with crizotinib and the response was evaluated according to the response evaluation criteria for solid tumors (RECIST) version 1.1. Results: 3 of 82 (3.6%) PSC showed ALK rearrangement positive by IHC and then were confirmed by FISH. Two were carcinosarcomas with a stage Ib (pT2bN0M0) and a stage IIIb (pT4N2M0) tumor, respectively, and the other one was a stage IV (T1bN1M1a) pulmonary pleomorphic carcinoma (PPC). Strong positive ALK rearrangement was observed in both the epithelioid and sarcomatoid components of all the three tumors. ALK rearrangment was mutually exlusive with muations in EGFR and KRAS. A partial response (-30%) to crizotinib was noted in a 40-year-old woman and a never-smoker who was diagnosed with an ALK rearrangement-positive stage IV PPC. The patient remains on treatment without side effects. Conclusions: The frequency of ALK rearrangement in PSC in Chinese patients is similar to that in other subtypes of NSCLC. ALK inhibitors may serve as an effective treatment for ALK rearrangement-positive PSC.