tbuckley/cabot-search huggingface dataset:
When is a patient high risk for resection? A changing paradigm with minimally invasive lung surgery.
Authors: Hiroko Nakahama, Kostantinos Poulikidis, James Lubawski, Wickii T. Vigneswaran
Journal: Journal of Clinical Oncology (2019)

e20059 Background: The predicted post-operative forced expiratory volume after 1 second (FEV1) and the diffusing capacity of the lung for carbon monoxide (DLCO) are predictors of postoperative complications and survival. Despite the benefits of minimally invasive surgery in patients with marginal lung function current practice guidelines advocates non-surgical approach for treatment from evidence derived from patients undergoing thoracotomy. It is necessary to define what should be minimum acceptable lung function for resection in the era of minimally invasive surgery. Methods: Single institution retrospective study of 61 patients with pre-operative predicted FEV1 and DLCO &lt; 60% that underwent lung resection for pulmonary lung nodules suspected to be malignant between January 2017 to June 2018. Patient demographic and clinical data were collected and the 30-day or in-hospital morbidity and mortality were assessed. Results: 28 (46%) patients with pre-operative predicted FEV1 &lt; 60% and 33 (54%) with DLCO &lt; 60% were reviewed. 10 patients had both FEV1 and DLCO &lt; 60%. There were 12 patients (28% in FEV1, 12% in DLCO group) who had &lt; 40% of pre-operative predicted values. 15 (65%) of FEV1 group and 15 (45%) of DLCO group had anatomic lung resections with either a lobectomy or a segmentectomy. 24 (39%) of cases were done robotically and the remaining with VATS. 80% of patients had cancer in their final pathology. Patients were 68± 7 years old, 34 (56%) were male. Significant baseline clinical findings include high incidence of smoking (82% in FEV1, 97% in DLCO group), HTN (71% in FEV1, 81% in DLCO group), COPD (61% in FEV1, 48% in DLCO group), CAD (25% in FEV1, 30% in DLCO group), and a total of 2 patients suffered previous CVD. Most common complications included persistent air leak &gt; 5 days (21% in FEV1 and DLCO group) and arrhythmia (14% in FEV1, 15% in DLCO group). Of those with an air leak, 50% in the FEV1 group and 29% in the DLCO group had predicted values &lt; 40%. Three patients developed pneumothorax post chest tube removal necessitating chest tube replacement, all of whom had predicted values &lt; 40%. One patient developed acute DVT and PE and another patient required mechanical ventilation for &gt; 48 hours. There were no 30-day mortalities. Conclusions: Lung resection using minimally invasive technique had low rates of 30-day morbidity in patients with reduced pulmonary function. Majority of complications observed were minor. Minimally invasive lung resection is possible and may be extended to selected patients with pre-operative predicted DLCO or FEV1 &lt; 40% suspected of malignancy.
Automated breast cancer lesion detection on breast MRI using artificial intelligence.
Authors: Nataly Tapia Negrete, Ruquaiyah Takhtawala, Madeleine Shaver, Turkay Kart, Yang Zhang, Min Jung Kim, Vivian Youngjean Park, Min-Ying Su, Daniel S. Chow, Peter Chang
Journal: Journal of Clinical Oncology (2019)

e14612 Background: Over 40,000 women in the US will die from breast cancer. Early detection of cancer is crucial and is a potential avenue to improve survival. The objective of this research study is to develop a convoluted neural network (CNN), a subset of artificial intelligence, in order to enhance computerized detection of breast lesions on MRIs. Methods: This is an institutional review board approved retrospective study with post contrast MRI data from 238 patients. Breast tumor segmentation was automated with a hybrid 3D/2D CNN designed adapted from U-net, a popular neural network architecture in biomedical image analysis. T1 post-contrast MRI volumes were used to train the network. The data set was separated into training (80%) and validation (20%) sets. Re-sampling and normalization using z-scores were applied to each volume before training. Contracting and expanding arms of the model consist of successive convolutions followed by batch normalization and ReLU operations. Ground truth was established through manual segmentation and previously conducted readings of the images used to train our network. Results: A 5-fold cross validation was performed for analysis. The Dice similarity coefficient was used to assess segmentation accuracy. The hybrid 3D/2D U-Net architecture yielded a Dice score of 0.753 and a Pearson correlation of 0.548 for the breast tumor segmentation. Conclusions: These results demonstrated the feasibility for artificial intelligence applications in accurately identifying the presence of lesions on breast MRI images.
Pembrolizumab in previously treated metastatic esophageal cancer: Longer term follow-up from the phase 2 KEYNOTE-180 Study.
Authors: Ken Kato, Takashi Kojima, Daniel Hochhauser, Jaafar Bennouna, Antoine Hollebecque, Florian Lordick, Sung-Bae Kim, Masahiro Tajika, Heung Tae Kim, Haeseong Park, Nabil F. Saba, Susan Urba, Anjali Desai, Qi Liu, Sandra Cruz, Manish A. Shah
Journal: Journal of Clinical Oncology (2019)

4032 Background: In the phase 2, open-label, KEYNOTE-180 (NCT02559687) study, after a median follow-up of 5.8 months, pembrolizumab (pembro) provided antitumor activity with durable responses in pts with previously treated, advanced/metastatic adenocarcinoma (EAC) including Siewert type 1 adenocarcinoma of the gastroesophageal junction or squamous cell carcinoma (ESCC) of the esophagus. Here we present results of an additional 10 months of follow-up. Methods: Eligible pts with metastatic esophageal cancer, ≥2 prior lines of therapy, and tumor samples evaluable for biomarker expression, received pembro 200 mg Q3W for up to 2 years, or until disease progression, unacceptable toxicity, or withdrawal. Tumor response was assessed Q9W (RECISTv1.1, central review). PD-L1+ pts had combined positive score ≥10 using IHC (22C3 antibody). Primary endpoint was objective response rate (ORR). Secondary endpoints included safety, DOR, PFS, and OS. Results: Of 121 pts enrolled, 63 (52%) had ESCC and 58 (48%) had PD-L1+ (combined positive score ≥10) tumors. As of July 30, 2018, median follow-up duration, from randomization to data cutoff, was 5.8 mo (range, 0.2 mo to 27.8+ mo). ORR (CR+PR) was 10% (95% CI, 5%-17%); 2 (2%) CR,10 (8%) PR, 25 (21%) SD. Median DOR was not reached ([NR] range, 2.1 mo to 25.1+ mo). Median PFS was 2 mo (95% CI, 1.9%-2.1%) with 9-mo PFS rate of 9%. Median OS was 5.8 mo (4.5-7.2) with 12 mo OS rate of 27%. In ESCC, ORR was 14% (95% CI, 7%-25%); 2 (3%) CR, 7 (11%) PR, with median DOR NR (range, 4.2 mo to 25.1+ mo). In EAC, ORR was 5% (95% CI, 1-14); 3 PR, with median DOR NR (range, 2.1 mo to 15.6+ mo). In PD-L1+ pts, ORR was 14% (95% CI, 6%-25%); 1 (2%) CR, 7 (12%) PR with median DOR NR (range, 4.2 mo to 25.1+ mo). In PD-L1- pts ORR was 6% (95% CI, 2%-16%); 1 (2%) CR, 3 (5%) PR; median DOR NR (range, 2.1 mo to 17.3+ mo). Overall, 19 (16%) pts had treatment-related grade 3-5 AEs. Seven (6%) pts discontinued due to a treatment-related AE. There was one treatment-related death from pneumonitis. Conclusions: Pembro continued to provide durable clinical benefit with a manageable safety profile for pts with heavily pretreated esophageal cancer, with conversions of PR to CR observed. Clinical trial information: NCT02559687.
A pilot safety study of gemcitabine and cisplatin (GC) with atezolizumab (A) as first-line therapy in patients (pts) with metastatic urothelial cancer (mUC).
Authors: Samuel Aaron Funt, Karan Jatwani, Michelle Makris, Ashley Marie Regazzi, Chung-Han Lee, Min Yuen Teo, Deaglan Joseph McHugh, Asia S. McCoy, Grace Hettich, Phillip Wong, Moshen Abu-Akeel, Jedd D. Wolchok, Taha Merghoub, Hikmat Al-Ahmadie, Irina Ostrovnaya, Joshua Chaim, Jeremy C. Durack, Gopa Iyer, Dean F. Bajorin, Jonathan E. Rosenberg
Journal: Journal of Clinical Oncology (2019)

4559 Background: GC has a high overall response rate (ORR) but a high relapse rate in pts with untreated mUC. Inhibition of programmed death-ligand 1 (PD-L1) with A can lead to long-term survival, but single-agent ORR is modest. We report the outcomes of GC+A in a cohort pts with mUC. Methods: This study was designed to assess the safety of GC + A in 10 pts with untreated mUC prior to testing GC + A in a neoadjuvant study in pts with muscle-invasive disease. The primary endpoint was safety as assessed by a predefined dose limiting toxicity (DLT) rate during the first cycle in the first 6 pts. Total accrual goal was 10 pts to collect preliminary data on ORR and progression-free survival (PFS). RECIST 1.1 assessments were performed every 9 wks. Pts received 6 cycles of GC + A induction and then A maintenance every 3 wks. Results: No DLTs occurred during the first cycle in the first 6 pts. Grades 3-4 neutropenia and anemia occurred in 6/10 and 7/10 pts, respectively. Three pts required gemcitabine dose reductions for hematologic toxicity and 2 pts had febrile neutropenia. One pt discontinued cisplatin after 2 cycles for grade 3 hearing impairment but completed induction with gemcitabine and A. Only 1 pt discontinued study therapy due to treatment-related adverse events (AEs), including A-related grade 4 encephalopathy and grade 3 polyneuropathy. Three of 10 pts had visceral (liver or bone) metastases. Of the 10 pts, 1 pt is completing induction but meets initial criteria for partial response (PR), 8 pts had confirmed PR, and 1 pt had progressive disease (PD). Of 9 pts with confirmatory scans, the median PFS was 10.6 months (95% CI 6.7, N/A). Of 8 pts with confirmed PR, 5 eventually had PD, 1 has just completed induction, 1 remains without PD at 25 months, and 1 had consolidation surgery with a pathologic complete response and remains disease-free at 21 months. Conclusions: This 10 pt study met its primary safety endpoint. The neoadjuvant study is ongoing (NCT02989584). Although there were a substantial number of grade 3-4 toxicities, therapy was discontinued due to treatment-related AEs in only 1 pt. Immune correlative studies are ongoing. Clinical trial information: NCT02989584.
Precision medicine for lung cancer decision-making: Evaluation of an -omics based FFT approach to personalized medicine.
Authors: Isa Mambetsariev, Benjamin Djulbegovic, Rebecca Pharaon, Blake Hewelt, Erminia Massarelli, Marianna Koczywas, Karen L. Reckamp, Ravi Salgia
Journal: Journal of Clinical Oncology (2019)

e20713 Background: The prevalence of next-generation sequencing and the availability of a large number of targeted therapies in the clinics, has complicated treatment decision-making in lung cancer. While national guidelines and commercial pathways offer a method to improve the oncologists’ adherence to appropriate testing and treatment modalities available, more effort is required to solidify this as a standard of care model at academic and community sites. A better understanding of the improved durable survival of targeted therapy assignment compared with non-targeted therapy outside of the clinical trial setting is needed to understand the efficacy and accuracy of precision medicine. Methods: We perform an in-depth analysis of a series of lung AD patients (n = 798) with genomic and clinical data in a recently created thoracic patient registry, who were treated at COH between 2009-2018 period. Results: 798 individuals with lung AD were identified in the Thoracic Oncology Registry who were treated or were intended to be treated at COH; 662 (83%) of the patients had genomic testing performed at the request of their treating oncologist and 460 (58%) of whom received a 1st-line targeted therapy decision (including clinical trial assignment based on bio-marker). Oncogenic alterations were detected in 653 (82%) patients with the majority presenting with EGFR (47%), who were mostly treated with erlotinib (78%). 462/653 (70%) patients had an alteration detected with an available FDA approved therapy and 90% (416/462) of the patients were appropriately matched to a targeted therapy based on the oncologist’s decision. Several decision-making algorithms were tested and fast-and-frugal trees (FFTs) proved superior with a positive predictive value (PPV) of 90% and only required two important cues in informing the decision of the type of treatment to give to the patient. Furthermore, a targeted therapy treatment decision showed a significant benefit with a median OS of 38 months as compared to 22 months in the non-targeted therapy decision-making group (p &lt; 0.00001). This was also evident in the PFS analysis where targeted therapy decision-making had a median survival of 9 months as compared with 5 months in the other groups (p &lt; 0.00001). Conclusions: FFTs are a novel tool to test the efficacy of precision medicine in a real-world setting and can provide a more streamlined method for clinical guidance and decision-making. FFTs were able to predict with 90% PPV a precision medicine decision that was correlated with improved PFS (9 vs 5 months) and OS (38 vs 22 months).
A Maximum Dose for Methylphenidate—How Much Is Too Much?
Authors: Douglas Russell, Margaret Weiss, Mark A. Stein
Journal: JAMA Pediatrics (2019)

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Combining denosumab (D) and trastuzumab (T) as a novel treatment strategy in HER2-positive (+) breast carcinomas (BC).
Authors: Michalis Karamouzis, Ilianna Zoi, Evangelia Xingi, Dimitra Thomaidou, Athanasios G. Papavassiliou
Journal: Journal of Clinical Oncology (2019)

e12506 Background: HER-2 is overexpressed in 20–30% of BC, indicating poor prognosis. RANKL/RANK pathway is implicated in HER-2(+) BC. The molecular mechanism and the potential of dual targeting have been evaluated and showed promising results. Methods: We used SKBR3, BT474, MCF7, MDA-MB-453 human BC cell lines. We examined the expression of RANK and RANKL using RT-PCR, Western-Blot and immunofluorescence. The interaction between RANK and HER-2 was detected using Proximity Ligation Assay (PLA) which enables the visualization of interacting proteins. NF-κB pathway activation was studied using Western-Blot. We used inhibitors of both pathways. Cell viability and cell migration was evaluated using XTT and scratch assay, respectively. Results: Cell lines differentially express RANK and RANKL. RANK receptor dimerizes with HER-2. RANK/ HER-2 dimer number depends on HER-2 expression (SKBR3: 5.4, BT474: 8.2, MCF7: 0.7, MDA-MB-453: 0.3). RANK/HER-2 dimers are decreased in the presence of the inhibitors D and T, while they are increased after RANKL (R) treatment in SKBR3 (m:5.4, D:1.2, T:1.9, DT:0.6, R:11.8,) and BT474 (m:8.2, D:3.1, T:4.3, DT:0.7, R:11.6). MCF7 and MDA-MB-453 do not correspond to inhibitors. The combination treatment of SKBR3 with the inhibitors further decreased NF-κB pathway activation compared to single targeting. SKBR3, after inhibitors treatment, also exhibit reduced cell proliferation (m:100%, D:84.7%, T:51.57%, DT:48.61%, R:111%) and lower metastatic potential (m:26.02%, D:33.56%, T:16.54%, DT:13.75%, R:32.36%) compared to mock cells (m) and increased values in RANKL presence. The combination treatment of SKBR3 with D and T has an advantage in functional proliferation assays compared to single targeting. Conclusions: The results indicate a direct association between HER-2 and RANKL/RANK pathway in HER-2(+) BC growth. We also present data suggesting that the combination of trastuzumab and denosumab may have therapeutic benefit in certain BC patients.
Analytical and clinical validation of a novel amplicon-based NGS assay for evaluation of circulating tumor DNA in metastatic colorectal cancer patients.
Authors: Beili Wang, Shengchao Wu, Fei Huang, Minna Shen, Huiqin Jiang, Yiyi Yu, Qian Yu, Yihui Yang, Ying Zhao, Yiwen Zhou, Baishen Pan, Tianshu Liu, Wei Guo
Journal: Journal of Clinical Oncology (2019)

e15084 Background: Evaluating the tumor RAS/BRAF status is important for treatment selection and prognosis assessment in metastatic colorectal cancer (mCRC) patients. Correction of artifacts from library preparation and sequencing is essential for accurately analyzing circulating tumor DNA (ctDNA) mutations. Here, we assessed the analytical and clinical performance of a novel amplicon-based next-generation sequencing (NGS) assay, Firefly, which employs a concatemer-based error correction strategy. Methods: Firefly assay targeting KRAS/NRAS/BRAF/PIK3CA was evaluated using cfDNA reference standards and cfDNA samples from 184 mCRC patients. Plasma results were compared to the mutation status determined by ARMS-based PCR from matched tissue. For samples with mutation abundance below the limit of detection (LOD), were retested again by droplet digital polymerase chain reaction (ddPCR) or NGS. Results: Firefly assay demonstrated superior sensitivity and specificity with 98.89% detection rate at allele frequency of 0.2% for 20ng cfDNA. Generally, 40.76% and 48.37% of the patients were reported to be positive by NGS of plasma cfDNA and ARMS of FFPE tissue, respectively. The concordance rate between the two platforms was 80.11%. In pre-treatment cohort, the concordance rate between plasma and tissue was 93.33%, based on the 17 common exons that Firefly and ARMS genotyped, positive percent agreement (PPA), and negative percent agreement (NPA) for KRAS/NRAS/BRAF/PIK3CA was 100% and 99.60%, respectively. Conclusions: Total plasma cfDNA detected by Firefly offers a viable complement for mutation profiling in CRC patients, given highly agreement with matched tumor samples. Together, these data demonstrate that Firefly could be routinely applied for clinical applications in mCRC patients.
Prognostic factors for severe diarrhea in patients with locally advanced rectal carcinoma treated with neoadjuvant chemoradiation with capecitabine: A single-center cohort study.
Authors: Wesley Hartman, Esther Oomen De Hoop, Cornelis Verhoef, Joost Nuyttens, Esther van Meerten
Journal: Journal of Clinical Oncology (2019)

e15176 Background: Chemoradiation with concomitant capecitabine (CRT) followed by total mesorectal excision is the standard of care for locally advanced rectal carcinoma (LARC). Grade ≥ 3 diarrhea is considered a dose-limiting toxicity of adding capecitabine to radiotherapy. The aim of this study is to describe the risk factors of grade ≥ 3 diarrhea in patients with LARC during CRT. Methods: A single centre retrospective cohort study was conducted in our tertiary center. All patients with LARC treated with CRT from 2009 to 2015 were included. Patients with local recurrence who received CRT for the first time were also included. Univariate logistic regression analyses were used, followed by a multivariate analysis of the significant factors with backward selection at p &lt; 0.05. Results: A total of 738 patients were included: 67% male, median age 64 years (range 17-88), 95% primary presentation. DPYD-testing was not performed upfront. In this cohort 69 patients (9%) developed ≥3 grade diarrhea. In the univariate analysis, factors significantly associated with ≥3 grade diarrhea were; female gender, age ≥65 years, body weight and decreased renal function (defined as MDRD GFR &lt; 60 ml/min/1,73 m2). The following factors remained significantly associated with ≥3 grade diarrhea in the multivariate analysis; female gender (odds ratio (OR) 2.77, 95% confidence interval (CI) 1.54-4.99, p 0.001), age ≥65 years (OR 2.85, 95% CI 1.63-4.98, p &lt; 0.001) and a lower bodyweight (OR 0.98, 95% CI 0.96-1.00, p 0.015). Conclusions: Female gender and age ≥65 years significantly increase the risk of grade ≥ 3 diarrhea caused by neoadjuvant CRT for LARC. So, older female patient must be closely watched during this treatment to intervene on time. The difference in toxicity between females and males might be explained by the pelvic anatomical differences between men and women. The found prognostic factors will be validated in a second cohort of patients with LARC treated with CRT. Besides, sarcopenia will be tested as a prognostic factor as well.
Profiling of 3,634 cholangiocarcinomas (CCA) to identify genomic alterations (GA), tumor mutational burden (TMB), and genomic loss of heterozygosity (gLOH).
Authors: Milind M. Javle, Karthikeyan Murugesan, Rachna T. Shroff, Mitesh J. Borad, Reham Abdel-Wahab, Alexa Betzig Schrock, Jon Chung, Lipika Goyal, Garrett M. Frampton, Robin Kate Kelley, Vincent A. Miller, Jeffrey S. Ross, Tanios S. Bekaii-Saab, Siraj Mahamed Ali, Lee A. Albacker
Journal: Journal of Clinical Oncology (2019)

4087 Background: The management of CCA has evolved as targeted and immune checkpoint inhibitor (ICPI) therapies have emerged. We used comprehensive genomic profiling (CGP) to characterize the genomic alterations (GA) that have potential to personalize therapy for CCA. Methods: 3634 CCA underwent hybrid capture based CGP on 0.8-1.1 Mb of the coding genome to identify GAs in exons and select introns in up to 404 genes, TMB, microsatellite status (MSI) and % monoallelic genome (gLOH). PD-L1 expression was determined by IHC (Dako 22C3). Results: 52% of CCA were female with a median age of 62 years (range 16 - &gt; 89). The most common biopsy sites were liver (74%), lymph node (4%), bile duct (3.3%), and lung (2%). MSI-high was rare (1%), 118 and 47 cases had TMB &gt; 10 and &gt; 20 mut/mb respectively. Of the latter, 51% (24/47) were MSI-H. PD-L1 amplification (AMP) was present in 0.27%. Of 490 CCA tested, 43 (9%) were positive for PD-L1 expression. 11% of cases had gLOH &gt; 16%, only 2 cases had both TMB &gt; 20 and gLOH &gt; 16%. GA were most common in TP53 (31%), CDKN2A (29%), KRAS (20%) and ARID1A (17%). Potentially targetable GAs included FGFR2 (11%, 85% fusions), BRAF (5%, 50% V600E), ERBB2 (5%, 72% AMP), MET (2%, 90% AMP), EGFR (0.52%) and rarer ( &lt; 0.5%) FGFR3, RET, FGFR1, ALK, and ROS1 fusions. The FGFR2 fusions had 128 unique 3’ partner genes including BICC1 (26%), CCDC6 (3.2%), AHCYL1 (2.6%) and KIAA1217 (2.6%). FGFR2 fusions occurred in a mutually exclusive fashion from high gLOH (p &lt; 0.002), but not high TMB. GA in IDH1 (15%) were mutually exclusive of FGFR2 fusions (p &lt; 1e-13), but co-occurred with PBRM1 GA (23%, p &lt; 1e-21), ARID1A (26% p &lt; 1e-10). IDH1 GA had gLOH similar to the overall CCA population but were enriched for low TMB (p &lt; 1e-3). Conclusions: Nearly 20% of CCA cases harbor targetable kinase GA, half of which were FGFR2 fusions. Independently, an additional 10% (gLOH) and 1% (high TMB, MSI and/or PD-L1 AMP) may benefit from PARP inhibitors and ICPI respectively. Independently, co-mutation of IDH1 and PBRM1/ARID1A defines a class of CCA that warrants further investigation for sensitivity to PARP inhibitors and may serve as a paradigm for other tumors (ie. gliomas) with a similar co-occurrence landscape.