tbuckley/cabot-search huggingface dataset:
Abstract IA34: Targeting cellular heterogeneity in lung adenocarcinoma
Authors: Nemanja Marjanovic, Matan Hofree, David Canner, Marianna Trakala, Katherine Wu, Olivia Smith, Jonathan Kim, Angelika Amon, Aviv Regev, Tyler Jacks, Tuomas Tammela
Journal: Clinical Cancer Research (2018)

Abstract Cancer arises from a single cell through a series of acquired mutations, and gradually develops into a complex tissue comprising phenotypically heterogeneous societies of cancer cells. The phenotype, or state, of each tumor cell is influenced by multiple cell-autonomous and cell-extrinsic factors; the diversity of these cellular states poses a challenge for effective cancer therapies. We characterized the evolution of transcriptomes at the single-cell level in genetically engineered murine lung tumors driven by oncogenic Kras. Tumor progression was accompanied by a dramatic increase in cellular heterogeneity, which was further exacerbated upon deletion of the p53 tumor suppressor, allowing tumor progression into advanced adenocarcinomas. This heterogeneity was manifested by the emergence of de-differentiated or transdifferentiated populations, the activation of latent developmental or regenerative programs, as well as heterogeneous activation of signaling pathways. Surprisingly, similar heterogeneous populations emerged in independent tumors irrespective of considerable intertumoral differences in genetic copy number alterations, suggesting a remarkable degree of convergence to achieve a common evolutionary endpoint. We used these data to computationally model cell-state transitions. Finally, treatment of the lung tumors with chemotherapy enabled the identification of cellular states associated with intrinsic sensitivity or resistance. These results associate tumor progression with increasing transcriptional heterogeneity. The identification of unique gene expression programs in cancer cell subpopulations provides a path towards reducing cellular heterogeneity in cancer. Citation Format: Nemanja Marjanovic, Matan Hofree, David Canner, Marianna Trakala, Katherine Wu, Olivia Smith, Jonathan Kim, Angelika Amon, Aviv Regev, Tyler Jacks, Tuomas Tammela. Targeting cellular heterogeneity in lung adenocarcinoma [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA34.
Preoperative visualization of the gastrocolic trunk of Henle variation providing more vascular anatomical information for gastrocolic surgery.
Authors: Yuan Gao, Guangwei Liu, Xianjun Zhou, Qian Dong, Guanrong Wang, Shuo Li, Jinlong Ma, Yun Lu
Journal: Journal of Clinical Oncology (2018)

e15710 Background: The aim of this study was to investigate variations of the anatomical tributaries of the gastrocolic trunk of Henle (GTH) that were detected by a Hisense computer-assisted surgery (CAS) system and to provide more vascular anatomical information for a gastrectomy and right colectomy. Methods: One hundred twenty patients with gastric carcinoma or right semicolon cancer who underwent visualization with the Hisense CAS system before a gastrectomy and right colectomy were reviewed. Hisense CAS system with stereoscopic 3D models was used to analyze both the composition and the variation of the GTH. Results: The GTH was identified in 102 patients (85.0%) by the Hisense CAS system. The branching patterns of the GTH that were described by the Hisense CAS system were classified into two types and ten subtypes based on the anterior superior pancreaticoduodenal vein (ASPDV) and the colic drainage vein joining sites as follows: Type I (Ia, Ib, Ic, Id and Ie) and Type II (IIa, IIb, IIc, IId and IIe). The frequencies of Types Ia, Ib, Ic, Id and Ie were 11.8%, 7.8%, 6.9%, 3.9% and 2.0%, respectively, and Types IIa, IIb, IIc, IId and IIe were 31.4%, 16.7%, 11.8%, 4.9% and 2.9%, respectively. Conclusions: Preoperative planning provides the more anatomic information of the GTH for optimal patient measurements.
P05.73 Nasoethmoidal meningioma with cytogenetic features of tumor aggressiveness in a 16-year-old child: a case report followed up over 15 years
Authors: R Ketter, S Hemmer, F Sahm, J Oertel, S Urbschat
Journal: Neuro-Oncology (2018)

The case of a 16-year-old girl is presented who was admitted to our hospital because of severe frontal headache in January 2002. Magnetic resonance scans revealed a nasoethmoidal tumor on the right side, with erosion of the skull base and invasion of the right orbit. A needle biopsy specimen revealed the histological diagnosis of a fibroblastic meningioma (WHO grade II), with histochemically determined partial activity loss of alkaline phosphatase. The tumor was completely resected by a combined intracranial-transbasal and transnasal approach. On the basis of the cytogenetic findings, as well as the DNA methylation profile (Illumina 850k analysis) the meningioma was investigated. The clinical course of the child until today, which was determined by five further resections due to tumor recurrence as well as radiotherapy is presented. In this case, we found a meningioma with deletion of the short arm of chromosome 1 through a translocation between chromosomes 1 and 11 [t(1;11)] as well as additional chromosomal aberrations, including partial or complete monosomy of chromosomes 2, 6, 7, 11, 13 and 22, a cytogenetic pattern known to be associated with elevated tumor aggressiveness in meningiomas of adult patients. The DNA methylation profile (Illumina 850k analysis) allotted the case to the meningioma methylation class intermediate-A. Since the initial surgery in 2002, this juvenile meningioma was biologically expected to recur. Until today our patient suffered from five recurrences. In our opinion the tendency of meningiomas to recur appears to depend on surgical rather than biological reasons. This case report shows that the genetic informations given by a tumor allows a more precise assessment of the prognosis of meningiomas.
Neutrophil-lymphocyte ratio (NLR) as a predictive biomarker for response to high dose interleukin 2 (HDIL-2) in patients with metastatic renal cell carcinoma (mRCC).
Authors: James Arthur Kuzman, David D. Stenehjem, Shiven B. Patel, Joseph Merriman, David Michael Gill, Andrew Hahn, Archana M. Agarwal, Sumati Gupta, Dan Albertson, Anitha Alex, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2016)

e16087 Background: Immunotherapy with HDIL-2 results in long-term survival in some mRCC patients but has significant toxicities. Biomarkers predicting response to therapy are needed to better select patients most likely to benefit. NLR (ANC/ALC ratio) is a prognostic and predicative biomarker in various malignancies. The goal was to determine whether NLR can predict response to HDIL-2 in this setting. Methods: Patients with clear cell mRCC treated with HDIL-2 were identified from an institutional database from 2003-2012. Baseline variables for the assessment of MSKCC risk category, and neutrophil and lymphocyte count, were collected. Best response criteria were based on RECIST 1.0. Wilcoxon rank-sum test was used to evaluate the association of continuous baseline variables with disease control. NLR was stratified by ≤4 or >4. Progression free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method and the log rank test was used investigate associations of NLR with survival. Results: In 71 eligible patients, median NLR in those with an objective response (n=14, 20%) was 2.3 vs 3.4 in those without (n=57, 80%, p = 0.02). NLR significantly correlated with inferior responses and survival outcomes (Table). After adjustment for MSKCC risk criteria, NLR remained a significant predictor of PFS (ANC/ALC ≤4 vs >4; HR 0.52; 95% CI 0.29-0.97; p = 0.039) and OS (≤4 vs >4, HR 0.32; 95% CI 0.16-0.64; p = 0.0015). Conclusions: In this discovery set, NLR predicts response to therapy with HDIL-2 in mccRCC, and may allow better patient selection in this setting. Data needs validation in an independent cohort. Survival outcomes by NLR. NLR≤4 vs >4 HR; 95% CI; P-value PFS, months 8.0 vs 3.3 0.51; 0.28-0.95; 0.0338 OS, months 40.9 vs 12.5 0.31; 0.16-0.61; 0.0009
Impact of TP53 mutations on efficacy of PD-1 targeted immunotherapy in non-small cell lung cancer (NSCLC).
Authors: Jennifer Wilkinson Carlisle, Nhu Thi Nho, Chaejin Kim, Zhengjia Chen, Shiyong Li, Charles Hill, Suresh S. Ramalingam, Gabriel Sica, Taofeek Kunle Owonikoko
Journal: Journal of Clinical Oncology (2018)

e21090 Background: Efficacy of PD-1 targeted therapy is limited to a subset of patients with advanced NSCLC. While there is correlation of benefit with PD-L1 expression, the hypermutated tumor phenotype appears more promising as a predictive classifier. Given the central role of TP53 in the maintenance of genomic fidelity, we hypothesized that alterations in TP53 mutations could also impact PD-L1 performance as a biomarker and represents a simpler alternative to mutation burden assessment. Methods: We used next generation sequencing (NGS) genomic profiling data from patients with NSCLC managed at our institution from January 2015 to August 2017. Patients treated with ≥1 cycle of PD-1 checkpoint inhibitor therapy and available NGS mutation data were included; those treated with combination chemo-immunotherapy were excluded. Clinical information was retrieved from electronic medical records including patient and tumor characteristics, treatment history, tumor PDL-1 expression and time to progression. Univariable (UVA) and multivariable (MVA) COX regression modeling was used to compare progression free survival (PFS) on immunotherapy for patients with TP53 mutations to patients without TP53 mutations. Results: A total of 52 NSCLC patients included 28 females (53.85%), median age of 66.4 years, 31 white (59.62%), 16 black (30.77%), and 5 other race (9.62%). There was no difference in PFS between TP53 wild type and mutant patients; median PFS (95% CI) and 1-year PFS rate: 5.03 (3.53, na) vs. 4.40 (1.87, na) months and 27.1% (11.5%, 63.5%) vs. 28.5% (14.0%, 58.0%), respectively; HR (95%CI): 1.1243 (0.5573, 2.268); p = 0.744. While there was a trend on UVA toward improved efficacy with high PD-L1 expression HR (95%CI): 0.4249 (0.0788, 2.2910; p = 0.3190, on MVA patients with TP53 mutation had a higher risk of progression regardless of PD-L1 expression; HR (95%CI): 3.3242 (0.9903, 11.1590); p = 0.0519. Conclusions: TP53 mutation correlates with poor efficacy of immunotherapy while controlling for PD-L1 expression in NSCLC. Additional validation of this finding in an independent patient group and analysis of TP53 mutation subtype is planned.
Relationship between pre-diagnosis tumor board and time interval from imaging to staging in lung cancer.
Authors: Prashanth Thalanayar Muthukrishnan, Maya Ratnam, Minh-Tri Nguyen, Michael Le, Douglas Gunzler, Debora S. Bruno, Michael Infeld
Journal: Journal of Clinical Oncology (2018)

e20536 Background: National guidelines support discussion of patients with newly diagnosed lung cancer in multidisciplinary tumor board (MTB). MTB is associated with greater adherence to treatment and staging per society guidelines as well as shorter time from diagnosis to treatment. To our knowledge, no studies have investigated the relationship between MTB discussion of lung nodules prior to tissue diagnosis and time-related patient outcomes. In 2015, our institution initiated pre-diagnosis MTB. We performed retrospective database review to see if discussion in pre-diagnosis MTB is associated with significant difference in time interval from cancer suspicion to completion of staging. Methods: We identified 216 patients, newly diagnosed with lung nodules suspicious for malignancy from December 2015 - January 2017. Fifty-five patients were excluded due to lack of tissue diagnosis or non-cancer tissue diagnosis. Of the 161 cancer cases included, 55 patients had pre-diagnosis MTB discussion and 106 patients did not. Patients that had MTB discussion after tissue diagnosis had been obtained were in the ‘no MTB’ control group. Primary outcome was difference in time interval from suspicious imaging to staging in patients discussed at pre-diagnosis MTB compared to controls. Results: Both groups were predominantly non- small cell lung cancer (90% MTB and 84% control). Stage I and IV cancer was reported in 29 and 36% of the MTB group and 24 and 51% of controls, respectively. Multiple regression analysis showed that patients of the same cancer type and stage who had pre-diagnosis MTB had on average 17.4 days longer (SE = 8.7, p = 0.048) from imaging to staging than the control group [unadjusted mean of MTB group = 70 +/-54 days (SD), control group = 49+/-55 days (SD) (p = 0.020)]. Conclusions: Significant increase in time from imaging to staging completion in patients presented at a pre-diagnosis MTB could be from differences in patient presentation, presence of symptoms, need for EBUS-guided staging, timing of oncology referrals or workflow processes. We intend to undertake dissection of individual case characteristics and comparison of time-related outcomes that may guide practice changing steps in institutional cancer care.
Immune checkpoint inhibitor rechallenge in patients with immune-related myositis
Authors: Julie Delyon, Florence Brunet-Possenti, Sarah Leonard-Louis, Dimitri Arangalage, Mathilde Baudet, Barouyr Baroudjian, Celeste Lebbe, Baptiste Hervier
Journal: Annals of the Rheumatic Diseases (2018)

Neither myositis-specific nor myasthenia gravis autoantibodies were detected.ICIs were stopped and three pulses of methylprednisolone followed by tapering doses of prednisone were given leading to complete remission within 8 weeks.Because of the lack of efficacy of the single infusion of ICI combination followed by three infusions of dacarbazine, pembrolizumab was introduced 8 months after the myositis episode.The patient presented no irAEs or myositis (table 1) but died due to melanoma progression.Despite the risk of recurrent irAEs, rechallenging ICIs after discontinuation due to previous irAEs remains critical, when considering their potential benefits in terms of survival. 5These two cases suggest that resuming ICIs can be safe in patients displaying persistent remission of ICI-related myositis.
Association of mannitol (MAN) with cisplatin (CIS)-induced nephrotoxicity (NTX) and cumulative CIS dose (CCD).
Authors: Sri Ramalingam, Aniko Szabo, Deepak Kilari, Chitra Bhosekar, Stuart J. Wong
Journal: Journal of Clinical Oncology (2017)

6051 Background: CIS is widely used in cancer therapy with CCD linked to survival outcome. CCD, however, is constrained by side effects—particularly NTX (incidence 20-30%). MAN is widely used to prevent CIS NTX despite low level of evidence. Herein, we took advantage of a national shortage of MAN to examine renoprotective effects of MAN in CIS treated patients. Methods: Between 2006-2012, 704 consecutive pts undergoing CIS therapy, with or without MAN, were analyzed. Pt characteristics, oncologic diagnosis, treatment, and renal function data were collected. The primary objective was to compare clinically significant NTX, as defined by &gt; 25% reduction in glomerular filtration rate (GFR) from baseline, between the treatment groups. Cox proportional hazards regression was used to model the hazard of NTX as a function of CIS dose. Results: Of 704 pts, 442 were treated with MAN and 262 without. The median age was 58.9 years. Age (p = 0.83), gender (p = 0.77), and race (p = 0.056) were similar between groups whereas baseline GFR (MAN 91.2 ± 22; CIS 86.3 ± 24; p = 0.005) and diagnoses (p &lt; 0.001) differed. The distribution of diagnoses was: head and neck (25.9%), genitourinary (26.0%), lung (14.3%), gastrointestinal (10.4%), lymphoma (4.5%), and other (18.9%). The mean CIS dose (mg) per cycle in MAN versus CIS only group was 126.1 ± 58 and 109.3 ± 58 respectively (p &lt; 0.001). The CCD (mg) was higher in the MAN compared to the CIS only group (469.8 ± 295 versus 299.0 ± 241; p &lt; 0.001). After adjusting for baseline GFR, age, gender, race, and diagnoses, the MAN group experienced lower risk of &gt; 25% decrease in GFR at any given CCD (HR: 0.68, CI: 0.51-0.91, p = 0.01). Females (HR: 1.72, CI: 1.28-2.32; p = 0.0003), older pts (HR: 1.24, CI: 1.10-1.40; p = 0.0003), and Hispanic pts (HR: 2.39, 1.04-5.50; p = 0.04) were more likely to sustain &gt; 25% reduction in GFR. Conclusions: MAN enhances CCD by protecting against CIS-induced NTX. Pts with MAN experienced a lower risk of clinically significant acute kidney injury (AKI) and received a higher average CIS dose per cycle and CCD. Women, older pts, and Hispanic pts had a higher risk of AKI. Future investigation is warranted to examine whether MAN-associated CCD effects translate into survival advantages.
An open label phase I study to evaluate the safety and efficacy of OBP-301 with pembrolizumab in patients with advanced solid tumors.
Authors: Takashi Kojima, Toshiyoshi Fujiwara, Yasuhiro Shirakawa, Hiromi Ono, Masako Nakamoto, Hiromi Hasegawa, Nami Hirano, Masashi Wakabayashi, Shogo Nomura, Yosuke Togashi, Hiroyoshi Nishikawa, Akihiro Sato, Atsushi Ohtsu, Toshihiko Doi
Journal: Journal of Clinical Oncology (2018)

TPS3117 Background: PD-1 blockade showed promising efficacy in facilitating tumor shrinkage for broad type of cancer patients, but objective response rates are very limited. The antitumor potential of oncolytic adenoviruses has been demonstrated in preclinical and clinical studies. In addition to the specific killing of cancer cells via oncolytic virus, these agents prompt the immune system to stimulate an antitumor immune response. OBP-301 is an oncolytic adenovirus in which gene is modified to be able to selectively replicate in cancer cells by introducing human telomerase reverse transcriptase (hTERT) promotor. Further antitumor effect will be expected activating of two different antitumor immunity by using OBP-301 in combination with pembrolizumab. Therefore, we initiated phase I study to evaluate the safety and efficacy of OBP-301 with pembrolizumab. Methods: The major eligibility criteria is patients with advanced or metastatic solid tumor not responded to or intolerant of standard chemotherapies, and with possibility of intratumoral injection. History of anti PD-1/PD-L1/PD-L2 antibody treatment is acceptable. Phase Ia part was designed to determine the recommended dose in a “3+3” cohort-based dose escalation design of OBP-301 (1x1010VP on cohort 1, 1x1011VP on cohort 2 and 1x1012VP on cohort 3) with pembrolizumab (200mg/body q3w). OBP-301 is administered at day1, day15, and, Day29 by intratumoral injection and pembrolizumab is administered at day 8 and thereafter every 3 weeks. Primary endpoint is dose limiting toxicity. Secondary endpoint is response rate, progression free survival, and rate of adverse event. Phase Ib part was designated to evaluate the safety and efficacy of the recommended dose OBP-301 selected in phase Ia part in combination with pembrolizumab in 10 patients. We will also investigate biomarker study using paired samples of both tumor biopsy and blood. The patient enrollment has been started in October 2017. Clinical trial information: NCT03172819.
Trends in utilization and in-hospital outcomes of high dose therapy and autologous stem cell transplantation among patients with AL amyloidosis in the United States.
Authors: Smith Giri, Kathan Mehta, Jessica R Hoag, Scott F. Huntington, Binod Dhakal
Journal: Journal of Clinical Oncology (2018)

e20000 Background: While autologous stem cell transplantation (ASCT) leads to deep hematological responses in patients with AL amyloidosis (AL), high treatment related mortality may limit its use. Recent studies show improving short-term outcomes after ASCT in AL. We sought to investigate national trends in the utilization of ASCT and in-hospital complications among patients with AL in the US Methods: Using Nationwide Inpatient Sample (NIS), we identified all hospitalizations for ASCT from 2002-2014. We estimated the proportion of AL among all ASCTs as a measure of utilization. Time trends in ASCT utilization was studied using survey enabled logistic regression. In-hospital outcomes including death, cardiorenal or infectious complications, length of stay (LOS) and total hospital charges, CHG (inflation adjusted) were modeled using appropriate multivariate methods. All hypotheses were two sided and the level of significance was 0.05. Results: Out of a total of 67,913 estimated hospitalizations for ASCT during the study period, 1,880 (2.8%) had AL. From 2002-2014, the proportion of AL among all ASCTs increased from 1.1% in 2002 to 3.6% in 2014 (OR 1.07; 95% CI 1.01-1.12; p < 0.01). AL cases had higher in-patient mortality rate compared to non-AL cases (4.5% versus 1.7%), even after adjusting for age and comorbidity index (OR 2.21, 95% CI 1.45-3.37; p < 0.01). Inpatient complications included febrile neutropenia (34%), cardiac arrhythmias (24%), acute kidney injury (16%) and congestive heart failure (12%). From 2002-2014, there was a significant progressive decline in in-hospital mortality (9.1% in 2002 to 2.9% in 2014), confirmed in multivariate analysis adjusting for age and comorbidity (OR 0.69; 95% CI 0.53-0.89; p < 0.01). The mean LOS remained unchanged (mean 19 d in 2002 vs 21 d in 2014; p = 0.38), but hospitalization costs nearly doubled (mean CHG $125,742 in 2002 vs 249,025 in 2014; p < 0.01). Conclusions: Over the past 14 years, the prevalence of AL amyloidosis in patients receiving ASCT has increased, whereas in-hospital mortality has declined, likely due to improved patient selection and supportive care.
Efficacy and tolerability of first-line anti-HER2 therapy for HER2+ advanced breast cancer: A single-centre real-world experience.
Authors: Nicolo Matteo Luca Battisti, David Odhiambo Okonji, Stefania Redana, Narda Chaabouni, Caroline Fong, Kabir Mohammed, Mark Allen, Alistair E. Ring
Journal: Journal of Clinical Oncology (2018)

e13014 Background: Taxanes+Trastuzumab+Pertuzumab (THP) is standard-of-care 1st line treatment for HER2 positive advanced breast cancer (ABC) based on the CLEOPATRA trial and Pertuzumab is available in the UK as of April 2013. However, there are concerns about the applicability of these findings in the real world. We evaluated clinical benefit rate (CBR), overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and tolerability of 1st line anti-HER2 treatment in our patients and compared outcomes across different anti-HER2 regimens. Methods: We retrospectively identified 241 patients receiving 1st line for HER2+ ABC at our Institution between April 2011 and August 2016. Demographics, disease characteristics, (neo-)adjuvant treatments, disease sites, toxicities, treatment delays and responses were recorded. Fisher’s exact test or chi-squared method were used as appropriate, along with Cox regression to explore differences among groups. Results: In our analysis median follow-up was 33 months. Median age of patients was 53 (range 22-93). ECOG PS was 0 in 138 patients (57.3%),1 in 87 (36.1%), 2 in 14 (5.8%) and 3 in 2 (0.8%). 87 patients (36.1%) had de novo ABC. Of 154 (63.9%) with relapsed disease, 82 (54.3%) had received adjuvant Trastuzumab. 168 (69.7%) had biopsy-proven ABC and 31(12.9%) brain involvement at baseline or during treatment. 88 patients (36.5%) received THP, 96 (39.8%) Trastuzumab+chemo, 7 (2.9%) Trastuzumab emtansine (TDM1), 6 (2.5%) Lapatinib+chemo, 32 (13.3%) Trastuzumab+endocrine therapy, 11 (4.64%) Trastuzumab alone and 1 TDM1+Pertuzumab. CBR was 90.9% (219 patients) and ORR 79.3% (191). Median OS was 86.7 months (95% CI 71.4-103.3). Patients on THP received a median 6 cycles of chemotherapy (range 1-8). 38 (43.2%) required a dose reduction and 32(36.4%) granulocyte-colony stimulating factor (G-CSF). Those on Trastuzumab+chemo received a median 6 cycles (1-19) with 30 (31.2%) requiring a dose reduction and 21 (21.9%) G-CSF. Conclusions: First-line anti-HER2 therapy is safe and provides long-term ongoing benefit to real-world patients. However, adjustments may be required based on individual patients’ characteristics.