tbuckley/cabot-search huggingface dataset:
Updated phase I trial of anti-LAG-3 or anti-CD137 alone and in combination with anti-PD-1 in patients with recurrent GBM.
Authors: Michael Lim, Xiaobu Ye, Anna F. Piotrowski, Arati Suvas Desai, Manmeet Singh Ahluwalia, Tobias Walbert, Joy D. Fisher, Serena Desideri, Zineb Belcaid, Christina Jackson, Louis B. Nabors, Patrick Y. Wen, Stuart A. Grossman
Journal: Journal of Clinical Oncology (2019)

2017 Background: Preclinical GBM data targeting the checkpoint molecules Lag-3 and CD137 have shown promising anti-tumor immune response with resultant improved survival when combined with anti-PD-1. Here we report our experience from a multi-arm safety study in patients with recurrent GBM treated with anti-Lag-3 and anti-CD137. Methods: The Adult Brain Tumor Consortium (ABTC) 1501 trial is a phase I, open label, multicenter, multi-arm dose-finding/safety study of anti-LAG-3 (BMS-986016) or anti-CD137 (BMS-663513) alone and in combination with anti-PD-1 in patients at first recurrence of GBM. The primary objective is to define MTD for the mono and combinational treatment. The major secondary objective is to explore for a signal in efficacy. The key inclusion criteria are adults, first recurrence of GBM following RT+TMZ, TLC≥1000/ul, KPS≥ 60%, stable corticosteroid regimen, measurable disease, and written informed consent. Sequential allocation was used for the treatment assignment at starting dose of 80mg for anti-LAG-3 and 8mg for anti-CD137. Anti-PD-1was given at a flat dose of 240 mg in the combination treatment arms. The 3+3 design is used for the dose finding with a target DLT rate &lt; 33%. Results: to date 44 patients were enrolled into the trial with median age at 57, median KPS at 90. Median treatment cycle was 3 and 39% tumors were MGMT methylated. The highest safe dose for Anti-LAG-3 alone is 800 mg without a DLT. The safe dose for anti-CD137 alone arm is 8mg with 1 DLT, and 2 grade 3 elevated serum ALT at end of cycle 2. Combination arms of Anti-LAG-3 +anti-PD-1 (160 mg/240mg as the highest dose combination) had one DLT (hypertension) and no toxicities were seen in the combination arm of Anti-CD137+Anti-PD-1 (3 mg/240 mg). mOS was 14 months for anti-CD137 alone, 8 months for Anti-Lag-3, and 7 months for Anti-Lag-3 + Anti-PD-1. Correlative data will be discussed. Conclusions: The trial is ongoing. The RP2D is 800mg for anti-LAG-3 as a monotherapy and 8mg for anti-CD137. For the combination arms, 160 mg of Anti-LAG-3 and 240 mg of anti-PD-1 and 3 mg of anti-CD137 and 240 mg antiPD-1 were the RP2D. Clinical trial information: NCT02658981.
Targeting differential response using molecular guided biopsies in bone-metastatic prostate cancer.
Authors: Alison Roth, Scott A. Tomlins, Michael Tuite, Glenn Liu, Robert Jeraj
Journal: Journal of Clinical Oncology (2019)

e16516 Background: Methods for molecular image-guided biopsies have been limited to targeting lesions with high radiotracer uptake. The purpose of this study is to determine the value of using molecular imaging response to select lesions for biopsy. Methods: 7 metastatic prostate cancer patients received 18 F-NaF PET/CT scans at baseline and after 12 weeks of enzalutamide therapy. Lesion uptake was quantified semi-automatically. Lesions were classified as partially responding (PR, significantly decreased uptake), stable disease (SD, no significant change), and progressing disease (PD, significantly increased uptake) using test-retest limits of agreement for the relative change in SUV total . In the case that response was stable by SUV total , the relative change of SUV max (and corresponding limits of agreement) were used to reclassify response. 3 candidate lesions from each response category (PR, PD) were selected, including SD lesions if needed. Interventional radiologists biopsied two lesions from different response categories per patient within 7 days of the week 12 scan. Up to 3 needle cores and aspirate were taken per biopsy. Core and aspirate samples were subjected to multiplexed PCR using custom Ampliseq panels targeted to common mutations (DNA) and alterations (RNA) in prostate cancer. The presence of androgen receptor splice variant 7 (AR-V7) was determined for each sample. Results: 8/13 lesions biopsied contained tumor, but one patient’s samples were not tracked (one lesion contained tumor). 7/11 tracked lesions contained tumor including 2/3 PR lesions, 1/4 SD lesions, and 4/4 PD lesions. The average tumor content in successful needle passes was 30.0% for PR (3/6 passes), 20.0% for SD (1/8 passes), and 35.7% for PD lesions (7/8 passes). Aspirate samples were acquired for 1 PR and 3 PD lesions; all 4 contained tumor. AR-V7 was identified in 0/2 PR, 0/1 SD, and 3/4 PD lesions. 3/7 patients had two biopsy lesions that contained tumor. Two patients had PR and PD biopsies and one patient had SD and PD biopsies). AR-V7 was identified in the PD lesions of one of the PR/PD patients and the SD/PD patient. Conclusions: Molecular imaging response has the potential to increase the success of difficult biopsy scenarios. Additional information about developing therapy resistance can be gathered by preferentially sampling PD lesions. Clinical trial information: NCT02677376.
Prognostic value of Tfh-like cells in breast cancer.
Authors: Linxiaoxi Ma, Liang Guo, Shyamal Goswami, Xiaoming Zhang, Jiong Wu
Journal: Journal of Clinical Oncology (2019)

e14285 Background: The treatment of breast cancer, one of the most common malignant tumors for female, focuses on the combined treatments based on subtypes including Luminal A, Luminal B, HER2 overexpression and triple negative. Given that none of those subtypes takes into consideration of immunological parameters, it is valuable to explore the biological characteristics and prognostic value of immune cells in breast caner. T follicular helper cells (Tfh cells) have been identified in different types of tumors with rare datas in breast cancer. One of them indicated the positive prognostic value of 8-gene Tfh signature. Exploration of Tfh cells may provide new clues to the potential immunotherapies in breast cancer. Methods: Freshly resected invasive breast cancer tissue from Fudan University Shanghai Cancer Center were collected during 06/2015 to 05/2017. Patients were divided into Luminal A (N = 61), Luminal B (HER2-) (N = 138), Luminal B (HER2+) (N = 72), HER2+ (non-luminal) (N = 57) and triple negative (N = 58) based on St Gallen International Expert Consensus. Results: A subpopulation of PD1 hi CD4 + T cells in the tumor tissues of breast cancer was identified as Tfh-like cells, with the specific expression of Bcl-6 and CXCL13, confirmed by IHC. Phenotypes of those cells were checked by flow cytometry. Tfh-like cells were of a high level of ICOS but negative for CXCR5, suggesting that they were atypical Tfh cells. Data showed that high grade (N = 166; mean±SEM, 17.62±0.87) compared with low grade (N = 220; mean±SEM, 12.41±0.46) or high Ki-67 level (N = 300; mean±SEM, 15.38±0.58) with low Ki-67 level (N = 86; mean±SEM, 12.10±0.67), and negative ER expression (N = 115; mean±SEM, 17.47±1.05) compared with positive ER expression (N = 271; mean±SEM, 13.46±0.50) or negative PR expression (N = 177; mean±SEM, 16.87±0.83) compared with positive PR expression (N = 209; mean±SEM, 12.77±0.50) was associated with higher frequency of Tfh-like cells (P &lt; 0.01 to all). Patients with triple negative had higher frequency of Tfh-like cells than those with Luminal A (difference, 6.83; P = 0.0006) and Luminal B (HER2-) (difference, 4.61; P = 0.0124). Patients with HER2+ (non-luminal) had higher frequency of Tfh-like cells than those with Luminal A (difference, 5.34; P = 0.0146). These results indicate that higher frequency of Tfh-like cells could have negative prognostic influence. Conclusions: Our study defined a PD1 hi Bcl6 + CXCL13 + CD4 + T cell subpopulation, which specifically secretes cytokine IL-21 as Tfh-like cells. Higher frequency of Tfh-like cells is more likely to be seen in patients with poor prognosis.
Case 20-1972
Authors: Richard C. Cabot, Benjamin Castleman, Robert E. Scully, Betty U. McNeely, John W. Burnside, Benjamin Castleman
Journal: New England Journal of Medicine (1972)

Presentation of CaseA 14-year-old boy was admitted to the hospital because of cardiac arrhythmias.Before the age of six years he was admitted to a hospital on three occasions because of pneumonia and once with "febrile convulsions." Thereafter he was well and active. One month before admission he was beaten by one or more assailants; trauma to the chest was denied. Subsequently, he was observed to be lethargic. Eleven days before entry a dry cough, coryza and sneezing developed. On the following day epistaxis occurred, and he began to cough up large quantities of clear sputum. He was dyspneic . . .
Changes in the proportion of squamous cell carcinoma in head and neck cancer in the United States and Canada, 1995-2015.
Authors: Matthew Gaubatz, Aleksandr R Bukatko, Katherine M. Polednik, Matthew C Simpson, Eric Adjei Boakye, Kahee A Mohammed, Nosayaba Osazuwa-Peters
Journal: Journal of Clinical Oncology (2019)

e17554 Background: There has been a shift in the epidemiologic landscape of head and neck cancer (HNC) with decreasing incidence of tobacco-related and increasing incidence of human papillomavirus (HPV)-related HNC. While it is often reported that ≥ 90% of HNC is considered squamous cell carcinoma (SCC), there is an apparent lack of recent population-based data to support this claim. This study aimed to estimate the current proportion and evaluate change in the proportion of SCC in HNC diagnoses in North America (United States and Canada) from 1995 to 2015. Methods: We queried the North American Association of Central Cancer Registries (NAACCR) database for HNC cases that were of either squamous (SQ) (ICD-0-3: 8050-8089) or squamous plus unspecified epithelial (SQE) (ICD-0-3:8010-8089) origin in the United States and Canada ( n = 1,054,409). All HNC included in the analysis were microscopically confirmed, malignant head and neck primary tumor sites of the oral cavity, nasopharynx, hypopharynx, oropharynx, nasal cavity, and larynx. Sub-analyses were conducted across more extensive cohort restriction combinations (country specific, registry specific, and primary sequence of cancer). Results: The overall proportion of SCC in HNC in North America from 1995-2015 was 81.7% (95% CI: 81.7 – 81.8) for SQ and 84.9% (95% CI: 84.8 – 85.0) for SQE. The proportion of SCC in HNC peaked in 2015 with 83.3% (95% CI: 83.0 – 83.6) for SQ and 85.9% (95% CI: 85.6 – 86.2) for SQE; and was lowest in 2005 with 80.7% (95% CI: 80.4 – 81.1) for SQ and 84.3% (95% CI: 83.9 – 84.6) for SQE. In the time period of this study (1995 – 2015), there were no years for which SQ or SQE made up 90% or more of HNC for any of the HNC cohorts. Conclusions: The changing landscape of HNC risk factors in the United States and Canada warrants re-evaluation and update of HNC epidemiological literature with regards to the proportion of SCC in HNC.
ctDNA as a noninvasive monitoring tool in metastatic melanoma.
Authors: Renata Varaljai, Kilian Wistuba-Hamprecht, Teofila Seremet, Joey Mark Santiago Diaz, Jeremie Nsengimana, Antje Sucker, Klaus Griewank, Peter Horn, Nils von Neuhoff, Batool Shannan, Heike Chauvistré, Felix Christian Eduard Vogel, Susanne Horn, Jürgen C. Becker, Julia Newton-Bishop, Andreas Stang, Bart Neyns, Benjamin Weide, Dirk Schadendorf, Alexander Roesch
Journal: Journal of Clinical Oncology (2019)

9548 Background: The field of liquid biopsy provides a promising alternative to standard tissue biopsies. Previous work has shown that plasma circulating cell-free DNA (ctDNA) can reflect the heterogeneous spectrum of mutations in cancer including metastatic melanoma. Our project aimed to establish and statistically validate plasma-based assays for tumour load and therapy monitoring in melanoma. Methods: On a large cohort of stage III and stage IV melanoma patients (N = 96) who received signalling targeted or immune checkpoint inhibitors we showed that the most common oncogenic drivers of this disease such as the BRAFV600E, NRASQ61 and the TERTC250T and TERTC228T promoter mutations (termed TERTprom) can be analysed in ctDNA with highly sensitive droplet digital PCR technology (detection of mutant ctDNA down to 0.01% analytical sensitivity). Results: Our research has demonstrated that ctDNA (irrespective of the genotype) significantly correlates with tumour stage (P &lt; 0.05). Using receiver operating characteristics (ROC) analyses thresholds were established for risk stratification and response prediction. Elevated ctDNA at baseline was a significant predictor of disease progression compared to elevated LDH or S100 in multivariable cox proportional hazards model (Hazard ratio [HR] 7.43, P = 0.05). During therapy, patients with low ctDNA load (below the ROC threshold) had significantly better radiological outcomes and prolonged progression free survival (PFS) compared to patients with high ctDNA load (P &lt; 0.0001). Our findings were confirmed on an independent cohort of metastatic melanoma patients (N = 35) treated with immune checkpoint inhibitors, where also during therapy low ctDNA load correlated with prolonged PFS (P = 0.003). An added benefit of ctDNA was demonstrated in about 80% of the patients, where ctDNA analyses preceded the radiological diagnosis of response or relapse. Progression was detected in plasma ctDNA in average 3.5 months earlier as compared to routine imaging techniques. Finally, we demonstrated that the occurrence of NRASQ61 mutation in BRAFV600-inhibitor treated patients at therapy baseline was associated with treatment failure. The sub-clonal NRASQ61 mutation at therapy baseline was an independent predictor of shorter PFS (HR 2.69, P = 0.02) as compared to BRAFV600E patients without the NRASQ61 mutation at therapy baseline. Conclusions: In sum, our results support the value of ctDNA as a sensitive biomarker for real-time therapy monitoring and early detection of disease progression.
Case 12-1984
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely, Ronald E. Kleinman, David L. Gang
Journal: New England Journal of Medicine (1984)

Presentation of CaseAn eight-week-old boy was admitted to the hospital after repair of gastroschisis with the short-bowel syndrome.He was born of a 36-week first gestation to a mother 20 years of age. She smoked cigarettes during the first trimester but used no alcohol or other drugs and experienced no illness during the pregnancy. Vaginal delivery was brief and uncomplicated, and the birth weight was 2100 g. Examination revealed gastroschisis and an Apgar score of 5 at one minute and 7 at five minutes. Ampicillin and kanamycin were administered by vein, and the child was transferred to another hospital. . . .
Crizotinib in patients with advanced or metastatic <i>ROS1</i>-rearranged lung cancer (EUCROSS): A European phase II clinical trial–Updated report on progression-free and overall survival.
Authors: Sebastian Yves Friedrich Michels, Jeremy Franklin, Bartomeu Massuti, Martin Sebastian, Hans-Ulrich Schildhaus, Enriqueta Felip, Christian Grohe, Delvys Rodriguez-Abreu, Helge Bischoff, Enric Carcereny, Jesús Corral, Anne-Marie C. Dingemans, Amelia Insa, Martin Reck, Sacha Rothschild, Egbert F. Smit, Mariano Provencio, Reinhard Büttner, Rafael Rosell, Juergen Wolf
Journal: Journal of Clinical Oncology (2019)

9066 Background: ROS1 rearrangements are found in 1% of non-small cell lung cancer (NSCLC) patients. Early clinical trials in the US and East Asia have proven the therapeutic efficacy of crizotinib in this subset of patients. EUCROSS is the first prospective European trial to evaluate the acitivity of crizotinib in ROS1-positive lung cancer. Here we present an updated analysis of the investigator-assessed progression-free survival (PFS) and overall survival (OS). Methods: EUCROSS is a multi-centre, single arm phase 2 trial (NCT02183870). Key eligibility criteria: ≥18 years of age, advanced/metastatic lung cancer, centrally confirmed ROS1-rearranged (fluorescence-in situ hybridisation). Treatment with crizotinib was initiated at a dose of 250 mg twice daily. Primary endpoint of the trial: investigator-assessed objective response rate (ORR) in the response-evaluable population (Response Evaluation Criteria in Solid Tumors, version 1.1). Key endpoints of this report: updated PFS and OS and updated molecular characterization of tumour tissue. Results: Thirty-four patients received treatment with crizotinib and were included in the intention-to-treat analysis. Four patients were excluded from the primary endpoint analysis due to violation of eligibility criteria (response-evaluable set, N = 30). Median follow-up period was 44.9 months. At the time of data cut-off for this report 19 patients (63%) discontinued treatment due to progression or death. Investigator ORR was 70% (95% CI, 51–85; 21/30), disease control rate was 90% (95% CI, 73.5-97.9; 27/30) and median PFS was 19.4 months (95% CI, 10.1-31.2). Median OS was not reached, but 24-months-OS probability was 66% (95% CI, 48.3-82.9). Tissue of 18 patients was available for hybrid-capture-based sequencing. Co-occurring genetic aberrations were found in 61% (11/18). TP53 mutations were most frequent (28%; 5/18). PFS (24-months probability, TP53-mut. 0% vs. TP53 wild-type (wt) 61%; p = 0.0219) and OS (24-months, TP53-mut. 40% vs. TP53 wt 83%; p = 0.015) were significantly shorter in TP53-mutant patients. Differences in OS and PFS stratified by number of prior treatment lines (0-1 vs. &gt; = 2), brain metastases (yes vs. no) or CD74-rearrangement ( CD74- ROS1 vs. other fusion type) status were not significant. Conclusions: Updated PFS and OS results show that crizotinib is highly effective in ROS1-rearranged lung cancer. Co-occurring TP53 mutations were associated with a significantly worse outcome. Clinical trial information: NCT02183870.
Association between MDM2/MDM4 amplification and PD-1/PD-L1 inhibitors-related hyperprogressive disease: A pan-cancer analysis.
Authors: Weiqiang Ju, Shiqing Chen, Guoqiang Wang, Shangli Cai, Jianping Xiong, Xiaojun Xiang
Journal: Journal of Clinical Oncology (2019)

2557 Background: Immune checkpoint inhibitors have demonstrated a clear survival benefit in various tumor types. However, accelerated disease progression, documented as hyperprogressive disease (HPD), was reported in a subset of patients treated with PD-1/PD-L1 inhibitors. Until now, the mechanisms underlying HPD have not been elucidated. Previous studies have demonstrated that MDM2/MDM4 amplification were associated with HPD. In the present study, we evaluated the relationship between MDM2/MDM4 amplification and HPD. Methods: We reviewed extensive clinical trials of PD-1/PD-L1 inhibitors in advanced solid tumor patients updated to January 2019, and estimated the incidence of HPD, which was defined as time-to-treatment failure (TTF) &lt; 2 months, and &gt; 50% increase in tumor burden compared with pre-immunotherapy imaging in this study. The proportions of MDM2/MDM4 amplification across different cancer types were obtained from The Cancer Genome Atlas (TCGA) and our own database respectively. Then we plotted the incidence of HPD and the corresponding proportion of MDM2/MDM4 amplification across various cancer types in TCGA. Results: Overall, 19 published clinical trials of 1318 patients treated with PD-1/PD-L1 inhibitors were included for analysis, covering 12 types of solid cancers. The incidences of HPD among these studies were ranging from 1.58% in renal clear cell carcinoma to 24.3% in sarcoma. Correspondingly, the proportions of MDM2/MDM4 amplification for these cancer types in TCGA were 0.74% in renal clear cell carcinoma to 20.38% in sarcoma. In our database, in total, 60 patients with MDM2/MDM4 amplification were identified in 2931 patients with the highest proportion of MDM2/MDM4 amplification in sarcoma (22 of 152, 14.5%). A significant correlation was detected between the incidence of HPD and the corresponding proportion of MDM2/MDM4 amplification in TCGA across various cancer types ( P &lt; 0.001, R 2 = 0.67). Conclusions: Our results suggest that MDM2/MDM4 amplification may be associated with rapid disease progression in patients receiving PD-1/PD-L1 inhibitors among various tumor types. The exact mechanisms underlying HPD are needed to be further evaluated.
Trends of Nontraumatic Lower-Extremity Amputation in End-Stage Renal Disease and Diabetes: United States, 2000–2015
Authors: Jessica L. Harding, Meda E. Pavkov, Edward W. Gregg, Nilka R. Burrows
Journal: Diabetes Care (2019)

OBJECTIVE Nontraumatic lower-extremity amputation (NLEA) is a complication of end-stage renal disease (ESRD) and diabetes. Although recent data show that NLEA rates in the U.S. ESRD population are declining overall, trends in diabetes and diabetes subgroups remain unclear. RESEARCH DESIGN AND METHODS We estimated annual rates of NLEA hospitalizations during 2000–2015 among &amp;gt;2 million adults (≥18 years) with ESRD from the U.S. Renal Data System. Age, sex, and race-adjusted NLEA rates were stratified by diabetes status, age, sex, race, and level of amputation (toe, foot, below the knee, and above the knee). Time trends were assessed using Joinpoint regression with annual percent changes (APC) reported. RESULTS Among adults with diabetes, NLEA rates declined 43.8% between 2000 and 2013 (from 7.5 to 4.2 per 100 person-years; APC −4.9, P &amp;lt; 0.001) and then stabilized. Among adults without diabetes, rates of total NLEAs declined 25.5% between 2000 and 2013 (from 1.6 to 1.1; APC −3.0, P &amp;lt; 0.001) and then stabilized. These trends appear to be driven by a slowing or stagnation in declines of minor NLEAs (toe and foot) in more recent years, while major NLEAs (above the knee) continue to decline. CONCLUSIONS Despite an initial period of decline, this analysis documents a stall in progress in NLEA trends in recent years in a high-risk population with both ESRD and diabetes. Increased attention to preventive foot care in the ESRD population should be considered, particularly for those with diabetes.
Effect of metformin on PARP inhibitors-induced epithelial-mesenchymal transition and PD-L1 expression in triple-negative breast cancer.
Authors: Ye Han, Chia-Wei Li
Journal: Journal of Clinical Oncology (2019)

1063 Background: Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising targeted therapies for BRCA-mutated cancers by blocking repair of DNA double-strand breaks. However, resistance to PARP inhibitors have been described in some patients lowering overall response rates. The mechanisms underlying PARP inhibitor (PARPi) resistance are an area of active investigation. Methods: PARPi adaptive resistant clones (MDA-MB-468, MDA-MB-231, HCC1806) were generated in triple-negative breast cancer cell lines. Through morphologic observation and functional analysis, we evaluated epithelial-mesenchymal transition (EMT) and changes in immune checkpoint programmed death-ligand 1 (PD-L1). We also downregulated the expression of PD-L1 by shRNA to study the role of PD-L1 in PARPi resistance. We evaluated the immunology sensitivity to cytotoxic T cell upon PD-L1 change using a murine ex-vivo CD8 + T cell killing assay and a comparison of total killing cells percentage per well. Results: We demonstrated that inhibition of PARP enhances EMT, which induces phosphorylation of Akt at S473. This in turn upregulates the expression of PD-L1 by 2-3 fold in triple-negative breast cancer cells. In addition, PARPi–induced EMT occurred independent of PD-L1 upregulation in triple-negative breast cancer cells. Metformin administration (10µM) was found to reverse EMT by blocking the p-Akt S473 axis through activation of AMPK, resulting in downregulation of PD-L1 expression and sensitizing PARPi-resistant cancer cells to T cell killing. Conclusions: In summary, we identified that induction of EMT is a new mechanism for PARP inhibitor resistance. Metformin was able to reverse EMT and therefore a combination of metformin and PARP inhibitors may be a promising therapeutic strategy to increase the efficacy of PARP inhibitors and tumor sensitivity to T cells.