tbuckley/cabot-search huggingface dataset:
Using machine learning algorithms to predict response and toxicity to immune checkpoint inhibitors (ICIs) in melanoma patients.
Authors: Paul Johannet, Nicolas Coudray, George Jour, Douglas MacArthur Donnelly, Shirin Bajaj, Una Moran, Zarmeena Dawood, Sofia Nomikou, Randie H Kim, Anna C. Pavlick, Jeffrey S. Weber, Aristotelis Tsirigos, Iman Osman
Journal: Journal of Clinical Oncology (2019)

2581 Background: There is growing interest in optimizing patient selection for treatment with immune checkpoint inhibitors (ICIs). We postulate that phenotypic features present in metastatic melanoma tissue reflect the biology of tumor cells, immune cells, and stromal tissue, and hence can provide predictive information about tumor behavior. Here, we test the hypothesis that machine learning algorithms can be trained to predict the likelihood of response and/or toxicity to ICIs. Methods: We examined 124 stage III/IV melanoma patients who received anti-CTLA-4 (n = 81), anti-PD-1 (n = 25), or combination (n = 18) therapy as first line. The tissue analyzed was resected before treatment with ICIs. In total, 340 H&amp;E slides were digitized and annotated for three regions of interest: tumor, lymphocytes, and stroma. The slides were then partitioned into training (n = 285), validation (n = 26), and test (n = 29) sets. Slides were tiled (299x299 pixels) at 20X magnification. We trained a deep convolutional neural network (DCNN) to automatically segment the images into each of the three regions and then deconstruct images into their component features to detect non-obvious patterns with objectivity and reproducibility. We then trained the DCNN for two classifications: 1) complete/partial response versus progression of disease (POD), and 2) severe versus no immune-related adverse events (irAEs). Predictive accuracy was estimated by area under the curve (AUC) of receiver operating characteristics (ROC). Results: The DCNN identified tumor within LN with AUC 0.987 and within ST with AUC 0.943. Prediction of POD based on ST-only always performed better than prediction based on LN-only (AUC 0.84 compared to 0.61, respectively). The DCNN had an average AUC 0.69 when analyzing only tumor regions from both LN and ST data sets and AUC 0.68 when analyzing tumor and lymphocyte regions. Severe irAEs were predicted with limited accuracy (AUC 0.53). Conclusions: Our results support the potential application of machine learning on pre-treatment histologic slides to predict response to ICIs. It also revealed their limited value in predicting toxicity. We are currently investigating whether the predictive capability of the algorithm can be further improved by incorporating additional immunologic biomarkers.
Paratracheal lymph node metastasis in operable localized esophageal and gastroesophageal junction adenocarcinoma.
Authors: Kazuto Harada, Hyunsoo Hwang, Xuemei Wang, Ahmed Abdelhakeem, Masaaki Iwatsuki, Mariela A. Blum Murphy, Dipen M. Maru, Brian Weston, Jeffrey H Lee, Jane E. Rogers, Irene Thomas, Namita Shanbhag, Manoop S. Bhutani, Quynh Nguyen, Naruhiko Ikoma, Brian D. Badgwell, Wayne Lewis Hofstetter, Hideo Baba, Jaffer A. Ajani
Journal: Journal of Clinical Oncology (2019)

e15526 Background: Paratracheal lymph node (LN) is considered regional for esophageal cancer, but its metastatic rate and influence to survival remain unclear. We aimed to evaluate the frequency of paratracheal LN metastasis and its prognostic influence. Methods: 1199 patients with localized esophageal or gastroesophageal junction adenocarcinoma (EAC) (January 2002 and December 2016) in our Gastrointestinal Medical Oncology Database were analyzed. 1R, 1L, 2R, 2L, 4R, and 4L according to 8th AJCC classification were defined as paratracheal LN. Results: Of 1199 patients, 73 (6.1%) had positive parataracheal LN at diagnosis. The median overall survival (OS) in 73 patients with initial paratracheal LN involvement was 2.10 years (range, xx). Of 1071 patients who were eligible for recurrence evaluation, 70 patients (6.5%) developed positive paratracheal LN recurrences as first recurrence. The median time to recurrence was 1.28 years (range; 0.28-5.96 years) and the median OS after recurrence was 0.95 years (range; 0.03-7.89). OS in 35 patients who had only patatracheal LN recurrence was significantly longer than in patients who had with other distant recurrences (median 2.26 vs 0.51 years; p &lt; 0.0001). Higher T stage (T3/T4) was an independently risk factor for paratracheal LN recurrence (OR 5.10, 95% CI 1.46-17.89). We segregated patients in 3 groups based on the distance from esophagogastric junction to tumor proximal edge (lower; ≤2cm, middle; 2.0-7.0cm, higher; &gt; 7.0cm), positive paratrachal LN metastases were more frequent in the proximal tumors (lower 4.2%, middle 12.0%, higher 30.3%; Cochran-Armitage Trend test, p &lt; 0.001). Conclusions: Paratracheal LN metastases were associated with shorter survival in localized EAC patients. Careful investigation and surveillance for paratracheal LN are warranted.
Clinical responses and survival in Hispanic patients with non-small cell lung cancer treated with immunotherapy compared with non-Hispanic whites.
Authors: Luis E. Raez, Diana Saravia, Rossana Ruiz, Daniel Sumarriva, Teresita Munoz-Antonia, Brian Hunis, W. Douglas Cress, Luis Mas, Paola Izquierdo, Diego Kaen, Gilberto Lopes, Scott Joseph Antonia
Journal: Journal of Clinical Oncology (2019)

e18109 Background: The main immunotherapy (IMMUNO) trials that led to the approval of these agents for non-small cell lung cancer (NSCLC) accrued a minimum number of Hispanic (HISP) patients (pts) or, in some studies, no HISP pts at all. Additional data is thus needed to validate outcomes in HISP pts with NSCLC treated with IMMUNO. While it is known that genomic profiles and cancer survivals are different between HISP, Non-Hispanic Whites (NHW), and African-Americans; no study has yet looked at differences in IMMUNO outcomes between these populations. Methods: We present data in 436 NSCLC pts treated with IMMUNO at 5 large institutions (3 in the US, 2 in Latin America). The agents evaluated include: nivolumab, pembrolizumab and atezolizumab. 256 pts were HISP and 180 pts were NHW. Most of the pts were treated with single agent therapy as second line (or beyond) while a small group of pts were treated as first line. The primary endpoints of the study were: response rate (ORR), progression free survival (PFS) and overall survival (OS). Results: Among NHW pts, disease control rate (DCR) was 67% for Adenocarcinomas (Adeno) and 46% for squamous cell carcinomas (SQCC). In HISP pts there were no differences in DCR rates between both histologies: 68% for Adeno and 67% SQCC. There were no statistical significant differences among HISP and NHW pts regarding ORR, PFS, OS, and responses according to PD-L1 status. Conclusions: This is the largest publication and comparison of NSCLC immunotherapy outcomes in HISP vs NHW pts. No significant differences were found in the clinical outcomes between these 2 ethnic groups despite expected genomic differences. Pts with actionable mutations were excluded as they usually do not get IMMUNO as first or second line; an approach that might change after IMPOWER 150. These results are comparable to the ones seen in Checkmate and Keynote studies. As expected, higher response rates were seen in first line therapy and pts with PD-L1 (+) status. Further comparisons will be better addressed by a larger prospective study.[Table: see text]
Predictors of benefits to chemoimmunotherapy (CIT) in stage IV non-small-cell lung cancer (NSCLC): A meta-analysis.
Authors: Hazem Edmond El-Osta, Anita Lyn Sabichi
Journal: Journal of Clinical Oncology (2019)

e20595 Background: Immune checkpoint inhibitors (ICIs) have changed the landscape of NSCLC therapy. In previous study, gender, smoking history, and PD-L1 status were found to influence the efficacy of ICI monotherapy in NSCLC. This meta-analysis evaluated the clinical and molecular factors predictive of benefit from the addition of ICIs to first-line (1L) chemotherapy in metastatic NSCLC. Methods: Using the random effect model, we computed and compared the pooled hazard ratio (HR) of progression-free survival (PFS) and overall survival (OS) among the selected subgroups. The correlation between PD-L1 expression level and outcome was analyzed by meta-regression. Results: 7 phase III randomized trials comparing CIT vs. chemo in the 1L treatment of stage 4 NSCLC were included. CIT evenly improved the PFS irrespective of age, gender, histology, smoking history and ECOG performance status (PS). While patients (pts) with liver metastasis or ALK/EGFR aberration had greater PFS with the addition of ICI to Bevacizumab (BEV) based chemo regimen, the derived benefit was no longer statistically significant among pts treated with non-BEV-based regimens. Whereas the PFS superiority conferred by CIT was noticed across all PD-L1 expression subgroups, the benefit correlated with PD-L1 level and was more pronounced in the “PD-L1 high” subset. Except for pts with EGFR/ALK abnormalities, squamous histology or liver metastasis, CIT yielded a consistent amelioration of OS across the other selected subgroups. Conclusions: Survival advantage associated with 1L CIT in metastatic NSCLC was observed in different pts population including those for which single-agent ICI has limited therapeutic benefit. Our findings support the role of chemo +/- VEGF blockade as enhancer of ICIs activity even in “less immunogenic” context. [Table: see text]
Effect of SSH1/SSH2 expression changes by shRNA in glioma cell lines on response to radiotherapy and cofilin-1 reactivation.
Authors: Hong Xiao
Journal: Journal of Clinical Oncology (2019)

e13505 Background: Radiotherapy has become the most important treatment for malignant glioma following surgery. However, development of radioresistance in glioma cells limits therapeutic efficacy. The slingshot (SSH) family of phosphatases is a potent regulator of Cofilin-1 activation. Methods: We investigate the role of SSH1(slingshot protein phosphatase 1) and SSH2 in radioresistance via using shRNA to block SSH1/2 expression in U251 and U373 cells as well as established radioresistant U251 (RR-U251) and U373 (RR-U373) cells. Results: We found that both SSH1 and SSH2-shRNA efficiently sensitized glioma cells to radiation with a sensitization enhancement ratio (SER) of 1.01-1.73. In SSH1-silenced cells, the cell viability, migration, and invasion abilities following radiation were remarkably reduced and radiation induced cell apoptosis was markedly enhanced compared with control cells. While in SSH2-silenced cells, the alterations were not as significant. Furthermore, the result of Western-blot suggested that radiosensization of SSH1/SSH2 silencing was mediated by inhibiting reactivation of phosphorylated CFL-1. Conclusions: Our study demonstrated that SSH1 and SSH2 are valid radiosensitizing targets in not only normal glioma cells but radioresistant lines, suggesting a novel therapeutic strategy to improve the efficacy of radiotherapy in patients with glioma.
Patterns of distant metastases in patients with endometrial carcinoma: A SEER population-based analysis.
Authors: Jun Li, Li Sun, Yuzi Zhang, Shangli Cai
Journal: Journal of Clinical Oncology (2019)

e17109 Background: Endometrial carcinoma is the most common gynecology malignancies in the worldwide. The clinical outcome of endometrial carcinoma is excellent, with disease specific survival rate over 90% in early stages. However, the prognosis of metastatic endometrial carcinoma is poor and the pattern of distant metastases has not been well characterized. In the present study, we sought to assess the incidence and prognosis of different distant metastatic sites in endometrial carcinoma. Methods: Patients who were diagnosed with endometrial carcinoma between 2010 and 2015 were identified according to the following criteria in the Surveillance, Epidemiology, and End Results (SEER) database: (1) confirmed age and older than 18 years old; (2) enrolled patients should have confirmed distant visceral metastatic status information. Kaplan-Meier analysis and log-rank tests were used to estimate the overall survival (OS) between difference groups. Data were analyzed with GraphPad Prism (version 7.01, GraphPad Software, USA), and R (version 4.3.1, R Development Core Team). Results: A total of 73328 patients with endometrial carcinoma were included. Median age of diagnosis was 62 years and 80.3% of patients were white. 92.8% of patents have received surgery. 4.2% of patients (3053/73328) suffered at least one site of distant metastases. The most common metastasis site was lung (1331/73328, 1.82%), followed by distant lymph nodes (1191/72703, 1.6%), liver (661/73328, 0.9%), bone (475/73328, 0.65%) and brain (133/73328, 0.18%). Median OS was 15 months, 4 months, 7 months, 9 months and 8 months for pure distant lymph node, brain, bone, lung and liver metastases, respectively. Furthermore, metastatic sites showed significant impact on OS in univariate analysis. Multivariate analysis with COX proportional regression model showed that distant metastatic sites were independent prognostic factors of OS. Conclusions: Lung is the most common distant metastatic site of endometrial carcinoma. Patients with pure distant lymph node metastasis exhibited the best overall survival, while patients with brain metastases had worst clinical prognosis compared with other metastatic sites.
Indirect treatment comparison of the efficacy and safety of olaparib 300 mg tablets BID and talazoparib 1 mg once daily in the treatment of patients with germline BRCA-mutated (gBRCA) HER2-negative metastatic breast cancer.
Authors: Charles McCrea, Robert Hettle
Journal: Journal of Clinical Oncology (2019)

e12570 Background: PARP inhibitor treatment with olaparib or talazoparib has been shown to improve progression-free survival (PFS) versus chemotherapy treatment of physician’s choice in patients with germline BRCA-mutated (gBRCA) HER2-negative metastatic breast cancer. In the absence of head-to-head evidence, an indirect treatment comparison (ITC) analysis was performed to simulate the comparative efficacy and safety of alternative PARP treatment in this setting. Methods: Bayesian fixed effects ITCs of data published for OlympiAD (NCT02000622) and EMBRACA (NCT01945775) was conducted using the gemtc package in R. Efficacy analyses were performed on the primary endpoint of PFS by blinded independent central review. Safety analyses included the odds ratio (OR) of adverse event (AE)-related discontinuations, and common AEs of any grade reported in each study. All analyses compared olaparib with talazoparib. Results: Efficacy analyses show no significant difference in PFS across treatments (PFS hazard ratio of 1.09, 95% credible interval [0.72; 1.65]). Safety analyses predict differences in AEs across PARP treatment, including hematological events, alopecia, nausea and vomiting (Table). No difference in AE-related discontinuations was observed (0.93 [0.25–3.42]). Conclusions: Results of the ITC suggest that olaparib and talazoparib are equally efficacious on PFS, and differ in AE risk profile, with olaparib predicted to have fewer common hematological and alopecia events, but an increased risk of nausea and vomiting versus talazoparib. Observed differences require confirmation in comparative studies. Limitations of the analysis include heterogeneity in study design, reporting of AEs, and mix of chemotherapies used in the control arm of the studies. [Table: see text]
Lipoprotein‐associated phospholipase A2: The story continues
Authors: Fubao Huang, Kai Wang, Jianhua Shen
Journal: Medicinal Research Reviews (2019)

Inflammation is thought to play an important role in the pathogenesis of vascular diseases. Lipoprotein-associated phospholipase A2 (Lp-PLA2) mediates vascular inflammation through the regulation of lipid metabolism in blood, thus, it has been extensively investigated to identify its role in vascular inflammation-related diseases, mainly atherosclerosis. Although darapladib, the most advanced Lp-PLA2 inhibitor, failed to meet the primary endpoints of two large phase III trials in atherosclerosis patients cotreated with standard medical care, the research on Lp-PLA2 has not been terminated. Novel pathogenic, epidemiologic, genetic, and crystallographic studies regarding Lp-PLA2 have been reported recently, while novel inhibitors were identified through a fragment-based lead discovery strategy. More strikingly, recent clinical and preclinical studies revealed that Lp-PLA2 inhibition showed promising therapeutic effects in diabetic macular edema and Alzheimer's disease. In this review, we not only summarized the knowledge of Lp-PLA2 established in the past decades but also emphasized new findings in recent years. We hope this review could be valuable for helping researchers acquire a much deeper insight into the nature of Lp-PLA2, identify more potent and selective Lp-PLA2 inhibitors, and discover the potential indications of Lp-PLA2 inhibitors.
Exploratory analysis of the effect of maintenance rucaparib on postprogression outcomes in patients (pts) with platinum-sensitive recurrent ovarian carcinoma (OC) and updated safety data from the phase 3 study ARIEL3.
Authors: Robert L. Coleman, Amit M. Oza, Domenica Lorusso, Carol Aghajanian, Ana Oaknin, Andrew Peter Dean, Nicoletta Colombo, Johanne I Weberpals, Andrew R. Clamp, Giovanni Scambia, Alexandra Leary, Robert W. Holloway, Margarita Amenedo, Peter C.C. Fong, Jeffrey C. Goh, David M. O'Malley, Teresa Cameron, Lara Maloney, Sandra Goble, Jonathan A. Ledermann
Journal: Journal of Clinical Oncology (2019)

5522 Background: In ARIEL3, rucaparib maintenance treatment significantly improved progression-free survival (PFS) vs placebo in all predefined, nested cohorts: BRCA mutation; BRCA mutation + wild-type BRCA/high loss of heterozygosity (LOH); and intent-to-treat (ITT) population. Methods: Pts were randomized 2:1 to receive oral rucaparib 600 mg BID or placebo. Exploratory endpoints of time to first subsequent therapy (TFST), time to investigator-assessed PFS on the subsequent line of treatment or death (PFS2), and time to second subsequent therapy (TSST) were assessed in the predefined cohorts. Results: Exploratory efficacy endpoint data are given in the Table. As of Dec 31, 2017, the most common treatment-emergent adverse events (TEAEs) of any grade (rucaparib vs placebo) were nausea (75.8% vs 36.5%), asthenia/fatigue (70.7% vs 44.4%), dysgeusia (39.8% vs 6.9%), and anemia/decreased hemoglobin (39.0% vs 5.3%). The most common grade ≥3 TEAEs were anemia/decreased hemoglobin (21.5% vs 0.5%) and alanine/aspartate aminotransferase increase (10.2% vs 0.0%). Conclusions: Rucaparib significantly improved the clinically meaningful endpoints TFST, PFS2, and TSST vs placebo in all predefined cohorts of pts with platinum-sensitive, recurrent OC. The updated safety profile was consistent with prior reports. Clinical trial information: NCT01968213. [Table: see text]
Screening for cancer-related distress among women with newly diagnosed breast cancer (BC).
Authors: Lauren Z. Rynar, Kristen B. Wendell, Patricia B. Mumby, Kathy S. Albain, Patricia A. Robinson, Hanh P. Mai, Cathy Grace-Louthen, Shelly S. Lo
Journal: Journal of Clinical Oncology (2019)

567 Background: The Loyola University Chicago Cardinal Bernardin Cancer Center multidisciplinary Breast Oncology Center evaluates new patients (pts) for cancer-related distress using a needs-based screening tool, in accordance with Commission on Cancer (CoC) Standard 3.2. Identifying distress among newly diagnosed pre-surgical and pre-neoadjuvant pts allows for comprehensive treatment planning and establishment of a baseline for repeated assessments. Methods: Pts with newly diagnosed BC between May 2017 and June 2018 completed the “Patient Screening Questions for Supportive Care” (Coleman Supportive Oncology Collaborative, 2017), a consolidated screening tool based on validated instruments (NCCN Distress, PHQ-4, PROMIS), prior to initial provider visit. Cancer staging, demographics, and supportive oncology referrals were obtained from medical records. Descriptive statistics and chi-square were used. Results: 100 pts aged 30-94 (mean(SD) = 61.56(12.03)) completed the screening tool; 14.9% had Stage 0, 43.6% Stage I, 34.0% Stage II, 3.2% Stage III, and 4.3% Stage IV disease. 39% of pts screened positive for anxiety on the PHQ-4, and over 20% for depression. Anxiety was associated with cancer stage ( X 2 (df) = 12.20(4), p = .016). The most common practical concerns included living alone (19%), issues with work/school (16%), and paying for medical care (12%). Common physical concerns included difficulty with sleep (40%) and concentration/memory (17%), and tingling hands or feet (14%). Poor sleep was associated with depression ( X 2 (df) = 6.50(1), p = .011) and anxiety ( X 2 (df) = 7.17(1), p &lt; .01). 57.7% reported at least "a little bit" of fatigue and 17.7% reported moderate to very severe pain. Nearly all pts wanted to better understand their diagnosis (87.8%), prognosis (87.8%), or treatment (91.8%). Conclusions: Pts with newly diagnosed, early stage BC experience high levels of physical and emotional distress at the earliest point in the treatment trajectory. This study captures BC patients at a unique time point and provides support for conducting routine screening for supportive oncology needs at initiation of care. Further studies should reassess needs sequentially to determine changes across the care continuum.
Organ site-specific radiological responses in anti-PD-1 monotherapy treated advanced melanoma patients.
Authors: Xue Bai, Michelle S. Kim, Gyulnara Kasumova, Justine Vanessa Cohen, Donald P. Lawrence, Christine Freedman, Riley Fadden, Krista M. Rubin, Tatyana Sharova, Dennie T. Frederick, Keith Flaherty, Ryan J. Sullivan, Genevieve Marie Boland
Journal: Journal of Clinical Oncology (2019)

9552 Background: Melanoma is notorious for its high degree of heterogeneity with the implication that metastases in different sites react differently to immunotherapy. We aimed to explore the site-specific response pattern in anti-PD-1 monotherapy treated advanced melanoma patients. Methods: Clinical data was collected retrospectively from advanced melanoma patients treated with anti-PD-1 monotherapy at Massachusetts General Hospital (MGH) from Sept 2009 to Dec 2017. Radiological evaluations were carried out by radiologists from the MGH Tumor Imaging Metrics Core using irRECIST 1.1. Statistical analysis was carried out using ANOVA test. Results: Among 61 evaluated patients, 56 (91.8%) had at least one measurable target lesion(s) at baseline, including 35 (57.4%) patients with measurable lymph nodes (LN)/subcutaneous lesion(s), 25 (50.0%) with lung lesion(s), and 21 (34.4%) with liver lesion(s). At week-12 radiological evaluation after anti-PD-1 monotherapy initiation, lesions at different sites responded differently at marginal statistical significance (P = 0.071), namely mean percent changes compared with baseline were 3.75%, 5.12%, and -30.95% for LN/subcutaneous, liver, and lung lesions, respectively. Among patients who had disease under control (CR/PR/SD) (n = 37, 60.7%) by week-12 evaluation, the mean tumor percentage change at week-24 compared with week-12 were -8.94%, -12.18%, and -5.91% for LN/subcutaneous, liver, and lung lesions, respectively (P = 0.479). Conclusions: Although our small sample size limits definitive discrimination in organ site-specific response differences, it appears that lung lesions respond more quickly and to a greater extent compared with LN/subcutaneous and liver lesions in advanced melanoma patients treated with anti-PD-1 monotherapy. We will explore this in a larger, multicenter cohort.