tbuckley/cabot-search huggingface dataset:
NSABP B-41, a randomized neoadjuvant trial: Genes and signatures associated with pathologic complete response (pCR).
Authors: Sandra M. Swain, Gong Tang, Heather Ann Brauer, David Goerlitz, Peter C. Lucas, Brent T. Harris, Andre Robidoux, Charles E. Geyer, Priya Rastogi, Eleftherios P. Mamounas, Norman Wolmark
Journal: Journal of Clinical Oncology (2019)

511 Background: NSABP B-41 randomly assigned 529 patients (pts) with HER2 positive breast cancer to neoadjuvant trastuzumab (T), lapatinib (L), or combination (T+L), with weekly paclitaxel following doxorubicin and cyclophosphamide. No significant differences in pCR were found, but overall survival was significantly increased for pCR. Methods: RNA was extracted from FFPE tumor specimens, run on the NanoString Breast Cancer 360 Plus panel. Gene counts were normalized to include housekeeping genes, 33 biological signatures from 776 genes across 23 pathways and transformed into logarithm scale with base two. Univariate logistic regression was used to screen candidate genes and signatures that are prognostic of pCR, with false discovery rate controlled at 0.1. Multivariable logistic regression with lasso regularization was used for model selection. Results: 194 core biopsy samples were available; 69 treated with T, 64 with L and 61 with T+L. 20 prognostic genes are selected for trastuzumab-based regimens (TBR), including the epithelial-mesenchymal transition (HEMK1, GRB7, ERBB2, TMPRSS4), adhesion and migration (ITGB6, COL27A1, NRCAM), JAK-STAT (SOCS2), Hedgehog (LRP2), ER signaling (ELOVL2, MAPT), DNA damage and repair (NPEPPS, PRKDC), MAPK (DUSP6, PRKCB), Apoptosis (BCL2), proliferation (TFDP1). ERBB2 expression are associated with pCR in patients on TBR (OR = 1.73), but not for patients on L (interaction p = 0.01). HER2-Enriched correlation (p &lt; 0.001), ESR1 (OR = 0.78, 95% CI = 0.69-0.88, p &lt; 0.001), PD1 (OR = 1.68, 95% CI = 1.12-2.52, p = 0.01) and Tumor Inflammation Score (OR = 1.58, 95% CI = 1.18-2.11, p = 0.002) are associated with pCR in TBR. No genes or signatures were found to be predictive of treatment benefit from L added to T. Conclusions: BC360 highlighted tumor progression and signaling genes prognostic for TBR. HER2-Enriched correlation, ERBB2 and PD1 expression, and immune activation signatures were associated with pCR in TBR and may provide personalized treatment guidance.
Modified ketogenic diet in solid tumors: A Veteran Affairs Pittsburgh Healthcare System case series.
Authors: Jocelyn Lai Tan, Jennifer Carrick, Vida Almario Passero, Jenna Shields, Andrew Dede Liman, Hema Rai, Lauri Harrold
Journal: Journal of Clinical Oncology (2019)

e14217 Background: Cancers prefer glucose due to mitochondrial dysfunction. Ketogenic diets fuel normal cells while starving cancer. Sparse data exists on ketogenic diets in solid tumors. Methods: Studied 5 advanced solid tumor patients on a modified ketogenic diet plus standard of care chemotherapy. Daily carbohydrate limited to 20-40 grams, no sweets or starch. Histories and clinical courses are presented. Results: Case 1: 70 year old male, medically inoperable Stage IIIA poorly differentiated squamous cell lung cancer and non-hodgkins lymphoma. Treated with radiation and paclitaxel/carboplatin. After 5 months, lung cancer relapsed in a neck mass, treated with chemoradiation plus the diet. At 46 months, scans and blood counts were normal. Case 2: 42 year old, 417 lb. male diabetic stage IV colon cancer, spread to lungs and liver. Progressed on 5FU/bevacizumab/oxaliplatin, irinotecan, tipiracil/trifluridine, regorafenib but responded to 5FU/irinotecan rechallenge plus liver chemoembolization. Dieted, mild ketosis but lost 64 lbs, stable disease at 6.5 years. Case 3: 42 year old male, Stage III BRAF V600 E melanoma, Vemurafenib intolerant. Bulky axillary nodes resected plus diet for 3 years. Complete remission at 7 yrs 9 months. Case 4: 57 year old male, medically inoperable liver cancer, normal AFP values and normal scans after 5 months of sorafenib. AFP later increased to 690 ng/ml. Advised to change treatment but he refused and started the ketogenic diet with the sorafenib. After 5 months, AFP improved to 445 ng/ml. Sorafenib and diet interrupted for 3 months, AFP rose to 1017. At 7 yrs, 4 months, back on sorafenib and diet, AFP 1520 mg/ml, negative scans. Case 5: 49 year old male, aggressive digital papillary skin adenocarcinoma, multi-organ metastases. Had side-effects with many chemotherapies (paclitaxel/bevacizumab/carboplatin, sorafenib, gemcitabine, oxaliplatin/5FU, cyclophosphamide) Stable disease on diet despite multiple therapy changes. At 34 months, he was off the diet, tumors grew plus new brain lesions (resected). Alive on atezolizumab at 36 months. Conclusions: Ketogenic diets in human solid tumors seem well tolerated and may improve response and survival after standard therapy.
Current status of immune checkpoint inhibition in early-stage NSCLC
Authors: J. Vansteenkiste, E. Wauters, B. Reymen, C.J. Ackermann, S. Peters, D. De Ruysscher
Journal: Annals of Oncology (2019)

Immune checkpoint inhibition (ICI) immunotherapy has revolutionized the approach to metastatic non-small-cell lung cancer (NSCLC). In particular, antibodies blocking the inhibitory immune checkpoints programmed death 1 (PD-1) and its ligand (PD-L1) are associated with higher response rates, improved overall survival and better tolerability as compared with conventional cytotoxic chemotherapy. Recently, ICI has moved from the second-line to the first-line setting for many patients with non-oncogene-addicted NSCLC, either alone or in combination with chemotherapy. The next logical step is to examine this therapy in patients with non-metastatic NSCLC to improve long-term overall survival and cure rates. For patients with unresectable stage III NSCLC, ICI with durvalumab after concurrent chemoradiotherapy has brought a major improvement in 2-year progression-free and overall survival, which holds promise for an improved cure rate. As the relapse pattern in patients with completely resected early-stage NSCLC is predominantly systemic, high expectations rest on the integration of ICI therapy in their treatment approach. A large number of studies with adjuvant or neo-adjuvant ICI are ongoing and will be discussed here. The advent of stereotactic ablative radiotherapy has brought a valid alternative treatment of patients unfit for or not willing to undergo surgery. Data on combining systemic therapy and stereotactic ablative radiotherapy are virtually non-existent, but there is a strong biological rationale to combine radiotherapy and ICI therapy. Early findings in small feasibility studies are promising and now need to be explored in well-designed phase III trials.
Timing of chemotherapy in small cell lung cancer: A National Cancer Database analysis.
Authors: Shruti Bhandari, Danh Pham, Rohit Kumar, Jeremy T Gaskins, Goetz H. Kloecker
Journal: Journal of Clinical Oncology (2019)

e20076 Background: Small cell lung cancer (SCLC) is an aggressive disease currently treated as soon as possible given its rapid doubling time. Evidence for appropriate timing of chemotherapy from diagnosis (TCD) for SCLC is lacking. This study evaluates TCD in SCLC on a national level. Methods: National Cancer Database identified SCLC patients treated with chemotherapy from 2010 - 2014. Factors associated with TCD were identified with multiple linear regression analyses. TCD was categorized into four groups using cutoff points of 7, 14, and 28 days. Using these categories, median overall survival (MOS) and log-rank test was used for univariate analysis of the survival outcome and the Cox model for multivariate analysis. Results: Among the 64491 SCLC, 42% received chemotherapy alone, 38% chemotherapy followed by radiation and 20% radiation followed by chemotherapy. Median TCD is 14 days with 21% treated within 7d, 21% 8-14d, 30% 15-28d and 28% &gt; 28d from diagnosis. Age, race, insurance, comorbidities and stage were associated with TCD (Table). Significant difference in survival was found by TCD categories (P &lt; .001). MOS for TCD within 7d was 8.2m, 8-14d was 9.2m, 15-28d was 10.3m, and &gt; 28d was 10.8m. In the multivariate analysis, increased TCD was associated with better survival across all stages. Among stage IV patients, compared to those treated within 1 week, the HR is 0.92 (P &lt; .001) for 1-2 weeks, HR 0.82 (P &lt; .001) for 2-4 weeks, and HR 0.77 (P &lt; .001) for &gt; 4 weeks. Results are similar for Stage III and for Stage I/II. Conclusions: These results show a trend towards poor survival with early treatment. While we do not suggest delaying treatment for SCLC patients, our results provide new evidence to inform a discussion about appropriate treatment timing and individualizing treatment. Optimization of patients' clinical baseline before hasty cytotoxic treatment may lead to better outcomes. [Table: see text]
The financial impact of fractionation scheme and treatment planning method for rectal cancer in the United States.
Authors: Assaf Moore, Robert Benjamin Den, Noa Gordon, Michal Sarfaty, Yulia Kundel, Baruch Brenner, Daniel A. Goldstein
Journal: Journal of Clinical Oncology (2019)

6518 Background: Preoperative long-course chemoradiotherapy (CRT) and short-course radiotherapy (SCR) for locally advanced rectal cancer (LARC) were found to have equivalent outcomes in three randomized trials. SCR may have lower acute toxicity and the down-staging following CRT is more well-established. At present, SCR is frequently used in Europe but has not been widely adopted in the United States (US). It is standard to deliver radiotherapy by 3D planning, while the use of Intensity-modulated radiotherapy (IMRT) is controversial. In recent years there has been an increasing focus on understanding the cost and value of cancer care. In this study we aimed to assess the economic impact of fractionation scheme and treatment planning method for payers in the US. Methods: We performed a population-based analysis of the total cost of radiotherapy for LARC in the US annually. The national annual target population of patients was calculated using the Surveillance, Epidemiology, and End Results (SEER) database. Treatment costs for various fractionation schemes were based on billing codes and 2018 pricing by Medicare's Hospital Outpatient Prospective Payment System (OPPS). The cost of chemotherapy was based on the Payment Allowance Limits for Medicare Part B Drugs by Centers for Medicare and Medicaid Services (CMS). Results: We estimate that 12,945 patients with LARC are treated with radiotherapy annually in the US. The cost of CRT with 3-D or IMRT is US$ 15,881.76 and US$ 23,744.82 per patient, respectively. With 3-D SCR the cost is US$ 5,457 per patient. The use of SCR would lead to 64-77% annual savings of US$ 125,701,387 - US$ 236,727,934 in the US compared with 3-D and IMRT based CRT, respectively. IMRT based planning increases the total cost of CRT by 49% and if adopted widely would lead to an excess cost of US$ 101,787,312 annually. Conclusions: SCR may have the potential to save in the region of US$ 0.12-0.23 billion annually in the US, likely without impacting outcomes. Lack of evidence showing benefit with costly IMRT should limit its use to clinical trials. SCR may also lead to lower personal financial toxicity. It would be reasonable for public and private payers to consider which type of radiation is most suited to reimbursement.
Osimertinib and dihydroartemisinin: A novel drug combination targeting head and neck squamous cell carcinoma.
Authors: Rafael Rosell, Imane Chaib, Xueting Cai, David Llige, Mariacarmela Santarpia, Eloisa Jantus-Lewintre, Martyna Filipska, Carlos Pedraz, Jie Yang, Jing Miao, Rongwei Sun, Jillian Bracht, Masaoki Ito, Andrés Aguilar, Itziar de Aguirre, Jordi Codony-Servat, Andres Felipe Cardona Zorrilla, Niki Karachaliou, Peng Cao
Journal: Journal of Clinical Oncology (2019)

e17526 Background: Recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) has a dismal prognosis with limited progression-free survival and overall survival, even when treated with different combinations of chemotherapy, targeted therapies and immunotherapy. We explored in vitro and in vivo the effect of the epidermal growth factor (EGFR) inhibitor, osimertinib, alone and in combination with dihydroartemisinin (DHA) in HNSCC. Methods: The combination of osimertinib with DHA was tested in the FaDu and CAL27 HNSCC cell lines. Tumor cell proliferation assays were conducted in cultured cells and mouse xenografts. Western blotting analysis of related signal pathways was performed to investigate the molecular mechanisms of the inhibitory effect of DHA and the combination. Other compounds, which inhibit signal transducer and activator of transcription 3 (STAT3), Src-family kinases (SFKs), sphingosine kinase 1 (SPHK1), or the receptor tyrosine kinase (RTK) AXL were also combined with osimertinib in vitro. Results: Osimertinib exerted synergistic cytotoxicity toward FaDu and CAL27 HNSCC cells when combined with DHA. DHA reversed the osimertinib-induced STAT3 and Src, phosphorylation. The double combination inhibited AXL expression. The anticancer potential of osimertinib plus DHA combination was validated in vivo on FaDu and CAL27 xenografts in mice without notable side effects. Conclusions: The results illustrate that the combinatory therapy of osimertinib and DHA, as a repurposing anticancer drug, could be a novel therapeutic strategy for recurrent and/or metastatic HNSCC patients. The findings indicate that a clinical trial is warranted to confirm the benefit of the combination.
Modeling Steatohepatitis in Humans with Pluripotent Stem Cell-Derived Organoids
Authors: Rie Ouchi, Shodai Togo, Masaki Kimura, Tadahiro Shinozawa, Masaru Koido, Hiroyuki Koike, Wendy Thompson, Rebekah A. Karns, Christopher N. Mayhew, Patrick S. McGrath, Heather A. McCauley, Ran-Ran Zhang, Kyle Lewis, Shoyo Hakozaki, Autumn Ferguson, Norikazu Saiki, Yosuke Yoneyama, Ichiro Takeuchi, Yo Mabuchi, Chihiro Akazawa, Hiroshi Y. Yoshikawa, James M. Wells, Takanori Takebe
Journal: Cell Metabolism (2019)
Epidemiologic and histologic characteristics of central nervous system lesions: A 20-year experience of a single institution in Lebanon.
Authors: Roland Eid, Stephanie Hage, Ingrid Antonios, Rita Moussa, Makram Khoury, Fady Haddad, Hampig Raphael Kourie, Carole Kesrouani, Claude Ghorra, Gerard Abadjian, Joseph Gergi Kattan
Journal: Journal of Clinical Oncology (2019)

e13544 Background: Lesions of the central nervous system (CNS) are a heterogeneous group of tumoral and non-tumoral lesions, benign or malignant, primary or metastatic. The overall incidence rate of all brain tumors is estimated to be 10.82 per 100 000 person-years. There is no data in Lebanon characterizing the CNS lesions. The aim of our study is to report the epidemiologic and histologic characteristics of these lesions in a Lebanese tertiary center. Methods: This is a retrospective study evaluating the characteristics of the CNS lesions diagnosed in 20 years (from January 1998 to June 2017) in the pathology laboratory of Hôtel Dieu de France, Saint Joseph University hospital of Beirut, Lebanon. The data were extracted from the computerized records of the laboratory. Different variables were evaluated, from the samples types and epidemiologic characteristics, to the revealing symptoms and the histologic subtypes. Statistical analysis was performed using SPSS 24.0. Results: 2025 tumoral lesions over 20 years were interpreted. 25.4% of the samples were obtained by biopsy, 65% by surgical resection, 3.7% were cerebral spinal fluid and 5.9% were undetermined. 52.2% of the patients were men and 47.8% were women with a median age of 50 years, from 0 to 89 years. The most frequent revealing symptoms were epilepsy (22.5%), headache (20.6%) and motor impairment (19.9%). 90.7% of the CNS tumors were primary and 9.3% were metastatic. Lung (35.6%) and breast (16.5 %) were the two most frequent primaries of the metastatic lesions. 46.2% of primary CNS tumors were glial, 42.5% non-glial, 3.5% mixed neuroglial and 6.4% mesenchymal. The two most frequent glial tumors were astrocytic (56.4%) and oligodendroglial (17.9%) tumors, while the most frequent non-glial tumors were meningeal tumors (58%) and cranial nerve and paraspinal tumors (16.3%). Conclusions: The histological and epidemiological characteristics of brain tumors in Lebanon are consistent in many features with what is known in the literature, but the Lebanese population differs by a younger age of onset, a lower rate of meningiomas, and a higher rate of gliomas.
Hybrid capture-based genomic profiling of circulating tumor DNA from patients with advanced hepatocellular carcinoma.
Authors: Mao Li, Ailin Wei, Wenzhuan Xie, Jing Zhao, Zhengyi Zhao, Yuzi Zhang, Guoqiang Wang, Shangli Cai, Ang Li, Dan Cao
Journal: Journal of Clinical Oncology (2019)

e15606 Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies with a particularly high prevalence in China. The genomic profiling in HCC had been widely explored with tissue biopsy, however, given the intrinsic risks of invasive approach, blood-based circulating tumor DNA (ctDNA) has been proposed as a promising alternative. In this study, we aim to investigate whether the ctDNA may serve as a reliable tool to provide a more accurate molecular snapshot of HCC in Chinese patients. Methods: Plasma samples from 385 Chinese patients with advanced HCC were assayed for somatic genomic alternations by hybrid capture-based next-generation sequencing (NGS) with 150 genes and a mean sequencing depth of more than 3000×. The results were compared with our internal tissue genomic database of Chinese HCC patients (N = 873) tested by NGS and TCGA database (N = 373) tested by whole exome sequencing. Genomic alterations including single nucleotide variation (SNV), insertions/deletions, copy number variations, gene rearrangement and fusions were assessed. Results: Among 385 patients with ctDNA testing, somatic genomic alternations were detected in 97% of the patients (median = 5 alterations/patient). The most prevalent SNV mutations from ctDNA sequencing were TP53 (45.7%), TERT (19.5%), CTNNB1 (12.5%), and LRP1B (8.3%) compared to our tissue database (TP53 (61.2%), CTNNB1 (15.6%), TERT (13.3%), and LRP1B (11.0%)). While in TCGA database, the most common SNV mutations were found in TP53 (30.1%), CTNNB1 (26.0%), LRP1B (8.8%), ARID1A (8.6%), and SPTA1 (7.5%). Moreover, the level of MSAF was associated with detectable variant types, evidenced by a significant higher MSAF level observed when amplifications (P &lt; 0.0001) or fusions (P = 0.008) were detected in the samples. Conclusions: Molecular analysis of patients with advanced HCC through ctDNA can serve as a reliable alternative to tissue biopsy. Chinese HCC patients may have different mutational landscapes to Western population. The utility of ctDNA analysis can provide therapeutically exploitable genomic profiles to identify potentially actionable gene alterations for targeted therapies.
Association of noninvasive, radiographic measurement of prostate-specific membrane antigen (PSMA) expression with response to PSMA-targeted radionuclide therapy (TRT).
Authors: Panagiotis J. Vlachostergios, Muhammad Junaid Niaz, Seyed Ali Mosallaie, Paul J. Christos, Amy Hackett, Joseph R. Osborne, Yuliya Jhanwar, Lauren Gracey, Ana M. Molina, David M. Nanus, Neil Harrison Bander, Scott T. Tagawa
Journal: Journal of Clinical Oncology (2019)

5013 Background: Prostate surface membrane antigen (PSMA) is usually overexpressed in PC and is enriched in castration-resistant tumors. PSMA-TRT is of increasing interest to the field. Many in the field of theranostics have assumed that PSMA uptake on imaging is a pre-requisite for response. We have conducted a number of trials which have incorporated PSMA imaging, but have not selected patients for treatment based upon imaging results and performed an analysis examining the relationship between imaging and response. Methods: Men with mCRPC had either planar radiolabeled J591 imaging (111In-J591 and/or 177Lu-J591) or 68Ga-PSMA11 PET/CT. Visual scores were assigned based upon PSMA uptake in tumors compared to liver uptake and scored on a 0-4 scale. Imaging scores were associated with PSA decline (≥30%, ≥50%) using Cox regression analysis. As several studies were dose-escalation in nature with prior demonstration of dose-response, we controlled for dose administered. Results: 216 men with metastatic CRPC, median PSA 72.45ng/dl, were treated with PSMA-TRT as follows: 177Lu-J591 (n=136), 177Lu-PSMA-617 (n=38), Lu-J591 + Lu-PSMA-617 combination (n=6), 225Ac-J591 (n=7), 90Y-J591 (n=29). 116 (53.7%) pts received low dose and 100 (46.3%) high dose as previously defined in the individual studies. 55 (25.5%) pts had low PSMA expression by imaging (VS 0-1) whereas 161 (74.5%) had high PSMA (VS 2-4). High PSMA expression was associated with more frequent PSA decline (≥30%: 39.2 vs 17.9% p=0.003; ≥50%: 27.5 vs 8.9% p=0.004). When controlling for dose level, this association remained significant for low (≥30%: 25 vs 8.6% p=0.04) and high doses of radionuclide therapy (≥50%: 34.9 vs 9.5% p=0.02). 13 (6%) pts with no PSMA uptake (VS=0) had PSA declines. Conclusions: This is the first study to formally analyze response to PSMA-TRT by PSMA imaging expression in an unselected patient population. The level of PSMA expression measured by imaging is associated with the chance of response. However, a subset of patients without any significant PSMA uptake on imaging did demonstrate response to PSMA-TRT, indicating that imaging cannot exclude all patients that might benefit. Clinical trial information: NCT03545165, NCT03276572, NCT03042468, NCT02552394.