tbuckley/cabot-search huggingface dataset:
COX-2 expression and mesenchymal-transition status on circulating tumor cells to predict survival in patients with nasopharyngeal carcinoma: A prospective analysis.
Authors: Yongjiang Li, Xiaoqi Xie, Hong Zhang, Chen Lv, Dongyan Miao, Zhigui Guo, Yumei Zhang, Changhu Li, Wei Ge, Feng Wang
Journal: Journal of Clinical Oncology (2019)

6042 Background: The prognostic significance of circulating tumor cells (CTCs) in head and neck cancer is still under active investigation. It remains unclear whether just CTC count alone is sufficient to predict outcomes or whether the functional status of the CTCs is also needed. We investigated the clinical significance of determining epithelial-to-mesenchymal transition status and geno-/pheno-typic biomarkers of aggressiveness of CTCs in predicting outcomes in nasopharyngeal carcinoma (NPC). Methods: The prospective study enrolled 131 patients with NPC. CTCs were isolated at baseline and at the end of concurrent chemoradiotherapy using the CanPatrol system. Subsequently, the epithelial-mesenchymal transition (EMT) biomarkers and cyclooxygenase-2 (COX-2) expression status of the CTCs were identified by RNA-in situ hybridization (ISH) method. Results: COX-2 expression was found in 87/131 (66.4%) patients at baseline and 53/115 (46.1%) patients post-treatment. Independent of initial COX-2 expression status, the patients with post-treatment COX-2 expression on CTCs had significantly poorer treatment response (P = 0.011), and higher risk of tumor relapse (P = 0.026) and metastasis (P = 0.007). Similarly, post-treatment mesenchymal transition was also associated with higher risk of tumor relapse and metastasis. In multivariate analysis, post-treatment COX-2 expression on CTCs remained an independent prognostic indicator of poorer overall survival (HR 2.41, 95% CI 1.12-5.19; P = 0.024). Post-treatment COX-2 expression and mesenchymal transition in CTCs was the strongest prognostic indicator of overall survival on multivariate analysis (HR 2.73, 95% CI 1.28-5.83; P = 0.009). Conclusions: Post-treatment COX-2 expression on CTCs, especially on the mesenchymal subtype, is a novel and promising prognostic indicator for NPC patients treated with chemoradiation therapy. Future studies are needed to validate our findings and further clarify the value of integrating the indicators with current clinical strategies in improving survival of NPC patients.
A pharmacogenetic analysis of peripheral sensory neuropathy related to administration of taxanes in breast cancer patients.
Authors: Alyson Leonard, Vinay K. Gudena
Journal: Journal of Clinical Oncology (2019)

e13133 Background: Commonly used in the treatment of breast cancer, the taxane class includes paclitaxel and docetaxel. Both medications are primarily metabolized by cytochrome P450 enzymes and transporters mediate drug membrane influx and efflux. Variability in metabolizing enzymes and drug transporter function can affect drug clearance. This study sought to determine if the presence of pharmacogenetic changes in metabolizing enzymes and transporters resulted in a patient experiencing peripheral sensory neuropathy. Methods: In this case-control study, patients were enrolled between April 13, 2018 and April 30, 2018. Electronic medical records of patients with current appointments at Cone Health Cancer Center- Wesley Long were reviewed to identify patients who completed treatment with taxanes for breast cancer after January 1, 2017 for evaluation for inclusion in the study. Buccal swabs for pharmacogenetics testing were collected. Genes of interest, ABCB1, CYP3A4, CYP3A5, and SLCO1B1, were evaluated and data was categorized by phenotype. Baseline characteristics and phenotype results were compared using Fisher's exact test for categorical variables and Wilcoxon Rank Sum for numeric variables as appropriate. Results: Thirty-three patients were included in the final analysis. The population was mainly white at 72% and all patients in the study were female. The average patient age was 57 years old. Most patients had stage 1 breast cancer. Most patients received docetaxel. Among patients with peripheral sensory neuropathy, nine were grade 1, five were grade 2, and seven were grade 3. Resulting phenotypes: CYP3A5, all patients were normal metabolizers. CYP3A5, 7 normal metabolizer, 4 intermediate, and 22 poor. SLCO1B1, 25 normal function, 8 intermediate, and no low. ABCB1, 13 normal function, 7 intermediate, and 13 low. For all genes, there was no statistically significant difference in phenotype between the neuropathy and no neuropathy study arms, CYP3A5 (p = 0.075) SLCO1B1 (p = 0.106), ABCB1 (p = 0.902). Conclusions: The findings of our study indicate that having pharmacogenetics changes in the genes, ABCB1, CYP3A4, CYP3A5, and SLCO1B1 did not influence the patients experience with peripheral sensory neuropathy.
ENGOT-OV43/KEYLYNK-001: A phase III, randomized, double-blind, active- and placebo-controlled study of pembrolizumab plus chemotherapy with olaparib maintenance for first-line treatment of BRCA-nonmutated advanced epithelial ovarian cancer.
Authors: Ignace Vergote, Jalid Sehouli, Vanda Salutari, Paolo Zola, Radoslaw Madry, Robert Michael Wenham, Jacob Korach, Patricia Pautier, David Cibula, Stephanie Lheureux, Kosei Hasegawa, Byoung-Gie Kim, Chyong-Huey Lai, Antonio González-Martín, Qi Liu, Stephen Michael Keefe, Martina Puglisi, Samet Topuz
Journal: Journal of Clinical Oncology (2019)

TPS5603 Background: There is a significant unmet need to develop new regimens for BRCA1/2-nonmutated advanced ovarian cancer (OC). The PARP inhibitor olaparib is approved for women with platinum-sensitive, recurrent OC regardless of BRCA1/2 status and, more recently, for newly diagnosed women with BRCA-mutated OC. In the TOPACIO/KEYNOTE-162 study, the combination of the PD-1–blocking antibody pembrolizumab (pembro) and niraparib demonstrated efficacy in platinum-resistant relapsed OCirrespective of BRCA1/2 status. ENGOT-OV43/KEYLYNK-001 (ClinicalTrials.gov, NCT03740165) is a phase 3, randomized, double-blind, active- and placebo-controlled study of pembro plus paclitaxel-carboplatin chemotherapy (CT) followed by olaparib maintenance for first-line treatment of patients with BRCA1/2-nonmutated advanced epithelial OC (EOC). Methods: Patients with stage III or IV BRCA-nonmutated EOC, primary peritoneal cancer, or fallopian tube cancer will be stratified by surgery status (no residual tumor after primary debulking surgery [PDS], residual tumor after PDS, or planned interval debulking), bevacizumab use, and PD-L1 status (combined positive score &lt; 10 or ≥10). After one lead-in cycle of CT, patients will be randomized 1:1:1 to receive: CT + pembro followed by olaparib maintenance; CT + pembro followed by placebo; or CT + placebo followed by placebo. The CT regimen will be administered for 5 cycles, and pembro 200 mg Q3W will be administered for 35 infusions. Olaparib 300 mg BID maintenance therapy will start after the end of CT as concomitant treatment with pembro until discontinuation or for 2 years if the patient has a complete response. Bevacizumab use is permitted at investigator’s discretion and determined prerandomization. Primary endpoints are investigator-assessed progression-free survival (PFS) per RECIST 1.1 criteria and overall survival. Key secondary endpoints are PFS per RECIST 1.1 assessed by blinded independent central review, PFS after next-line treatment, and safety. Enrollment is currently ongoing. Clinical trial information: NCT03740165.
Comparison of efficacy and safety of second-line palliative chemotherapy with paclitaxel plus raltitrexed and paclitaxel alone in patients with metastatic gastric adenocarcinoma: A randomized phase II trial.
Authors: Xiaoying Zhao, Weijian Guo, Zhiyu Chen, Xiaowei Zhang, Xiaodong Zhu, Wen Zhang, Lei Yang, Lixin Qiu, Chenchen Wang, Mingzhu Huang, Hui Yu, Jin Li, Zhe Zhang, Wenhua Li
Journal: Journal of Clinical Oncology (2019)

4054 Background: Paclitaxel is a microtubule stabilizing agent that has been the standard second line chemotherapy in the treatment of advanced gastric cancer. This study was designed to find out the clinical outcome of paclitaxel plus raltitrexed regimen as second line treatment in MGC patients. Methods: In an open, randomized, multi centers phase II clinical trial , 148 patients were randomly assigned and treated with either RP (raltitrexed 3 mg/m2 d1 and paclitaxel 135mg/m2 d1,3w) or P (paclitaxel 135mg/m2 d1,3w) as second-line palliative chemotherapy. The primary endpoint is PFS, secondary endpoint is ORR, OS and safety. Results: In 148 randomly assigned and treated patients (RP = 73; P = 75), the majority of patients were males (94 vs. 54). Progression free survival has a tendency to be prolonged with RP versus P (2.7m vs. 1.7m, p = 0.148). Overall survival also has a tendency to be prolonged with RP versus P (10.2m vs. 6.1m, p = 0.140). Overall response rate was equal with RP versus P (6.8% vs.4.0%, p = 0.72). DCR in the RP group was 56.2%, P group was 36.0%. Grade 3 to 4 treatment-related adverse events occurred in 36.2% (RP) v 28.2% (P) of patients. Frequent grade 3 to 4 toxicities for RP v P were: neutropenia (11.0% v 4.0%), anemia (1.4% v 4.0%), thrombocytopenia (1.4% v 5.3%), and all grade peripheral neurotoxicity (12.3% v 17.3%),all grade elevated aminotransferase (27.4% v 14.1%). Subgroup analysis shows if the disease combined with ascites or peritoneal involved , OS of RP regimen is more longer (p = 0.05). Conclusions: Second-line palliative chemotherapy with paclitaxel plus raltitrexed provides a tendency to prolong PFS and OS, and the patients with ascites or peritoneal involved may get benifits from combined chemotherapy, which needs to be confirmed by larger sample studies. Clinical trial information: NCT02072317.
Surveillance in stage I MOGCTs (malignant ovarian germ cell tumors): A MITO prospective study (multicenter Italian trials in ovarian cancer).
Authors: Alice Bergamini, Giorgio Giorda, Gabriella Ferrandina, Gennaro Cormio, Domenica Lorusso, Chiara Cassani, Francesco Raspagliesi, Marco Marinaccio, Elena Bertone, Luigi Frigerio, Giovanna Scarfone, Myriam Perrone, Luca Bocciolone, Antonella Savarese, Sandro Pignata, Giorgia Mangili
Journal: Journal of Clinical Oncology (2019)

5516 Background: The standard of treatment of stage I MOGCTs is surgery followed by BEP (bleomycin + etoposide + cisplatin) chemotherapy, except for stage IA dysgerminoma (D) and IAG1 immature teratoma (IT). Surveillance has emerged as a possible option to avoid adjuvant chemotherapy in IB-C1 D, IA-C G2 – G3 IT, and in stage IA mixed and yolk sac tumors (YST), after comprehensive surgical staging (CSS) with negative postoperative markers. The aim of this study was to analyze oncological outcome of stage I MOGCT patients included in the MITO9 study. Methods: MITO9 was a prospective observational study analyzing data collected between 2013 and 2018. 41 patients with stage I conservatively treated MOGCTs were included. Three groups were identified: group A. IA D and IAG1 IT candidate to surveillance according to guidelines; group B. stages IB-C1 D, stage IA-C G2-G3 IT, stage IA mixed and YST were consulted about the option of close surveillance vs adjuvant chemotherapy in case of CSS; group C. all other patients receiving BEP. Results: Median age was 25.6 years (range 14-40). Median follow up was 36,4 months. Group A included 12 patients, 5 IA G1 IT and 7 IA D. Group B included 24 patients. Of these, 2 out of 5 patients (40%) were positive at restaging and were excluded from surveillance protocol. Seven of the 22 remaining patients (31.8%) received chemotherapy, while 15 (68.1%) were enrolled in the surveillance protocol. Out of these 15 patients, 4 were stage IC D (one IC1, one IC2 and two IC3), 2 were mixed stage IA with YST tumor, 9 were G3 IT (four IA, three IC2, one IC3 and one IB). The 7 patients receiving chemotherapy were: 1 dysgerminoma IC2, 2 YST IA, 3 IT G3 (one IA and one IC2) and 1 mixed IA tumour. Group C included 5 patients, three IC YST and two mixed IC2 with YST. Survival of these patients was 100%, while disease free survival was 97.5%. Only one patient in C Group, a stage IA G3 IT treated with adjuvant BEP, relapsed as mature teratoma. None of the patients in the surveillance protocol experienced relapse. Conclusions: These data suggest that close surveillance could be an alternative option to avoid adjuvant chemotherapy in properly staged IB-C1 D, stage IA G2 – G3 IT, stage IA mixed and YST. These findings deserve further confirmation in an international cooperative setting.
PDIGREE: An adaptive phase III trial of PD-inhibitor nivolumab and ipilimumab (IPI-NIVO) with VEGF TKI cabozantinib (CABO) in metastatic untreated renal cell cancer (Alliance A031704).
Authors: Tian Zhang, Karla V. Ballman, Atish Dipankar Choudhury, Ronald C. Chen, Colleen Watt, Yujia Wen, Tyler Zemla, Hamid Emamekhoo, Ulka N. Vaishampayan, Michael J. Morris, Daniel J. George, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2020)

TPS760 Background: First-line treatment of mRCC has rapidly changed to include IPI-NIVO or CABO, with clinical benefit of each based on the Checkmate 214 and CABOSUN trials. Combination immunotherapy with VEGF therapies have shown benefit in the JAVELIN 101 and KEYNOTE 426 trials over sunitinib. It is yet unclear which patients (pts) benefit most from combination immunotherapy-VEGF inhibitors, and the optimal sequence of drugs. Methods: In an adaptive, randomized, multicenter, phase 3 trial (Alliance A031704, PDIGREE), pts start treatment with induction IPI 1mg/kg and NIVO 3mg/kg intravenously (IV) once every 3 weeks. Key inclusion criteria include clear cell mRCC, IMDC intermediate or poor risk, Karnofsky performance status &gt;70, and no prior treatments for mRCC. Based on 3-month radiographic assessment (after completing IPI-NIVO combination), pts with complete responses (CR) undergo maintenance NIVO 480mg IV every 4 weeks, pts with progression of disease (PD) switch to CABO 60mg oral daily, and pts with non-CR/non-PD are randomized to NIVO 480mg IV every 4 weeks versus NIVO 480mg IV every 4 weeks with CABO 40mg oral daily. Randomization is stratified by IMDC risk criteria and presence of bone metastases. The primary endpoint of the study is overall survival (OS). We hypothesize that 3-year OS rate will improve to 70% for NIVO-CABO compared to 60% for NIVO alone; to achieve 85% power with a two-sided alpha of 0.05 and exponential distribution, 696 patients will be randomized. Accounting for 30% patients with either CR or PD, and 5% dropout from toxicity, up to 1046 pts will be enrolled. Key secondary endpoints include PFS, 12-month CR rate, ORR based on RECIST 1.1 and irRECIST criteria, and toxicity profiles. Quality of life will be assessed based on the FKSI-19, PROMIS-fatigue, and EQ5D-5L questionnaires. Biomarkers associated with CR and association of IL-6 with treatment benefit will be assessed. Other tissue-based and plasma-based biomarkers are planned. Updated enrollment will be presented. Clinical trial information: NCT03793166.
The prognostic role of a novel TP53 mutation classifier in resectable esophageal squamous-cell carcinoma.
Authors: Dan Su, Minran Huang, Jiaoyue Jin, Yingxue Wu, Lisa Ying, Fanrong Zhang, Kaiyan Chen
Journal: Journal of Clinical Oncology (2019)

e14749 Background: TP53 is the most recurrently mutated gene in esophageal squamous-cell carcinoma (ESCC). However, the effect of TP53 mutation status on the prognosis for patients with ESCC remains controversial. Also, there has been no consensus on the minimal genomic region necessary for clinical TP53 genetic testing. Methods: We retrospectively examined somatic mutations in all coding exons of the TP53 gene in 161 resectable ESCC patients by next-generation sequencing. We then stratified patients by multiple TP53 mutation classifiers based on different mutant features and analyzed its association with clinicopathological features and disease outcome by univariable and multivariable analysis. Results: We detected TP53 mutations in 138 of the 161 patients (85.7%), among which 61 patients harbored a non-disruptive mutation in the DNA-binding domain (DBD). The presence of TP53 mutation, hotspot mutant, and the mutation number alone was not predictive of any disease features and prognosis. We identified a prognostic effect of harboring the non-disruptive and DBD mutation of TP53 with an HR 0.362 (95% CI: 0.212–0.620, P &lt; 0.001) and 0.486 (95% CI: 0.277–0.853, P = 0.012) for 5-year progression-free (PFS) and overall survival (OS), respectively. Multivariable analysis revealed it as an independent prognostic predictor for PFS (HR: 0.414, 95% CI: 0.230–0.746, P = 0.003) and OS (HR: 0.414, 95% CI: 0.207–0.825, P = 0.012). In particular, this TP53 mutation classifier defined a patient subset more beneficial from peri-operative radiotherapy with improved 5-year PFS (P = 0.020) and OS (P = 0.036). Conclusions: It is of clinical importance to examine and identify the non-disruptive somatic mutation in DBD of the TP53 gene for resectable ESCC.
Long-term survival in patients (pts) with locally advanced or disseminated malignant melanoma (MM) or renal cell carcinoma (RCC), treated with tag-7 gene-modified (GMV) tumor cells: A phase II trial.
Authors: Alexey Viktorovich Novik, Anna Borisovna Danilova, Irina Alexandrovna Baldueva, Maksim Ivanovich Sluzhev, Tatyana Leonidovna Nehaeva, Sergei Larin, Svetlana Protsenko, Anna Semenova, Aleksei Olegovich Danilov, Vladimir Moiseyenko, Georgii Pavlovich Georgiev
Journal: Journal of Clinical Oncology (2019)

e14022 Background: Immunotherapy may produce long lasting effects on survival.Magnitude of efficacy may be depended from immune factors. We evaluated the overall survival (OS) in pts treated with GMV with biomarker analysis of immunosuppressive factors (ISF) production by their tumor cells. Methods: Since 2001 to 2014 80 pts received GMV: 68 with MM and 12 pts with RCC. Treatment was given in the metastatic setting in 61 pts (MM-51, RCC – 10) and in the adjuvant (after complete cytoreduction) setting in 19 pts (MM-17, RCC-2). Stage 3 was in 26 (33%) pts, stage 4 in 54 (67%). Pt’s tumor samples were transferred to culture, transfected with TAG7and inactivated by radiation. Produced product was injected SC every 3 weeks until progression or 2y of therapy. ISF (MICA, TGF-β1, IL-10 and VEGF) were measured in the supernatants of the tumor cell cultures and used as predictive factors. Results: The 5-yr OS in intention to treat population was 25.1%. There was no differences in MM and RCC OS (Log-rank p = 0.44). Median OS in metastatic setting was 0,7 y, in adjuvant – 3,1 y. Classification trees were built on the basis of ISF production. The median OS was 6.6 y in favorable prognosis (FP) group (MICA level ≤582 pg/ml, n = 15), 4.6 mo in unfavorable (UF) group (MICA level &gt; 582 pg/ml, n = 12) (p &lt; 0.0001). No significant differences were found between classification trees based on the other ISF (TGF-β1, IL-10 and VEGF). In stage 3-4 MM pts with FP median OS was 2,3 y with 31% pts alive in 10y, in UF group – 0,4 y; log-rank p = 1,94E-5. No FP pts received modern immunotherapy. Conclusions: GMV shows high results in carefully selected pts with low ISF production. Method should be further investigated in pts with FP. [Table: see text]
The role of low dose aspirin, vitamin D, or metformin in EGFR, ALK, and ROS positive non-small cell lung cancer: A single institution retrospective analysis.
Authors: Carolina Bernabe Ramirez, Sandhya Sharma, Jose G Sanchez-Escobar, Kevin M. Sullivan, Nagashree Seetharamu
Journal: Journal of Clinical Oncology (2019)

e20656 Background: Tyrosine kinase inhibitor (TKI) is the backbone therapy for EGFR, ALK and ROS positive (pos) non-small cell lung cancer (NSCLC). Metformin has shown to sensitize EGFR resistant lung cancer cells in vitro through IL-6/STAT pathways. COX-2 overexpression triggers activation of a transcription factor that binds to EGFR that activates MAPK signaling pathway. Vitamin D receptor (VDR) has shown to directly inhibit EGFR transcriptional activity. Some studies have shown that adding metformin, aspirin and vitamin D (MAD) to chemotherapy may improve progression free survival (PFS) and overall survival (OS) in lung cancer. However, data supporting use of MAD is unknown in EGFR, ALK and ROS pos NSCLC. Methods: Patients (pts) with EGFR, ALK, ROS pos NSCLC treated with first line TKI from January 2014 to June 2017 were included. Information on concurrent use of MAD was obtained. Patients were dichotomized based on use of these individual supportive medications. Two sample t-test was used to compare mean PFS and chi-square test to compare proportions of disease control rate (DCR) at 3 months between groups. Results: 74 patients were included. Vitamin D supplementation (n = 38, 51.3%) prolonged PFS by 16 m vs 11 m (p = 0.04; 95%CI 0.23 to 9.34). For those on aspirin (n = 23, 35%), mean PFS was 16m vs 12.5 m (p = 0.72; 95% CI -5.58to 3.88). Mean PFS for pts on metformin (n = 8, 10%) was 14 months (m) vs 13.5 m for those who were not (p = 0.93, 95% CI -7.27 to 7.87). DCR for metformin use was 26.5% vs 89% (p = 0.0001); for aspirin was 50% vs 65% (p = 0.17) and for vitamin D 48.6% vs 43.7% (p = 0.69). Conclusions: To our knowledge, no data has been published regarding use of MAD in NSCLC with driver mutations. In our study, concurrent use of vitamin D with TKI prolonged PFS in these pts. However, this effect was not seen with metformin or aspirin. Our study was limited by retrospective design, possible under-reporting of medication use by patients and small patient population. Further prospective studies using these medications is important to evaluate the synergistic benefit with the approved targeted therapy.
Case 38-1984
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely
Journal: New England Journal of Medicine (1984)

Presentation of Case A 24-year-old man was admitted to the hospital because of multiple trauma. He was well until 20 minutes earlier, when he was involved in a motor-vehicle accident. He was found unresponsive at the scene and was brought to this hospital a few minutes before midnight, unable to give a history. The temperature was 36.9°C, the pulse was 90, and the respirations were 24. The blood pressure was 90 mm Hg systolic by palpation. On examination the patient was overweight. The extremities were well perfused. A 6-cm laceration over the right side of the forehead extended to bone, . . .