tbuckley/cabot-search huggingface dataset:
Successful salvage therapy with cetuximab-based modalities in the non-sensitive EGFR-mutant lung cancer patients with leptomeningeal metastasis who have heavily pretreated histories.
Authors: Jinchun Wu, Jie Zhao, Xiangping Li, Jin Zhang, Shan Zeng, Rongrong Zhou, Bin Li
Journal: Journal of Clinical Oncology (2021)

e14011 Background: Leptomeningeal metastasis (LM) is the deadliest complication of lung cancer. No standard therapy for the LM harbor non-sensitive epidermal growth factor receptor (EGFR)-mutant|(neither E19 del, E21 p.L858R nor E18 p. G719X mutation ). Previous studies showed cetuximab held the potential for treating the EGFR mutants who had failed 2 or more lines of standard cytotoxic chemotherapy and reversible EGFR TKIs. Methods: We screen the lung cancer patients with LM treated with Cetuximab-based regimen from July 1st, 2020 to Dec 31th 2020. The medical records were retrospectively reviewed and analyzed. Results: Three lung cancer patients with LM were included. All of them were heavily pretreated with various TKIs, chemotherapy, or/and with antiangiogenesis and PD-1 antibodies. When they were referred to our department, all these patients were in severe medical conditions. Case 1 has severe multiple cranial nerve impairment with cauda equina syndrome and massive malignant pleural effusion. Case 2 has intensively violent headaches with vomit and lumbosacral pain due to more than 500mm H2O of intracranial hypertension. Case 3 has acute pancreatitis due to oppressive obstruction of pancreatic duct by multiple metastatic tumors. The molecule test of tumor tissue or liquid from malignant pleural fluid have revealed E20 p.C797S in cis with p.T790M accompanied E19 del of EGFR gene in case 1, E21 p. R831H with E19 p.L747P of EGFR gene in case 2, and E20 p.S768_D770dup of EGFR gene in case 3, respectively. Their therapies were changed to cetuximab combined with TKI of afatinib or osimertinib, and local treatment including local radiation, intraventricular pemetrexed administration, or with intrathoracic drain. The disease control rate (DCR) was 100% of one partial remission (PR) and two stable disease (SD). The intracranial response was also observed in all the 3 patients showing CSF cytology turning negative or enhanced meningeal disappearance in MRI image with obviously relieved headache or/and improved cranial nerve palsy. The performance status of two patients was largely improved from Karnofsky Performance Status (KPS) scoring 20 to 90 and 50, respectively, and that of the other patient was stable with KPS scoring 50. The side effect is manageable skin rashes (grade II-III). Until this abstract was written, all the 3 patients were still alive. Conclusions: Cetuximab-based systemic therapy combined with local treatment demonstrated preliminary clinical activity in the rare EGFR-mutant lung cancer with LM who have already undergone heavily previous therapy, warranting further investigation.
Capecitabine maintenance therapy after induction chemotherapy in newly diagnosed metastatic nasopharyngeal carcinoma: An open-label, randomized, controlled, phase trial.
Authors: Guo-Ying Liu, Wang-Zhong Li, De-Shen Wang, Hu Liang, Xing Lv, Yan-Fang Ye, Chong Zhao, Liang-Ru Ke, Mengyun Qiang, Xun Cao, Shu-Hui Lv, Nian Lu, Wei-Xin Bei, Zhuocheng Cai, Xi Chen, Jun-Zhi Xie, Chixiong Liang, Xiang Guo, Weixiong Xia, Xiang Yanqun
Journal: Journal of Clinical Oncology (2021)

6044 Background: Capecitabine maintenance therapy improves outcomes in various tumor types, but minimal data are available on the effect of capecitabine maintenance therapy in metastatic nasopharyngeal carcinoma (NPC). We aimed to investigate whether capecitabine maintenance therapy would prolong the progression-free survival (PFS) of newly diagnosed metastatic NPC, in comparison to best supportive care (BSC). Methods: This was an open-label, randomized, controlled, phase trial. Eligible patients for maintenance randomisation were aged 18-65 years old with newly diagnosed metastatic NPC at the Sun Yat-Sun University Cancer Center (SYSUCC), had completed 4 to 6 cycles of induction chemotherapy as per protocol and had achieved disease control to protocol treatment, including capecitabine. Patients were randomly assigned 1:1 to capecitabine maintenance (oral 1,250 mg/m 2 /day on days 1-14 every 21 days) for up to 24 months with BSC or BSC alone. The primary endpoint was PFS. The secondary endpoints included overall survival, duration of response, objective response rate and adverse effects. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02460419 and is ongoing and no longer recruiting new patients. Results: Between May 16th, 2015, and January 9th, 2020, 140 metastatic NPC patients were screened, and 104 eligible patients were randomly assigned to capecitabine maintenance plus BSC (n = 52) or BSC alone (n = 52). After a median follow-up of 33.1 months (IQR, 21.5-50.7 months), median PFS was 35.2 months in the capecitabine maintenance group and 9.1 months in the BSC group (HR: 0.426; 95%CI: 0.248-0.731, P = 0.001). The most commongrade 3 or 4 adverse events during maintenance therapy were hand-foot syndrome (10.0%), nausea/vomiting (6.0%), fatigue (4.0%), and mucositis (4.0%). Totally 37 deaths occurred during follow-up, 14 (26.9%) in the capecitabine maintenance group and 23 (44.2%) in the BSC group. Overall survival data was immature. No deaths in the capecitabine maintenance group were deemed treatment related. Conclusions: Capecitabine maintenance significantly improved PFS in patients with newly diagnosed metastatic NPC who achieved disease control after induction chemotherapy compared to BSC and exhibited low grade and manageable toxicities. Clinical trial information: NCT02460419.
Genomic landscape of cell-free DNA in a diverse cohort of metastatic breast cancer patients.
Authors: Shirley Cheng, Edward Nguyen, Ian Pagano, Jami Aya Fukui
Journal: Journal of Clinical Oncology (2021)

e13066 Background: Breast cancer is the most prevalent cancer and the second leading cause of cancer deaths among women in the United States. Once the primary breast cancer has metastasized to other parts of the body, despite treatment, patients have an incurable disease. Compared to the primary tumor, often the metastasized tumor sites have different mutational profiles that are not represented in the initial biopsy. Liquid biopsy is becoming a more commonly accepted method in clinical practice to determine the heterogeneity of metastatic tumors by analyzing cell-free DNA (cfDNA). Several studies have demonstrated that cfDNA can be utilized as an effective prognostic tool and can reveal multiple clinically targetable alterations in metastatic breast cancer (mBC). Methods: We characterized the genomic landscape of cfDNA in a diverse patient population and across different subtypes of mBC. We performed a retrospective chart review in patients (n = 41) with metastatic breast cancer from a medical oncology clinic within the Hawaii Pacific Health system. Patients who had at least one cfDNA testing by Guardant360 were evaluated. Patient demographics, age at diagnosis, race, subtype and mutations were reviewed along with treatment information. Results: We found no statistically significant differences in genomic landscape according to race, however there were differences seen in tumor genomics according to age and subtype. Older patients were less likely to have detectable disease on liquid biopsy compared to younger patients (age 70+ and 60-69 vs 30-39; xp 0.02). Consistent with subtype, mutations in ESR1 (n = 12) and PIK3CA (n = 14) were more commonly seen in hormone positive (HR+) mBC where known tailored treatment options are available (ie. fulvestrant and alpelisib respectively). Postmenopausal patients were more likely to have ESR1 mutations than premenopausal patients (50-59 and 70+ vs 30-39 and 40-49, xp 0.009). About half (n = 20) had TP53 mutations, followed by PIK3CA (n = 14), ESR1 (n = 12), CCND1 (n = 7) and MYC (n = 6). Conclusions: We evaluated 41 unique cases of mBC and correlated them with their genomic profiles. We plan to further investigate genomic changes according to treatment with subsequent repeat liquid biopsies. We hope to utilize these findings to help prognosticate and guide future treatment options.
Association between germline DNA damage repair-related genes mutation and tumor mutational burden in lung cancer patients.
Authors: Wei Nie, Hua Zhong, Ding Zhang, Shiqing Chen, Baohui Han
Journal: Journal of Clinical Oncology (2021)

e21163 Background: Deleterious somatic DNA damage repair (DDR) gene mutations are frequent in non-small cell lung cancer (NSCLC) and are associated with improved clinical outcomes of immunotherapy. DDR gene mutations are associated with higher tumor mutational burden (TMB) in cancer. However, the effect of germline DDR-related genes mutation with different functional annotations on TMB in NSCLC patients is still unclear. Methods: 1671 Chinese patients with NSCLC were enrolled in this study. Genomic profiling was performed on formalin-fixed paraffin-embedded tumor samples or peripheral blood by next generation sequencing (NGS) with 733 cancer-related genes panel. The germline mutation data were obtained. All annotations in clinical significance were according to the 2015 American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines. Results: 1076 patients (64.39%) had germline DDR-related gene mutations and 595 (35.61%) had no germline DDR-related gene mutations. Among patients with DDR-related gene mutations, 78 (7.25%) patients had the pathogenic (P) mutations or likely pathogenic (LP) mutations and 1056 (98.14%) had variants of unknown significance (VOUS) mutations. In total, the median TMB was 3.91 mutations/MB (range, 0-68.16) and 4.47 mutations/MB (range, 0-51.40) in patients with P, LP or VOUS mutations and no germline DDR-related gene mutations, respectively. To the further analysis, we divided patients with germline DDR-related gene mutations into three groups: only P or LP mutations (Group 1), only VOUS mutations (Group 2) and concurrence with P/LP/VOUS mutations (Group 3). Compare to the DDR-negative group, TMB was significantly lower in Group 2 (P &lt; 0.001). No significant differences in Group 1 and Group 3 were observed. In addition, we found that mutations in different DDR pathway could not affect TMB value significantly. Conclusions: Germline DNA damage repair-related genes mutation may be not associated with TMB.
EMBR-10. INOSITOL TREATMENT INHIBITS MEDULLOBLASTOMA THROUGH SUPPRESSION OF EPIGENETIC-DRIVEN METABOLIC ADAPTATION
Authors: Sara Badodi, Nicola Pomella, Xinyu Zhang, Gillian Morrison, Steve M Pollard, Christopher D Bennett, Steven C Clifford, Andrew Peet, Silvia Marino
Journal: Neuro-Oncology (2021)

Abstract Medulloblastoma (MB) is the most common paediatric malignant brain tumour and is classified into four distinct molecular subgroups (WNT, SHH, G3 and G4), each of them further subdivided into subtypes with different prognosis and responses to therapy. Deregulation of chromatin modifier genes plays an essential role in MB, particularly in the G4 subgroup, the least understood of all subgroups, despite being the most common and associated with poor prognosis. A BMI1High; CHD7Low molecular signature identifies patients with poor survival within this subgroup. We show that BMI1High; CHD7Low mediates a novel epigenetic regulation of inositol metabolism in both G4 MB cells and patients. These tumours display hyperactivation of the AKT/mTOR pathway which leads to energetic rewiring characterized by enhanced glycolytic capacity and reduced mitochondrial function. We demonstrate that inositol administration counteracts this metabolic alteration, impairs MB proliferation in vitro and significantly extends survival in an in vivo pre-clinical model. Moreover, inositol synergises with cisplatin, a chemotherapy agent currently used in MB treatment, enhancing its therapeutic effect in vivo. Importantly, cerebellar neural stem cells bearing the BMI1High; CHD7Low signature do not show metabolic adaptation and are thus resistant to inositol treatment, highlighting a fundamental difference between normal and neoplastic metabolism in the developing cerebellum. In summary, we have identified an actionable vulnerability in a pre-clinical setting modelling a molecularly defined group of MB patients, the translational value of which can now be explored in signature-matched clinical trials in MB.
Effect of Coronary CTA on Chronic Total Occlusion Percutaneous Coronary Intervention
Authors: Sung-Jin Hong, Byeong-Keuk Kim, Iksung Cho, Hee-Yeol Kim, Seung-Woon Rha, Seung-Hwan Lee, Sang Min Park, Yong Hoon Kim, Hyuk-Jae Chang, Chul-Min Ahn, Jung-Sun Kim, Young-Guk Ko, Donghoon Choi, Myeong-Ki Hong, Yangsoo Jang
Journal: JACC. Cardiovascular imaging (2021)
Treatment dependent improvements in survival of stage 2/3 rectal cancer patients treated with trimodality therapy between 2006-2016, an NCDB analysis.
Authors: Hagen Fritz Kennecke, Henry T. Bahnson, Bruce Shih-Li Lin, Jennifer Kaplan, Huong Pham, Andrew Suen, Val Simianu
Journal: Journal of Clinical Oncology (2021)

e15543 Background: Trimodality therapy (TT) with chemo/radiation (C/RT), chemotherapy and total mesorectal excision (TME) surgery remains the standard for patients with stage 2/3 rectal cancer. Use of pre-operative (pre-op) C/RT is an important Commission on Cancer (CoC) quality benchmark but has not previously been shown to improve overall survival when compared to post-op C/RT. The objective of this study was to document the impact on survival of peri-op C/RT in stage 2/3 rectal cancer in a broad population. Methods: The National Cancer Database was used to identify all patients diagnosed with stage 2/3 rectal cancer from 2006-16. Included patients received true TT and were classified into groups A, Total Neoadjuvant Therapy (TNT) with pre-op C/RT + pre-op multi-agent (MA) chemotherapy (CT); group B, pre-op C/RT+ post-op single-agent CT; group C, pre-op C/RT + post-op MA CT; and group D, post-op C/RT and MA CT. Cox multivariate survival analysis were performed including demographics, peri-op C/RT, surgery type, stage, lymph node count, year of diagnosis and facility type: academic (Acad), Comprehensive (Comp)/Community (Comm), Integrated (Integ) and unknown (Unkn). Results: Of 110,372 stage 2/3 patients, 32,467 received TT (mean age 58, 61% male) and were included. Of these, 8883 (27%, group A) received TNT, 5967 (18%) were in group B, 12,928 (40%) in group C, while 4,689 (14%) were in group D. A reduction in use of post-operative C/RT (group D) was observed between 2006 (28%) and 2016 (8%), p &lt; .001, accompanied by a reciprocal increase in patients receiving pre-op C/RT and post-op MA CT (Group C) between 2006 and 2016 (24 to 45%, respectively, p&lt;0.001). Increasing use of pre-op C/RT led to a migration to lower pathologic stages 0/1/2/3 from 0.60/10/31/57% in 2006, to 2.8/22/29/45% in 2016, respectively (p &lt; .001), while clinical stage 2/3 distribution remained unchanged. Receipt of pre-operative C/RT (Groups A/B/C) was associated with improved survival compared to post-op C/RT (group D) (table). Conclusions: Between 2006-2016 the proportion of patients with stage 2/3 rectal cancer treated with post-op C/RT declined dramatically and in 2016 accounted for 8% of all patients treated with TT. Multivariate analysis documented superior overall survival among patients treated with pre-operative C/RT, justifying the introduction of the CoC quality benchmark.[Table: see text]
A Still-Ignored Cardiovascular Risk Factor—A History of Preeclampsia
Authors: Edoardo Sciatti, Rossana Orabona
Journal: JAMA Cardiology (2021)

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Neither ‘Crisis Light’ nor ‘Business as Usual’: Considering the Distinctive Ethical Issues Raised by the Contingency and Reset Phases of a Pandemic
Authors: Lucy Frith, Heather Draper, Sara Fovargue, Paul Baines, Caroline Redhead, Anna Chiumento
Journal: The American Journal of Bioethics (2021)

This article refers to:Between Usual and Crisis Phases of a Public Health Emergency: The Mediating Role of Contingency Measures
Comprehensive molecular profiling of pleural mesothelioma according to histologic subtype.
Authors: Ibiayi Dagogo-Jack, Russell Madison, Douglas A. Mata, Alexa Betzig Schrock, Tyler Janovitz, Brennan Decker, Richard S.P. Huang, Douglas I. Lin, Jonathan Keith Killian, Shakti H. Ramkissoon, Ole Gjoerup, Natalie Danziger, Jeffrey Michael Venstrom, Brian M. Alexander, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2021)

8555 Background: Malignant pleural mesothelioma (MPM) is an aggressive malignancy with limited therapeutic options. Immunotherapy has emerged as an effective therapeutic strategy, particularly in the non-epithelioid MPM subgroup. An improved understanding of the molecular profile of MPM may inform targeted therapeutic approaches and provide insights into factors underlying differential sensitivity to therapies. Methods: We performed comprehensive genomic profiling of MPMs from 980 patients, with histologic subtyping on a subset (n = 340; n = 235 epithelioid, n = 48 sarcomatoid, n = 57 biphasic). Analyses included quantifying tumor mutational burden (TMB), assessing microsatellite instability (MSI), and evaluating PD-L1 expression (Dako 22C3). Results: Median TMB of MPM was 1.74 (0.87-2.61) mutations per megabase (mut/mb). Median TMB was comparable for non-epithelioid (biphasic, sarcomatoid) vs epithelioid MPM (1.25 mut/mb vs 1.25 mut/mb, p = 0.43). In the overall cohort, inactivating alterations in the following genes were most prevalent: CDKN2A (49%), BAP1 (44%), CDKN2B (42%), MTAP (35%), and NF2 (33%). MTAP loss co-occurred with CDKN2A and CDKN2B loss in &gt; 99% and 94% of cases, respectively. MTAP loss was observed in 28% of epithelioid vs 46% of non-epithelioid MPMs (p = 0.03). BAP1 alterations were detected in 51% of epithelioid vs 36% of non-epithelioid MPMs (p = 0.81). PD-L1 expression was assessed in 308 MPMs, among which 153 (49%) had PD-L1 ≥1%, including 35 (11%) with PD-L1 ≥50%. Among 164 specimens that underwent histologic subtyping and PD-L1 evaluation, PD-L1 was expressed in 46 (71%) non-epithelioid MPMs compared to 49 (51%) epithelioid MPMs (p = 0.03). Given the high prevalence of alterations involving the two genes, we evaluated impact of BAP1 and MTAP status on PD-L1 and TMB. TMB (1.74 mut/mb vs 1.74 mut/mb) and PD-L1 expression (50% vs 54%) were comparable in BAP1-altered vs wildtype specimens. Although TMB was comparable in MTAP-deficient and MTAP-intact tumors (1.25 mut/mb vs 1.74 mut/mb), more tumors with MTAP loss expressed PD-L1 (68% vs 44%, p = 0.0004). Conclusions: Compared to epithelioid MPM, non-epithelioid tumors demonstrate comparable TMB, higher PD-L1 expression, and enrichment for MTAP loss. As MTAP is frequently altered in MPM, further study is indicated to explore the relationship between MTAP status and MPM biology, including sensitivity to therapeutics such as immunotherapy and synthetic lethal approaches.
Transcriptomic landscape of circulating mononuclear phagocytes in Langerhans cell histiocytosis at the single-cell level
Authors: Hui Shi, Han He, Lei Cui, Egle Kvedaraite, Zhilei Bian, Tao Huang, Christopher Z. W. Lee, Zhigang Li, Jian He, Yandong Gong, Zongcheng Li, Jie Zhou, Yang Zeng, Xianlong Li, Yanli Ni, Zhijie Bai, Chen Liu, Na Li, Honghao Ma, Dong Wang, Yu Lan, Florent Ginhoux, Rui Zhang, Bing Liu
Journal: Blood (2021)
Impact of COVID-19 on initial treatment of breast and colorectal cancers in one integrated healthcare system.
Authors: Jayasree P. Sundaram, Su-Ying Liang, Natalia Colocci, Monique A. De Bruin
Journal: Journal of Clinical Oncology (2021)

e18806 Background: There has been a significant decline in office visits and cancer screening interventions such as mammograms and colonoscopies during the COVID-19 pandemic. The aim of this study is to analyze treatment patterns and to identify if there was also a delay in time to treatment for breast and colorectal cancers diagnosed during the pandemic. Methods: We utilized a dataset linking the institutional tumor registry and electronic health records from a large ambulatory group practice in Northern California. We analyzed data from 1,047 patients with newly diagnosed breast and colorectal cancers between 1/2019 and 8/2020 who received care at Sutter Health-Palo Alto Medical Foundation until 12/2020. We performed a T-test to examine whether patterns of treatment status (surgery vs chemotherapy vs neither) and time-to-treatment are different in pre-COVID vs pandemic eras. Results: The proportion of patients who did not receive surgery or chemotherapy during the pandemic was significantly higher, compared to the pre-COVID era (34.5% vs. 13.0%, p &lt; 0.01). Among the breast and colorectal cancer patients who received care, the time to initial treatment did not significantly vary in the pre-COVID (median 34 days, mean 36.8 days) era as compared to during the pandemic (median 30 days, mean 32.2 days) (p = 0.15). There was no difference when accounting for surgery (p = 0.15) vs chemotherapy (p = 0.52) as the initial treatment modality. A statistically significant difference was seen amongst the 888 breast cancer cases identified during the study period, but the mean time to treatment during the pandemic (31 days) was actually shorter than the mean time to treatment identified prior to the pandemic (38 days). This difference in breast cancer time to treatment was mainly driven by a statistically shorter time to surgery (p = 0.04) in the pandemic era with no statistically significant difference in time to chemotherapy following a breast cancer diagnosis in the pandemic era as compared to the pre-COVID era (p = 0.99). Conclusions: There was a significant difference in the number of patients who did not receive surgery or chemotherapy during the pandemic for newly diagnosed breast and colorectal cancers. However, amongst those patients who did receive treatment, there were no significant delays observed in time to initial treatment, regardless of treatment modality.[Table: see text]