tbuckley/cabot-search huggingface dataset:
TENERGY: Multicenter phase II study of atezolizumab monotherapy following definitive chemoradiotherapy with 5-FU plus cisplatin in patients with locally advanced esophageal squamous cell carcinoma.
Authors: Hideaki Bando, Daisuke Kotani, Takahiro Tsushima, Hiroki Hara, Shigenori Kadowaki, Ken Kato, Keisho Chin, Kensei Yamaguchi, Shun-ichiro Kageyama, Hidehiro Hojo, Masashi Wakabayashi, Miki Fukutani, Yosuke Togashi, Nozomu Fuse, Hiroyoshi Nishikawa, Takashi Kojima
Journal: Journal of Clinical Oncology (2019)

TPS4141 Background: The standard treatment for patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC) is definitive chemoradiotherapy (CRT) using 5-FU plus cisplatin. However, complete response (CR) rates are only 11% to 25%, and median overall survival (OS) is 9 to 10 months. The improved therapeutic efficacy of combining immunotherapy with radiation has been gaining interest. Our basic research suggested that sequential treatment with anti-PD-L1 agents soon after completion of CRT is the best combination. Twelve months of anti-PD-L1 antibody following platinum-based CRT significantly improved progression-free survival (PFS) and OS in patients with locally advanced non-small cell lung cancer (Antonia SJ, et al. N Engl J Med. 2018). Based on this background information, we have planned a phase II clinical trial to evaluate the safety and efficacy of atezolizumab monotherapy following definitive CRT in patients with locally advanced ESCC. Methods: The main inclusion criteria are unresectable locally advanced ESCC without distant metastasis, completion of treatment with 60 Gy of radiation plus two concomitant cycles of chemotherapy (cisplatin 70 mg/m 2 on day 1 and 5-FU 700 mg/m 2 on days 1–4, every 28 days), and adequate organ function. Within 4 weeks after CRT, patients will be registered in the study and started on 1200 mg of atezolizumab every three weeks until 12 months or disease progression. The primary endpoint is the CR rate by the investigator’s assessment. Overall response rate, PFS, OS, treatment-related adverse events, and CR rate by central assessment are secondary endpoints. A total of 50 patients will be enrolled, including 40 with primary locally advanced ESCC and 10 with postoperative loco regionally recurrent ESCC. As an exploratory biomarker study, biopsies from the primary site and blood collections will be performed at 3 time points (before CRT, after CRT, and four weeks after the start of atezolizumab). We will analyze the phenotype of immune-competent cells, neoantigens, tumor mutation burden, PD-L1 status, and Human Leukocyte Antigen haplotyping. Clinical trial information: UMIN000034373.
Expression of human leukocyte antigen-a and b2-microglobulin in prostate cancer.
Authors: Ying-Chun Shen, Yung-Ming Jeng, Jhe-Cyuang Kuo, Yu-Chieh Tsai, Chung-Hsin Chen, Kuo-How Huang, Chao-Yuan Huang, Yeong-Shiau Pu, Ann-Lii Cheng
Journal: Journal of Clinical Oncology (2019)

e16550 Background: Prostate cancer (PC) is generally resistant to current immune checkpoint blockade. Reduced expression of human leukocyte antigen-A (HLA-A) and b2-microglobulin (B2M) of cancer cells can cause deficit immune recognition and attack by cytotoxic T cells, and may be the major mechanism of intrinsic resistance to immune checkpoint blockade in PC patients. Methods: Formalin-fixed paraffin-embedded tissue of human localized or metastatic PC was used for evaluation of expression of HLA-A and B2M by Immunohistochemical staining. The expression was scored as: 0, no tumor cells stained; 1+, &lt; 10% of tumor cells stained; 2+, 10-50% of tumor cells stained; and 3+, &gt; 50% of tumor cells stained. Differences in HLA-A or B2M expression among groups were assessed by Chi-Square or Fisher’s exact test. Results: A total of 134 PC specimens [69 localized PC (LPC), 32 metastatic castration-naïve PC (mCNPC), and 33 metastatic castration-resistant PC (mCRPC)] from 115 patients were assessed. Significant loss (0 or 1+) of HLA-A was found in 56 (81.2%) LPCs, 30 (93.8 %) mCNPCs and 29 (87.9%) mCRPCs; while significant loss of B2M was found in 22 (32.6%) LPC, 11 (34.4%) mCNPCs, and 17 (51.2%) mCRPCs. In localized PCs, the expression of HLA-A or B2M was similar between high-grade prostate intraepithelial neoplasia foci and corresponding malignant counterpart, and did not significantly correlate to biochemical failure. In 14 patients with paired CN and CR PC specimens, significant loss of HLA-A was found in all tumors. B2M expression varied between CN and CR PCs, and progressive loss of B2M was found in 7 (50%) patients. Among 3 patients receiving immune checkpoint blockade, 1 patient with intact expression of HLA-A and B2M in pre-treatment tumor specimen achieved partial response; whereas the others with reduced expression of HLA-A (0) and B2M (1+) did not. Conclusions: Reduced expression of HLA-A or B2M is an early event in prostate carcinogenesis.
Zero delay plasma vs. Streck cfDNA tubes: Does immediately centrifuging blood at the point of draw improve cell-free DNA signal-to-noise?
Authors: Greg Sommer, Laura Fredriksen, Gabriella Iacovetti, Kyungjin Hong, Ulrich Schaff
Journal: Journal of Clinical Oncology (2019)

e14529 Background: Sample quality is a critical consideration for high fidelity cell-free DNA (cfDNA) testing. Oncological cfDNA tests used for liquid biopsy typically employ specialty blood collection tubes containing chemical preservatives to minimize degradation of samples prior to lab testing. Here we describe a newly developed device, Zero Delay Plasma– a portable centrifuge and disc system designed to immediately isolate cell-free plasma at the point of blood draw – and evaluate its performance against the Streck cfDNA collection tube. Methods: Whole blood was collected, processed, and stored at room temperature for up to 7 days with both the Zero Delay Plasma system and the Streck cfDNA blood collection tube. Sample hemolysis was measured via cell-free hemoglobin. Genomic contamination and cfDNA signal-to-noise were evaluated by qPCR and electrophoresis, comparing signal from target 150-200bp cfDNA to contaminating longer length genomic sequences in the sample. 2 sets of hemolysis experiments, 2 sets of electrophoresis experiments and 4 sets of qPCR experiments were conducted. Results: Plasma processed with the Zero Delay Plasma system yielded ~4X lower hemolysis levels, ~10X lower genomic contamination, and ~20X higher cfDNA signal-to-noise compared to the Streck cfDNA collection tube after 7 days of storage at room temperature. Conclusions: The Zero Delay Plasma system minimizes sample degradation and analytical background signal for cfDNA testing by immediately removing cells and other contaminants at the point of blood collection. Clinical evaluations are in process.
An observational study to evaluate the potential of Onlife to improve chemotherapy-induced peripheral neuropathy: Final results of the STEFANO trial.
Authors: Matthias R. Zaiss, Jens Uhlig, Mark-Oliver Zahn, Thomas Decker, Helmar C. Lehmann, Johanna Harde, Corinne Vannier, Cathrin Hogrefe, Norbert Marschner
Journal: Journal of Clinical Oncology (2019)

e23143 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, long-term side effect of many antineoplastic agents and has a detrimental impact on patients (pts)’ quality of life and functional activities of daily living. Currently, preventive measures and treatment options for CIPN are quite limited. OnLife is a dietary supplement that contains a patented mixture of fatty acids with anti-inflammatory, neuroprotective and antinociceptive properties. Methods: The STEFANO study – an observational, prospective, two-cohort, multicenter study of dietary supplementation – was designed to evaluate the potential of OnLife to improve CIPN in adult pts with completed neo-/adjuvant chemotherapy and manifest CIPN (grade 1-3) (Cohort A: colon cancer, oxaliplatin-containing therapy; cohort B: breast cancer, paclitaxel therapy). Pts received OnLife for 3 months. The primary objective – assessment of changes in CIPN – was evaluated by comparing the severity of sensory and motor CIPN according to CTCAE v4.03 before, during and after treatment with OnLife. Secondary endpoints included patient-reported experience of symptoms and functional limitations related to CIPN. Descriptive statistics were used to analyze data. Results: In total, 75 breast cancer pts with paclitaxel-induced and 71 colon cancer pts with oxaliplatin-induced peripheral neuropathy, respectively, received OnLife. Based on physician-rated CTCAE grades, 21.3% of breast cancer pts and 12.7% of colon cancer pts had a sustained improvement of sensory CIPN after OnLife treatment. Concerning motor CIPN, the proportions were 12.0% and 9.9%, respectively. According to patient-reported outcomes, 45.3% of breast cancer pts and 23.9% of colon cancer pts had less symptoms and functional limitations related to sensory CIPN after OnLife treatment. Concerning motor CIPN, the proportions were 32.0% and 22.5%, respectively. Conclusions: STEFANO provides indications of the potential of OnLife to reduce severity of objective and subjective CIPN-related symptoms. Therefore, it is a promising agent to meet the unmet medical need of management options for patients with established CIPN. Clinical trial information: NCT03065478.
Single cell analysis of urothelial carcinoma (UC) liver metastases identifies epithelial-mesenchymal transition (EMT) as a potential mechanism of resistance to immunotherapy.
Authors: Michael Lattanzi, Lily M. Tredwin, Fang-Ming Deng, Luis Chiriboga, Briana Zeck, Claudio Forcato, Jonathan Serrano, Hussein Mohamed, Matija Snuderl, Arjun Vasant Balar
Journal: Journal of Clinical Oncology (2019)

e16018 Background: UC liver metastases are associated with a low response rate to immune checkpoint blockade (ICB) and short survival. We sought to identify tumor specific factors promoting resistance to ICB. Methods: DEPArray is a dielectrophoresis based cell sorting platform for isolating immunohistochemically-defined cell populations from formalin-fixed paraffin-embedded (FFPE) tissue. Available FFPE tissue blocks of mUC liver metastases from patients (pts) treated with ICB were selected for analysis. Following histologic evaluation, tissue blocks were digested to yield cellular suspensions for immunophenotypic DEPArray sorting by keratin (K) and vimentin (V) to identify carcinoma cells and stromal cells, respectively. Cell pools were further analyzed for recurrent mutations and copy number alterations by a targeted OncoSeek panel and by MiSeq. Results: 12 unique patient samples were profiled. Median age was 73 (range 65-89), 11/12 male, 7 (58%) were platinum-refractory, and 4 (33%) received only ICB. 7 (58%) biopsies were obtained prior to initiation of ICB (1PR, 1SD, 5PD). Routine H&amp;E sections generally revealed tumors completely devoid of immune cells, but admixed with atypical mesenchymal cells ranging from 5% to 60% of cellular composition. DEPArray sorting by K and V identified three discrete cell populations: K+/V- carcinoma cells, K-/V+ stromal cells, and K+/V+ cells that exhibited mesenchymal morphology. Of 8 samples with adequate cell counts (range 75-154 cells), next-generation sequencing (NGS) identified that K+/V- carcinoma cells and K+/V+ double positive cells shared unique somatic alterations in 7 (88%) pts, including point mutations in FGFR3, ERBB2, FBXW7, PIK3CA, FLT3 and STK11, and amplification of CDK4. In one liver responder to ICB, V+ stromal cells carried a putative germline TP53 R248W mutation. Conclusions: Archival FFPE tissue from mUC liver metastases can be digitally sorted by DEPArray to yield pools of ~100 cells suitable for NGS. UC liver metastases exhibit a population of K+/V+ cells with clonal somatic alterations suggestive of an EMT cancer cell phenotype that may be playing a role in ICB resistance.
Efficacy and tolerability of adjuvant gemcitabine and capecitabine in patients with resected pancreatic cancer in US population: A single network experience.
Authors: Gurveen Kaur, Vida Jahangiri, Seon Jo Park, Rodney E Wegner, Dulabh K. Monga
Journal: Journal of Clinical Oncology (2019)

e15789 Background: Adjuvant chemotherapy with combination of gemcitabine and capecitabine improved overall survival (OS) with an acceptable toxicity profile in the European patient population. However, limited data is available for tolerability and efficacy of the combination regimen in the adjuvant setting in the US population. Herein, we report a single network experience with the combination regimen. Methods: We retrospectively evaluated 45 patients with pancreatic cancer who were treated at our institution from 1/1/2017 – 12/31/2018. Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas. These patients received adjuvant combination chemotherapy with gemcitabine (1000 mg/m 2 ) and capecitabine (1660 mg/m 2 ). Electronic medical record was reviewed to collect patient data. Medcalc software was used for statistical analysis including Kaplan Meier analyses. Results: Median age of patients was 64.6 years (range 47-87). Majority of patients had stage II disease (73.5%). Seventy-one percent of patients were able to receive 6 cycles of chemotherapy. Median OS for all patients was 20.2 months (95% CI 11.7-22.7). Median OS for patients who received &lt; 6 vs 6 cycles was 14.9 months (95% CI 6.6-14.9) vs 21.5 months (95% CI 11.9-22.9) (p = 0.21). Median progression free survival (PFS) for all patients was 19.3months (95% CI 13.1-25.7). Median PFS for patients with &lt; 6 vs 6 cycles was 7.3 months versus 22.2 months (p = 0.0002). Overall, 31.1% of patients developed disease progression. Of note, 33.3% and 71.1% of patients required dose reductions for gemcitabine and capecitabine respectively. Fifteen grade 3-4 adverse events were reported of which 11 were hematologic and 4 non-hematologic. Conclusions: This single institution analysis shows a trend in improvement for PFS for patients able to complete adjuvant therapy with gemcitabine and capecitabine following pancreatic resection. It is worth noting, however, that dose reductions were required in the majority of patients. Therefore, we propose investigating a modified regimen of gemcitabine and capecitabine in the US population.
Cutaneous eruption as a prognosis indicator for cancer patients treated with EGFR tyrosine kinase inhibitors: A systematic review and meta-analysis.
Authors: Yensheng Wang, Jennifer Wu, Shi-Yi Wang, Mario E. Lacouture, Mei Wu, Wen-Hung Chung
Journal: Journal of Clinical Oncology (2019)

e23063 Background: Clinical symptom is often a direct method to evaluate the treatment effects. With the emergence of EGFR-targeted drugs on market, it is unclear to apply cutaneous toxicity in evaluating treatment effects and outcomes in cancer patients. This study aimed to determine whether adverse skin event as a survival indicator for patients treated with EGFR tyrosine kinase inhibitors. Methods: PubMed, EMBASE, Scopus, trial register and Cochrane Library were searched on November 11, 2018 to identify studies reporting survivals outcomes. The following search/exploded terms were used: “ EGFR-TKIs: gefitinib/erlotinib/afatinib/osimertinib ”, “ cutaneous toxicity”, “ survival”. Two investigators performed study selection independently and assessed risk of bias with ROBINS-I method. Data were pooled with random effects models and further subgroup by cancer types. Funnel plot, Egger test and Begg test were performed for detection of publication bias. Sensitivity analysis was performed by excluding potential outliers. Results: There were 24 studies identified with 4696 patients included. Skin adverse event was found to be significantly associated overall survival rate (HR, 0.48; 95% CI, 0.43-0.53; P &lt; 0.00001; I 2 = 83%) and progression free survival rate (HR, 0.59; 95% CI, 0.41-0.85; P= 0.004; I 2 = 88%). Subgroup analysis suggested among non-small cell lung cancer patients, skin adverse event was significantly associated with overall survival (HR, 0.39; 95% CI, 0.25-0.60; P &lt; .0001; I 2 = 86%) but not progression free survival (HR, 0.65; 95% CI, 0.29-1.45; P= 0.29; I 2 = 95%). Among other cancer types patients, skin adverse event was significantly associated with overall survival (HR, 0.59; 95% CI, 0.41-0.84; P= 0.004; I 2 = 70%) and progression free survival (HR, 0.61; 95% CI, 0.41-0.91; P= 0.02; I 2 = 80%). Begg test and Egger test suggested no evidence of publication bias. Sensitivity analysis also showed similar results. Conclusions: Skin eruption had 52% lower risk of death and 41% lower risk of progression in cancer patients treated with EGFR-TKIs. This association should be further incorporated with cancer survivorship care planning.
Efficacy of re-irradiation with carbon ions (RiCi) in patients with recurrent high-grade glioma (rHGG) compared to the standard re-irradiation with photons (RiP): The reference multicenter cohort of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG).
Authors: Maximilian Knoll, Maria Waltenberger, Nina Bougatf, Denise Bernhardt, Sebastian Adeberg, Volker Budach, Michael Baumann, Martin Stuschke, Emmanouil Fokas, Anca Grosu, Daniel Zips, Claus Belka, Stephanie E Combs, Andreas von Deimling, Martin Bendszus, Wolfgang Wick, Andreas Unterberg, Stefan Rieken, Juergen Debus, Amir Abdollahi
Journal: Journal of Clinical Oncology (2019)

2057 Background: Local recurrence after surgery and radio(chemo)therapy remains a major obstacle in curative treatment of patients with HGG. Eradication of radioresistant glioma subpopulations (hypoxic- and stem cell like cells) together with formation of an antiangiogenic and immuno-permissive glioma niche are among beneficial radiobiological effects recently attributed to carbon ion irradiation in preclinical models. The impact of this novel therapy in management of rHGG patients remains elusive. Methods: 197 patients with rHGG (grade III: 71, IV: 126) received RiCi between Nov 2009 and Feb 2018 at HIT with a median dose of 42GyRBE in 14 fractions. In DKTK-ROG multicenter cohort n:565 rHGG patients (grade III: 63, IV: 479) underwent RiP between 1997-2016 with a median dose of 36 Gy in 14 fractions. Median follow up was 34.2 months (M) for RiCi and 7.1 M for RiP (DKTK) cohort. All three prognostic scores validated in DKTK-ROG cohort were evaluated and re-irradiation risk score (RRRS) considering initial grade, Karnofsky Performance Score and age at re-irradiation was utilized for stratification and matched comparisons. Results: Median PFS was 5.08 [4.26-5.87] M (grade III: 6.79, grade IV: 3.64) after RiCi, data was not available for RiP. Median OS was 10.52 [9.28-12.66] M (grade III: 28.2, grade IV: 8.53) after RiCi compared to 7.93 [7.15-8.79] M (grade III: 10.89, grade IV: 7.93) after RiP. Among the three prognostic scores evaluated, RRRS most robustly correlated with OS. RiCi was associated with HR of 0.52 ([0.49-0.72], p = 0.0000002), and HR 0.66 ([0.51-0.85], p = 0.001) for RRRS matched analysis. Conclusions: Carbon ions demonstrated activity in rHGG. This effect is most prominent in grade III while grade IV patients may further benefit from innovative multimodal strategies. Based on these encouraging results prospective randomized trials utilizing RRRS for stratification are recommended.
EWOC-1: A randomized trial to evaluate the feasibility of three different first-line chemotherapy regimens for vulnerable elderly women with ovarian cancer (OC): A GCIG-ENGOT-GINECO study.
Authors: Claire Falandry, Aude Marie Savoye, Laetitia Stefani, Fabien Tinquaut, Domenica Lorusso, Jorn Herrstedt, Emmanuelle Bourbouloux, Anne Floquet, Pierre Emmanuel Brachet, Alain Zannetti, Marie-Ange Mouret-Reynier, Robert Sverdlin, Veronique D'hondt, Olivier Guillem, Oana Cojocarasu, Laurence Venat-Bouvet, Frederique Rousseau, Alain Lortholary, Eric Pujade-Lauraine, Gilles Freyer
Journal: Journal of Clinical Oncology (2019)

5508 Background: The Geriatric Vulnerability Score (GVS) combining albumin, lymphocyte count, ADL, IADL and HADS scores has been reported (Falandry C Ann Oncol 2013) to identify vulnerable elderly OC patients (pts) as those with a GVS≥3. For such pts, Carboplatin (Cb) monotherapy or weekly Cb plus paclitaxel (Pa) are often proposed as an alternative to Cb-Pa given every 3 weeks. Methods: Pts ≥70 yrs with first line FIGO stage III/IV epithelial OC were screened for GVS. Those with GVS≥3 were randomized to receive either arm A: Cb AUC5-6 + Pa 175mg/m², d1q3week or arm B: Cb AUC5-6 d1q3week or arm C:weekly Cb AUC2 + Pa 60mg/m² d1-d8-d15 q4week. Primary endpoint is treatment feasibility defined as the ability to complete 6 chemotherapy courses without disease progression, early treatment stopping due to unacceptable toxicity or death. Inclusion of 240 pts was planned. Results: Among 444 screened pts, 120 were randomized from 12/2013 to 04/2017 (armA = B = C = 40). Pts characteristics were well balanced between arms A-B-C respectively: median age (79-82-80 yrs), FIGO stage IV (32-37-27%), primary surgery (65-72-70%), absence of macroscopic residuals (CC-0) (7-5-7%), ECOG≥2 (50-50-47%). Feasibility per protocol for arms A-B-C is 65%, 47% and 60% (p = 0.15). Main reasons for treatment arrest are treatment toxicity (A:20%; B:15%; C:22.5%; p = 0.771) and disease progression (A:7.5%; B:30%; C:2%; p = 0.004). Median PFS for arm A-B-C are 12.5 mos (95%CI 10.3-15.3), 4.8 (3.8-15.3) and 8.3 (6.6-15.3), respectively (p &lt; 0.001) and median OS for arm A-B-C is not reached (NR) (21, NR), 7.4 (5.3-NR) and 17.3 (10.8-NR), respectively (p = 0.001). At the pre-planned intermediate analysis, the IDMC recommended to prematurely close the study as survival in armB was found significantly worse and the number of potential pts required to find a significant difference between both Cb-Pa regimens (arms A&amp;C) was out of reach. Conclusions: Compared to 3-weekly and weekly Cb-Pa regimens, Cb single agent was reported to be less active with significant worse survival outcome in vulnerable elderly pts. In this population Cb-Pa combination remains a standard. Clinical trial information: NCT02001272.
Case 8-1987
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, Sherwin V. Kevy, Eugene J. Mark
Journal: New England Journal of Medicine (1987)

Presentation of CaseA 44-month-old girl was admitted to the hospital because of fever and bleeding per rectum.She had a normal birth and was well during the neonatal period, although a pediatrician heard a murmur and noted a supernumerary right thumb. At the age of 3 1/2 weeks the patient was first seen at this hospital, where examination revealed findings consistent with the tetralogy of Fallot, and this diagnosis was verified by echocardiographic examination. At the age of three months her physician observed a trace of cyanosis at rest, and a few weeks later cyanosis during crying was evident . . .