tbuckley/cabot-search huggingface dataset:
Intraperitoneal hyperthermal chemotherapy combined with general chemotherapy after surgery for malignant gastrointestinal tumors
Authors: Jun-li Cao, Zong-lan Hu, Zhan-zhao Fu, Tao Gu, Shao-hui Cheng, Hai-xia Hua, Sen Yang, Li-jiao Zhang, Yan-hong Yang, Li-xin Dong
Journal: BMJ (2009)

A total of 101 patients undergoing operations for malignant gastrointestinal tumors (stage Ⅱ to Ⅲ) were enrolled and randomly assigned to receive intraperitoneal hyperthermal chemotherapy plus intravenous chemical injection (treatment group, n=51) or routine intravenous chemical injection (control group, n=50). Our results indicated that the recurrence rate and the metastatic rate in the treatment group were significantly lower than those in the control group (25.5% vs. 50.0%, 13.7% vs. 30.0%, both P< 0. 05), although the 3-and 5 year-survival rates were significantly higher (both P < 0. 05). Our data suggest that intraperitaneal hyperthermal chemotherapy plus general chemotherapy after surgery for malignant gastrointestinal tumors could effectively reduce tumor recurrence and metastases and improve long-term survival.

Key words: 
Gastrointestinal neoplasms;  Chemotherapy,cancer,regional perfusion
The development of a homologous recombination deficiency (HRD) score to identify HR-deficient tumors.
Authors: Xiaohua Wu, Hao Wen, Zheng Feng, Lin Shao, Chenglin Liu, Hao Liu, Lu Zhang, Xinru Mao, Xiaoqian Guan, Ting Hou, Han Han-Zhang, Zhou Zhang
Journal: Journal of Clinical Oncology (2020)

e18085 Background: BRCA1/2 mutated cancers are homologous recombination repair (HRR) deficient and often sensitive to drugs targeting DNA repair pathway. Emerging evidences suggest tumors with mutations in other HRR genes might also respond favorably to DNA repair pathway targeted drugs; however, the results were inconclusive. Genomic instability is characterized by telomeric allelic imbalance (TAI), large-scale transition (LST) and loss of heterozygosity (LOH). Here, we developed an HRD score based on assessing the status of these patterns in tumors. Methods: 73 cancer patients, including 36 breast cancer (BC), 35 ovarian cancer (OC) and 2 prostate cancer (PC) patients were recruited. 28 were BRCA-deficient tumors (10 BCs, 17OCs and 1 PC) harboring pathogenic/likely pathogenic (P/LP) germline mutation in BRCA1/2 with LOH. 13 BRCA-mutated tumors (10 BCs, 2 OCs and 1 PC) carried P/LP BRCA1/2 mutation without LOH. The rest 33 were HRR wild type controls (16 BCs and 16 OCs). All samples were profiled using a panel consisting of 24 classic HRR genes and their adjacent SNPs. The scores for TAI, LST and LOH were developed separately and an incorporated HRD score based on the 3 patterns was established. Clinical data of 42 OC pts were collected to validate the algorithm. Results: All pairwise correlations of TAI, LST and LOH scores showed high correlations (TAI vs. LOH: r = 0.89; TAI vs. LST: r = 0.92; LST vs. LOH: r = 0.83). The univariate logistic regression was used to assess the correlation of the score with BRCA deficiency. In the cohort of BRCA-deficient vs. HRR-negative, the scores of TAI (P = 9.72 x 10 −4 ), LST (P = 8.75 x 10 −5 ), LOH (P = 0.01) and HRD (P = 3.35 x 10 −4 ) all showed significant associations with BRCA-deficiency. In the cohort of BRCA-deficient vs. BRCA-mutated +HRR-negative, all the scores also highly correlated with BRCA-deficiency (TAI: P = 2.35 x 10 −4 , LST: P = 1.48 x 10 −5 ; LOH: P = 2.36 x 10 −4 , HRD: P = 6.29 x 10 −5 ). Using 42 as a cutoff, it achieved sensitivities of 94.1%, 60% and 82% for identifying BRCA-deficient tumors in the 35 OCs, 36 BCs and in all 73 tumors, respectively. We further validated the predictive value of HRD score in an additional 42 OC pts and found significantly higher HRD sore in pts sensitive to platinum therapy (P = 0.036). Patients having an HRD score &gt; 42 had a significantly longer PFS than pts with a score &lt; 42 (p = 0.04). Conclusions: Our study developed a HRD score base on assessing 3 patterns of genomic instability (TAI, LST and LOH). The HRD score revealed a promising value in detecting HR-deficient tumors (especially BRCA-deficient).
Whole exome and transcriptome sequencing of colorectal and pancreatic cancer.
Authors: Gargi D. Basu, Kevin Drenner, Audrey Ozols, Candyce M Bair, Tracey White, Janine R LoBello, Thomas Royce, Sunil Sharma
Journal: Journal of Clinical Oncology (2020)

e15666 Background: Integration of Whole Exome Sequencing (WES) into clinical cancer therapeutics has revolutionized medicine in recent years. DNA sequencing alone may miss clinically actionable variants or identify aberrations that are not being transcribed. In this study we investigated the utility of integrating DNA and RNA sequencing in clinical samples. Methods: A cohort of 32 patient samples were analyzed by WES and RNA sequencing. Differential expression analysis was performed using a cohort of controls. Pathway analysis was performed using Ingenuity Pathway Analysis. WES and RNA analysis detected alterations including SNVs, indels, copy number events, fusions, alternate transcripts, TMB, MSI status and differential expression. Results: A total of 25 CRC (39-78yrs) and 7 pancreatic cancers (PCs) (51-91 yrs) were profiled by WES and RNA seq. A 66 yr old pt with neoplasm of rectosigmoid junction tumor was found to be KRAS wildtype and was treated with cetuximab plus FOLFIRI. Patient failed therapy after 2 yrs and sequencing revealed MET amplification which is a known mechanism of resistance to cetuximab treatment. Further, RNA expression analysis showed 44-fold increase in MET expression along with overexpression of AREG and EREG. Out of the 7 PCs, 3 cases that did not harbor KRAS mutation were found to harbor VTCN1/NRG1 fusion, FGFR1/G3BP2 fusion and BRAF V600E mutation respectively. A 50 year-old stage IV metastatic (met) PC pt was treated with standard of care regimens. Upon relapse the sample was found to harbor VTCN1/NRG1 fusion along with a TERT promoter mutation. RNA expression analysis revealed 54-fold increased expression of NRG1 which may lead to clinical trial enrollment. A 52 year-old male met Stage IV PC, was treated with rucaparib and irinotecan based on prior sequencing data. Upon relapse, the pt went on ATR inhibitor (BAY1895344) and progressed very quickly. Sequencing of the met lesion was found to harbor FGFR1/G3BP2 fusion which was also confirmed by RNA expression. A 55 year-old met pt with PC was treated with standard chemotherapy. Upon disease progression pt was sequenced and based on presence of BRAF V600E, pt was treated with trametinib and dabrafenib. Following disease progression on BRAF/MEKi, met sample was resequenced and RNA expression analysis found increased expression of MET, MACC1 and SMAD7 and 4-fold decrease in PTEN which could potentially cause resistance to BRAF/MEKi therapy. Conclusions: Our study highlights the utility of comprehensive testing integrating genomic and transcriptomic data, in identifying targeted therapy options for cancer patients.
Evidence of intratumoral localization, activation, and immunomodulatory effect of CX-072, a probody therapeutic targeting PD-L1, in a phase I/II trial.
Authors: Susan Lyman, Aung Naing, Ivan Adiputra Zein, Bruce Howng, Michael B. Winter, Olga Vasiljeva, William Garner, Beiyao Zheng, Mark Stroh, W Michael Kavanaugh, Luc Roland Desnoyers
Journal: Journal of Clinical Oncology (2020)

3108 Background: PROBODY therapeutics (Pb-Tx) are masked antibodies designed to be selectively activated in the tumor microenvironment by tumor-associated proteases and to remain largely inactive in normal tissue. CX-072, a Pb-Tx directed against PD-L1, is designed to reduce the potential for immune-associated adverse events in normal tissues while maintaining anti-tumor activity. CX-072 is being investigated in PROCLAIM-CX-072 (NCT03013491), a first-in-human phase 1/2 trial. CX-072 is administered as monotherapy or in combination with ipilimumab to patients with metastatic or recurrent solid tumors or lymphomas for which approved PD-1/-L1–based therapy is not available. We present the updated results of a tissue-based biomarker program designed to assess activation, localization, and mechanism of action of CX-072 in patient tumors. Methods: Tumor biopsies were collected during the screening phase, and also 3–5 days after the first or third dose of 0.3–30 mg/kg CX-072. Tumor-associated protease activity was measured by tissue zymography. Intratumoral CX-072 activation was measured using capillary immunoelectrophoresis, and PD-L1 levels were measured by an ultrasensitive ELISA. Intratumoral CD8 expression was analyzed using immunohistochemistry. Intact and total CX-072 in plasma were measured by LC-MS/MS. Results: Twenty-six of 30 (87%) evaluable predose biopsies had detectable levels of relevant protease activity. Intratumoral activation of CX-072 was quantifiable in 3 of 8 (38%) biopsies from patients treated with CX-072 at 3 mg/kg and in 12 of 12 (100%) biopsies from patients treated with ≥10 mg/kg. In contrast, CX-072 remained predominantly in the intact form in circulation. The molar ratio of activated intratumoral CX-072 to total intratumoral PD-L1 ranged from ~14x to &gt; 100x in patients dosed at 10 mg/kg, and the calculated tumor receptor occupancy for these patients was ≥99%, congruent with quantitative systems pharmacology model predictions. An increase in CD8 + T cells and elevation of cytotoxic T-cell markers was observed in the tumors of 11 of 18 (61%) CX-072 monotherapy patients, consistent with inhibition of the PD-L1 pathway. Conclusions: These results demonstrate that the Pb-Tx CX-072 behaves as designed in patients. Clinical trial information: NCT03013491 .
Patient engagement in clinical trial design and implementation: A pragmatic approach to valued insights.
Authors: Dawn Aubel, Susan Hayes, Geoffrey Cook, Alexey Salamakha, Andrew Ciupek, Gunjan Patel, Ginny Mason
Journal: Journal of Clinical Oncology (2020)

e14084 Background: Evidence-based guidance on how to best facilitate patient engagement in the drug development process is lacking 1,2 .Well-informed, engaged patients and advocates can contribute meaningfully throughout drug development process for new therapeutics 3 . Regulatory agencies, including the FDA and EMA, concur 4,5. However, identifying and effectively implementing meaningful, and structured patient engagements has been challenging for research organizations 6 . Methods: Patient advocates with deep knowledge of the special needs of patients within their respective disease areas and experience in patient-centered research and programming were identified by the patient relations’ team of the organization. Participating advocates were generally contracted for consulting support across the development lifecycle to provide timely feedback for emerging topics and agreed to provide feedback within a 3-4 week timeframe to requests for support. Called “Global Oncology Patient Insight Panel” (GOPIP), the approach facilitated fast-moving development teams to quickly engage advocates for advice while enabling projects remain on timeline. GOPIP members engaged with teams within the organization on an ad-hoc basis across the drug development process, as early as protocols’ and informed consents’ review and PRO selection, among many others patient-centered projects. Results: GOPIP engagements included 49 advocates from 19 countries, across 14 disease areas, in the program’s first 18 months. 54 projects were completed. Multiple engagements for three clinical trials, part of the development program, have been accomplished. Seven plain language summaries of published data results were reported publicly with consultants’ input. Satisfaction was high among advocates as well as internal teams. Conclusions: The Patient Insight Panel model is a valuable resource to facilitate patient engagement efforts. More research is needed to evaluate the outcomes and effectiveness of the method. References: 1. Chalasani, M., et al. 2018. Res Involv Engagem. 4,10 2. de Wit, M., et al. 2019. The Lancet, 393(10176),1095-1096 3. Kuehn, C. M. 2018. Ther. Innov. Regul. Sci., 52(5),661–668 4. FDA. 2020. https://www.fda.gov/about-fda/oncology-center-excellence/patient-focused-drug-development . Accessed February 8, 2020 5. EMA. 2016. https://www.ema.europa.eu/en/documents/other/appendix-2-guideline-evaluation-anticancer-medicinal-products-man_en.pdf Accessed February 8, 2020 6. Geissler, J., et al. 2017. Ther. Innov. Regul. Sci., 51(5),612-619.
Mitochondrial DNA Copy Number and Incident Heart Failure
Authors: Yun Soo Hong, Ryan J. Longchamps, Di Zhao, Christina A. Castellani, Laura R. Loehr, Patricia P. Chang, Kunihiro Matsushita, Megan L. Grove, Eric Boerwinkle, Dan E. Arking, Eliseo Guallar
Journal: Circulation (2020)
Infigratinib and treatment response in advanced/unresectable or metastatic urothelial carcinoma in first-line and later-line treatment settings.
Authors: Yung Lyou, Petros Grivas, Jonathan E. Rosenberg, Jean H. Hoffman-Censits, David I. Quinn, Daniel Peter Petrylak, Matt D. Galsky, Ulka N. Vaishampayan, Ugo De Giorgi, Sumati Gupta, Howard A. Burris III, Jessica Rearden, Corina Andresen, Hao Wang, Siamak Daneshmand, Dean F. Bajorin, Sumanta K. Pal
Journal: Journal of Clinical Oncology (2020)

5038 Background: Infigratinib (BGJ398) is a potent and selective FGFR1–3 tyrosine kinase inhibitor (TKI), previously reported to be effective and well tolerated in patients with locally advanced/unresectable or metastatic urothelial carcinoma (mUC) bearing FGFR3 alterations [Pal et al. Cancer Discovery 2018]. However, this previous study did not examine differences in infigratinib activity based on number of prior lines of treatment (LOT). TKIs studied in other indications (e.g. VEGFRis in renal cell carcinoma) have shown consistent activity in both the first and later LOT. Given the effect seen with other TKIs, we sought to determine if infigratinib showed consistent treatment responses in patients with mUC according to LOT. Methods: Eligible patients had mUC and prior platinum-based chemotherapy unless contraindicated and activating FGFR3 mutations/fusions. Infigratinib was dosed at 125 mg orally daily (3 weeks on/1 week off). The primary endpoint of objective response rate (ORR: partial response [PR] and complete response [CR]) was assessed, as well as disease control rate (DCR: CR + PR + stable disease [SD]). After classification of LOT for each patient, subgroup analysis of response by LOT was performed. Results: 67 patients were enrolled; 81% received ≥1 prior LOT for mUC. 13 patients (19.4%) received infigratinib as 1 st LOT for mUC due to ineligibility to receive platinum-based chemotherapy. ORR for the 67 patients was 25% (95% CI 15.5–37.5) and DCR was 64% (95% CI 51.5–75.5). The ORR with 1 st -line infigratinib was 31% (95% CI 9.1–61.4) compared with 24% (95% CI 13.5–37.6) for 2 nd and later (salvage) LOT. DCR was 46% (95% CI 19.2–74.9) for 1 st -line and 69% (95% CI 54.4–80.5) for ≥2 LOT. 13 of the 59 patients with urothelial bladder carcinoma (UBC) received 1 st -line treatment with an ORR of 31% (95% CI 9.1–61.4) and 46 patients in ≥2 LOT had an ORR of 20% (95% CI 9.4–33.9). All 8 patients with upper tract urothelial carcinoma (UTUC) received salvage therapy, with an ORR of 50% and a DCR of 100%. An analysis of other outcome measures (e.g. PFS, OS) will be presented. Conclusions: These results indicate that infigratinib has activity in patients with mUC regardless of LOT. Additionally, patients with UTUC showed a trend for better ORR and DCR. Taken together, these results support the ongoing adjuvant PROOF 302 study comparing infigratinib with placebo in patients with resected disease, assessing infigratinib in an even earlier setting in a UTUC-enriched population (NCT04197986). Clinical trial information: NCT01004224 .
Tepotinib in Non–Small-Cell Lung Cancer with <i>MET</i> Exon 14 Skipping Mutations
Authors: Paul K. Paik, Enriqueta Felip, Remi Veillon, Hiroshi Sakai, Alexis B. Cortot, Marina C. Garassino, Julien Mazieres, Santiago Viteri, Helene Senellart, Jan Van Meerbeeck, Jo Raskin, Niels Reinmuth, Pierfranco Conte, Dariusz Kowalski, Byoung Chul Cho, Jyoti D. Patel, Leora Horn, Frank Griesinger, Ji-Youn Han, Young-Chul Kim, Gee-Chen Chang, Chen-Liang Tsai, James C.-H. Yang, Yuh-Min Chen, Egbert F. Smit, Anthonie J. van der Wekken, Terufumi Kato, Dilafruz Juraeva, Christopher Stroh, Rolf Bruns, Josef Straub, Andreas Johne, Jürgen Scheele, John V. Heymach, Xiuning Le
Journal: New England Journal of Medicine (2020)

A splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driver MET occurs in 3 to 4% of patients with non-small-cell lung cancer (NSCLC). We evaluated the efficacy and safety of tepotinib, a highly selective MET inhibitor, in this patient population. In this open-label, phase 2 study, we administered tepotinib (at a dose of 500 mg) once daily in patients with advanced or metastatic NSCLC with a confirmed MET exon 14 skipping mutation. The primary end point was the objective response by independent review among patients who had undergone at least 9 months of follow-up. The response was also analyzed according to whether the presence of a MET exon 14 skipping mutation was detected on liquid biopsy or tissue biopsy. As of January 1, 2020, a total of 152 patients had received tepotinib, and 99 patients had been followed for at least 9 months. The response rate by independent review was 46% (95% confidence interval [CI], 36 to 57), with a median duration of response of 11.1 months (95% CI, 7.2 to could not be estimated) in the combined-biopsy group. The response rate was 48% (95% CI, 36 to 61) among 66 patients in the liquid-biopsy group and 50% (95% CI, 37 to 63) among 60 patients in the tissue-biopsy group; 27 patients had positive results according to both methods. The investigator-assessed response rate was 56% (95% CI, 45 to 66) and was similar regardless of the previous therapy received for advanced or metastatic disease. Adverse events of grade 3 or higher that were considered by investigators to be related to tepotinib therapy were reported in 28% of the patients, including peripheral edema in 7%. Adverse events led to permanent discontinuation of tepotinib in 11% of the patients. A molecular response, as measured in circulating free DNA, was observed in 67% of the patients with matched liquid-biopsy samples at baseline and during treatment. Among patients with advanced NSCLC with a confirmed MET exon 14 skipping mutation, the use of tepotinib was associated with a partial response in approximately half the patients. Peripheral edema was the main toxic effect of grade 3 or higher. (Funded by Merck [Darmstadt, Germany]; VISION ClinicalTrials.gov number, NCT02864992.).
Difference in clinicopathological characteristics between pure and mixed invasive micropapillary breast carcinomas from eastern China.
Authors: Rong Wang, Nani Li, Wang Xiao Jia, Wen-Ming Cao
Journal: Journal of Clinical Oncology (2020)

e12500 Background: Invasive micropapillary carcinoma of the breast (IMPC) is a rare pathologic subtype of breast cancer with frequent lymph node metastases. Since the differences in pathological features between pure and mixed IMPCs are not fully understood, we aimed to investigate the difference in clinicopathological characteristics between pure and mixed IMPC. Methods: Overall 121 IMPC cases were included from Zhejiang Cancer Hospital, China during May 2010-August 2018. The clinicopathological features and survival estimates between the pure IMPC and mixed IMPC groups were compared. Targeted sequencing was performed to investigate the genomic profile of paired primary breast cancer and metastatic tissue samples from two pure IMPC and four mixed IMPC. The copy number variations (CNVs) and the tumor mutation burden (TMB) from metastatic tissues were analyzed. Results: Overall 48 cases were pure IMPC and 73 were mixed IMPC. The pure group had significantly higher proportion of luminal B compared to the mixed group (37.5% vs.15.1%), but lower proportion of luminal A (33.3% vs. 45.2%). The pure group had similar HER2 overexpression rate (31.2% vs. 32.9%) and mean age at diagnosis (51.0 vs. 50.2 years), compared to the mixed group. The pure group had significant higher proportion of stage Ⅲ C cases compared to the mixed group (38.3% vs.17.8%). We found no significant difference in 3-year disease-free survival (DFS) between the two groups (83.7% vs. 80.0%), but the mixed group had a better overall survival (OS), compared to the pure group (HR = 0.28 (0.091-0.868), P = 0.047). Conclusions: We found that pure IMPC had more aggressive behavior with locally advanced disease and higher proportion of luminal B than mixed IMPC. Mixed IMPC had a longer OS compared to pure IMPC, but no significant difference in 3-year DFS between two groups.
Relationship between vulnerability of carotid artery plaques evaluated by contrast-enhanced ultrasonography and the prognosis of cerebral infarction
Authors: Changyu Zhu, Zhendong Zhang, Weiqun Guo, Wei Zhang, Heping Shen
Journal: BMJ (2019)

Seventy two patients with initial cerebral infarction admitted in the Second Hospital of Jiaxing from March 2017 to October 2017 were enrolled. Patients underwent conventional ultrasonography and contrast-enhanced ultrasonography for two-dimensional echo grading and neovascularization grading of carotid artery plaques respectively. There were 113 carotid plaques in 72 patients with cerebral infarction,27 cases recurred after 1 years with 44 patches. The echo grading of recurrence group was mainly grade Ⅰ and grade Ⅱ,the number of Ⅰ,Ⅱ,and Ⅲ plaques was 23,18,and 3,respectively. The echo grading of non-recurrence group was mainly grade Ⅲ,the number of Ⅰ,Ⅱ,and Ⅲ plaques was 36,23,and 40,respectively. The echo grading of carotid artery plaque between the two groups was significantly different (P Ⅰ,neovascularization grade>Ⅱ and neovascularization grade>Ⅲ in predicting the recurrence of cerebral infarction were 0.553,0.641,0.587,0.793 and 0.557,respectively,the AUC of neovascularization grade>Ⅱ was significantly higher than the other four criteria (P<0.01). The recurrence curves of carotid plaques with different neovascularization grades were significantly different (χ2=49.18,P<0.01). Carotid plaque vulnerability evaluated by contrast-enhanced ultrasonography is an effective indicator for predicting recurrence of cerebral infarction.


Key words: 
Cerebral infarction; Recurrence; Carotid plaque; Ultrasonography