tbuckley/cabot-search huggingface dataset:
A retrospective study of low-dose apatinib combined with S-1 in patients with advanced non-small cell lung cancer.
Authors: Tong Zhou, Xiaoyue Zhou, Peng Li, Changling Wu, Changsong Zhang, Huajie Dong, Hongjun Lu, Martin Qi, Yang Ling
Journal: Journal of Clinical Oncology (2019)

e20666 Background: Currently regimen for advanced non-small cell lung cancer (NSCLC) failing from standard treatment is deficient. This retrospective study aimed to assess the efficacy and safety of low-dose apatinib in combination with S-1 therapy in this NSCLC setting. Methods: In this retrospective study, advanced NSCLC patients who failed from standard treatment in Changzhou Cancer Hospital of Soochow University were screened for eligibility. Progression-free survival (PFS) was set as the primary endpoint. Overall response rate (ORR), disease control rate (DCR), Overall survival (OS) and safety profile were considered to be the secondary endpoints. Results: 31 eligible patients were included in this study. The median PFS (mPFS) was 102 days (95% CI: 57-147). 7 patients (23%; 95% CI: 11-38%) achieved an objective response and the DCR was maintained in 23 patients (75%; 95% CI: 58-86%). The median OS (mOS) was 422 days (95% CI: 148-696).Patients with smoking had a tendency for shorter overall survival without significant differences (HR = 4.105, 95% CI: 0.874-19.288, P = 0.074). Treatment-related grade 3 toxicity was observed in five patients (16%) and the common grade 1 or 2 adverse events were fatigue (42%), hypertension (32%), and hand-foot-skin reaction (23%). Conclusions: Combination of low-dose apatinib and S-1 could be effective and tolerable for advanced NSCLC patients failed from standard treatment, but further exploration in larger clinical trials is needed.
Circulating cell-free DNA (ctDNA) assessments before, during, and after neoadjuvant therapy (NAC) in nonmetastatic inflammatory breast cancer (IBC).
Authors: Carolyn S. Hall, Salyna Meas, Vanessa Nicole Sarli, Anthony Lucci
Journal: Journal of Clinical Oncology (2019)

e12113 Background: : IBC is a rare and aggressive subtype of breast cancer. A significant number of IBC patients who achieve pathologic complete response (no residual tumor in breast and axillary nodes, pCR) relapse after NAC. We hypothesized that circulating cell-free DNA (ctDNA) identified in blood before, during, and after NAC would identify novel ctDNA targets. Methods: Plasma ctDNA was extracted from 43 non-metastatic IBC patients (IRB: LAB04-0698) pre, mid, and post-NAC. The Oncomine Pan Cancer ctDNA Assay (ThermoFisher) was used for library preparation, and high throughput next generation sequencing was performed on a GeneStudio S5XL System (ThermoFisher), following manufacturer’s directions. ThermoFisher Ion Reporter 5.10 Software was used to analyze single nucleotide variants (SNVs), and copy number variants (CNVs). Results: Seventeen patients had pre-NAC ctDNA assessments; 7/17 (41%) had PIK3CA SNVs; 5/7 also had MYC or FGFR2 CNVs. Five of 17 (29%) had TP53 SNVs; 2/5 also had FGFR2 CNVs. Ten patients had mid-NAC ctDNA assessments; 9/10 (90%) had PIK3CA SNVs; 5/9 also had FGFR2 CNVs, 2/9 had FGFR2 and FGFR3 CNVs, 2/9 also had TP53 SNVs, 1/9 had FGFR2 and ERB2 CNVs. Thirty-one patients had post-NAC ctDNA assessments; 5/31 (16%) had PIK3CA SNVs; 2/5 had FGFR2 CNVs, 1/5 also had a TP53 mutation and an FGFR2 CNV, 1/5 had FGFR2 CNV, and FGFR3 CNV. Six of 31 (19%) had TP53 SNVs, 1/6 had CCND1 CNVs, no CNVs were detected in 6 patients with TP53 SNVs. Six of 31 (19%) had MAP2K1 SNVs. Three of 31 (10%) had MET SNVs; 1/3 had CCND3 CNVs, no CNVs were detected in 2 patients with MET SNVs. No SNVs or CNVs were detected in 10/31 (32%) of patients post NAC. Conclusions: ctDNA assessments before, during, and after NAC identified novel targets that could be tested in future adjuvant therapies trials in IBC patients who remain at high risk for relapse.
The Unripe Akee — Forbidden Fruit
Authors: Rubin Bressler
Journal: New England Journal of Medicine (1976)

For many years, the poor people of Jamaica have been subject to an illness, characterized by a sudden onset of vomiting, usually two to three hours after a meal. This most conspicuous characteristic and the early lack of clues to its cause earned this type of food poisoning the descriptive name of "vomiting sickness of Jamaica." A review of the vomiting sickness by Hill1 summarized knowledge on the subject up to 1952, and it was enriched by his personal observations of many patients. Hassall and Reyle2 later reviewed the literature from 1952 to 1955.Subjects with vomiting sickness were observed . . .
Improving access to genetic counseling services in an adolescent and young adult (AYA) clinic.
Authors: Jessica Ross, Donna Bell, Angela R. Yarbrough, Susan K. Peterson, Sukh Makhnoon, Banu Arun, J Andrew Livingston, Michael Roth
Journal: Journal of Clinical Oncology (2019)

e13009 Background: Numerous studies have explored genetic testing access and benefits in adult and pediatric cancer patients, however little is known about the use of these services in adolescents and young adult (AYA) cancer patients. Routine genetic counseling may be particularly important for AYAs who are survivors of childhood cancer, as 8.5% of children with cancer have an inherited pathogenic germline variant. Genetic testing also helps reduce cancer morbidity and mortality in adolescents, as well as helps to guide cancer prevention strategies in family members. This study describes an innovative approach to fostering AYA patients’ access to genetic counseling services. Methods: AYA patients (ages 15-29) with a new or prior cancer diagnosis were referred to MD Anderson Cancer Center’s AYA multi-disciplinary clinic. Prior to their clinic visits, a genetic counselor reviewed relevant medical and family history information for patients seen from 7/12/18 through 1/11/19. For those at risk for a hereditary cancer syndrome, a recommendation for a genetic counseling referral was given to the AYA medical provider based on established guidelines, professional consensus, and clinical judgement guided by thorough literature reviews. Results: In total, 254 AYA patients’ charts were reviewed and 70 (27.6%) patients had histories that warranted a genetic counseling referral. Of these 70 patients, 53 (75.7%) were not previously seen by genetics. Of the 53 patients newly recommended to be referred, 29 (54.7%) had referrals placed. Of the 24 patients not referred, 17 did not attend their AYA visit, 5 refused the referral, and 2 were not referred for undetermined reasons. Of those referred, 10 completed genetic counseling, 14 are scheduled for counseling, 3 did not attend their appointment, and 2 had counseling at another institution. This process led to a 41.3% absolute increase in referrals to genetic counseling for those at risk for hereditary cancer syndromes. Conclusions: The described clinic workflow identified gaps in genetic referrals and showed an innovative approach to fostering AYA access to genetic services. This approach may be useful for other institutions interested in increasing access to genetic services for AYAs.
The impact of heart radiation dose in lung SABR.
Authors: Hao Wen, Gerald Gan, Jon Stobo, Nazia Mohammed
Journal: Journal of Clinical Oncology (2019)

e20054 Background: Lung cancer has poor outcomes, but those patients diagnosed with stage 1 NSCLC have 5-year survival of 60-70%. Stereotactic ablative body radiotherapy (SABR) is routinely considered for patients unfit for surgery. SABR is very well tolerated hence a treatment option for patients unfit for surgery, with &gt; G2 lung toxicity of 1.8-9.1%, but propensity-matched analyses of stage 1 NSCLC treated with surgery or SABR have shown superiority of surgery in terms of overall survival, but not lung cancer-specific survival. Excess risk of CVD is a complication of breast cancer RT, but there is limited evidence in lung cancer. The aims of this study is to investigate the impact of radiation dose to the heart in lung SABR. Methods: In a single centre from November 2011-2012, patients who treated with lung SABR outwith the “no fly zone”, using ROSEL guidelines for OARS and with the lowest or highest heart maximum point dose were selected. 9 patients in each group were analysed for dose and clinical factors retrospectively from electronic patient notes. Results: The median (range) heart dose of the high dose (HD) group was 25.3Gy (17.6–34.1) and that of the low dose (LD) group was 0.88Gy (0.18–4.8). At the end of a median follow-up of 6.7 years, OS was poorer in the HD group at 11% than the LD group at 56% (p = 0.127). While 5-year cancer-specific mortality was similar in both groups at 22%, non-cancer-associated mortality was higher in HD (44% vs 11%, p = 0.127). In addition, HD were associated with a greater risk of CV hospital admission (56% vs 11%, p = 0.131) and new cardiac abnormalities (56% vs 0%, p = 0.029). Conclusions: In this group of medically unfit NSCLC patients treated with lung SABR, there were differences in outcome possibly associated with heart dose. The HD group showed higher mortality, specifically non-cancer-related mortality and cardiac events. Investigation of a larger cohort is warranted. [Table: see text]
Anti-PD-1 therapy combined with chemotherapy in patients with advanced pancreas cancer in a real-world clinical setting.
Authors: Danyang Sun, Junxun Ma, Jinliang Wang, Chun Han, Yuanyu Qian, Guangying Chen, Xiaoyan Li, Juan Zhang, Pengfei Cui, Wushuang Du, Zhaozhen Wu, Shixue Chen, Xuan Zheng, Zhichao Yue, Jia Song, Shangli Cai, YI HU
Journal: Journal of Clinical Oncology (2019)

e14103 Background: Pancreatic cancer (PC) is a highly lethal disease and characterized by a strong resistance to current radiotherapy and chemotherapy. As PC has the presence of a microenvironment filled with immunosuppressive mediators and a dense stroma which involved in immune system control, the immune system has been hypothesized to play an important role in PC. However, there was no response in patients who received immune checkpoint inhibitors (ICIs) monotherapy. Though small sample studies revealed that ICIs combined with chemotherapy is effective, a head-to-head comparison of ICIs plus chemotherapy and chemotherapy is limited. Methods: Advanced PC patients treated with chemotherapy alone or plus ICIs were retrospectively screened for eligibility. Patients previously treated with any agent targeting T-cell co-stimulation or checkpoint pathways was excluded. The primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS), overall response rate (ORR) and safety. Results: In total, 58 patients were included (combination, n = 22; chemotherapy, n = 36). Combination group presented significantly longer OS than chemotherapy group (median, 18.1 vs 6.1 months, HR 0.46 [0.23-0.90], P = 0.021). Median PFS was 3.2 months in the combination group and 2.0 months in the chemotherapy group (HR 0.57 [0.32-0.99], P = 0.041). The ORR was similar between the combination group and the chemotherapy group with no significant difference (18.2% vs 19.4%, P = 0.906). And all the patients, who reached partial response, accepted a two-chemotherapic-drugs regimen regardless of combinating with ICIs. Adverse events of grade 3 or higher occurred in 31.8% of the patients in the combination group and in 16.9% of those in the chemotherapy group. Though the incidence rate of serious treatment-related adverse events (TRAEs) was higher in the combination group than the chemotherapy group, no statistical significance existed (P = 0.183). Conclusions: Combination of ICIs plus chemotherapy is effective and tolerable for advanced PC. Accepting ICIs combined with a two-drug chemotherapy regimen might be the better choice.
Case 35-1992
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely
Journal: New England Journal of Medicine (1992)

Presentation of Case An eight-month-old boy was admitted to the hospital because of chronic diarrhea and inadequate weight gain. He was born of a full-term uncomplicated second pregnancy by spontaneous vaginal delivery. The birth weight was 3.55 kg (75th percentile). The boy was well until the age of six weeks, when a nasal discharge and cough developed, with the passage of loose stools as often as five times daily, without blood. He continued to be active and nursed well. One week later the patient was admitted to another hospital. The temperature was 37.9°C, and the weight 4.24 kg (25th percentile). . . .
Effect of a multi-disciplinary approach and incorporation of reflex testing on genomic profiling of non-squamous lung cancer in a community oncology practice.
Authors: Niraj K. Gupta, Brent Toney, Sajeev Uprety, Mark Mastrodicasa, Anthony Ascioti, Vijay Nuthakki, Christopher A. Leagre, Raja Mahidhara, Richard K Freeman, Sunil Jhajria, Ryan Schroeder, Ed Mintz, Kristen Schmidt, Vas Tumati, Robert H. Liebross
Journal: Journal of Clinical Oncology (2019)

e20719 Background: Genomic profiling of advanced non-squamous lung cancer is integral for appropriate management. Appropriate testing and timeliness in getting the results often pose a challenge in a community setting. We share our experience in a community setting and the importance of an integrated approach to improve outcomes. Methods: Retrospective review of the charts of patients with stage- III-B/IV was conducted to gather data. Effect of Multi-disciplinary meetings to improving coordination among treating physicians and Incorporation of reflex testing for complete mutational profiling on diagnosis was studied. Results: Between 04/2016 and 10/2018, 127 patients charts were reviewed. 83% were stage-IV and 17% stage-III-B. Males (61%), Females (49%). Median age was 62 yrs. 76% had smoking history.There were 53% core biopsies, 42% FNAs and 5% resections. Mutational profiling panel was based on the NCCN guidelines. Adequate specimen for complete profiling was available in 111/127 (87%) of the patients. Two/16 (12%) of pts with in-adequate sample had a repeat biopsy and 12/16 ( 75%) had liquid biopsies done. Remaining 2 pts didnot have further w/u due to declining PS. Complete mutational profile (EGFR/ALK/ROS-1/MET/RET/BRAF/PDL-1) was available in 100% of pts. after re-biopsy/liquid bx. Incorporation of reflex testing decreased the reporting time from an average of 11.6 days to 6.9 days. The results of mutational profiling were available in 94% of pts. before starting the treatment. Prevalence of mutations were, EGFR:14%, ALk:3%, BRAF:1%, MET:0%, RET:1%, ROS-1:2%. Conclusions: Multi-disciplinary integrated approach and reflex testing upon diagnosis is essential for appropriate and timely genomic profiling of locally advanced/ metastatic non-squamous lung cancer patients to deliver appropriate treatment in a community setting.
Phase II trial PD-L1/PD-1 blockade avelumab with chemoradiotherapy for locally advanced resectable T3B-4/N1-2 rectal cancer: The Ave-Rec trial.
Authors: Michael Michael, Rachel Wong, Sanjeev Singh Gill, David Goldstein, Sam Ngan, Alexander Graham Heriot, Emma Link, Maria Farrell, Paul J Neeson, Robert George Ramsay, Kasmira Wilson, Catherine Mitchell, Jeanne Tie, Nick Pavlakis, John Raymond Zalcberg, Eva Segelov
Journal: Journal of Clinical Oncology (2019)

TPS3622 Background: Standard neoadjuvant long course chemoradiotherapy (LCCRT) for locally advanced rectal cancer (LARC) results in a complete pathological response rate of 10-30%: but 20-40% of patients (pts) are non-responders, 10-15% have local recurrence. Tumoural immune infiltrates are predictive of response. Preclinical studies show that radiotherapy (RT) via interferon signaling is immuno-stimulatory, enhancing local/distant tumour cell death. RT also stimulates PDL1 production and the immunosuppressive activity of myeloid derived suppressor cells. Hence PDL1 inhibition may be required to enhance the immuno-stimulatory effects of RT. Hypothesis: In pts with resectable LARC, the anti-PDL1 antibody Avelumab post LCCRT may enhance the pathological/imaging response rates whilst potentially reducing local/distant relapse rates. Methods: (1) Trial Design: Phase II single arm trial, across 6 Australian sites (2) Endpoints: (a) Primary; Pathological response rate post-LCCRT, as documented by central pathologist, (b) Secondary; MRI/FDG PET imaging responses at 8 weeks post LCCRT (pre-surgery). Toxicity. (c) Exploratory; Tumoural immune cell subsets/checkpoint expression (by multiplex immunohistochemistry and in-vitro functional assays) and ctDNA analysis at baseline and during treatment. Distant relapse-free survival and the documentation of sites of relapse. (3) Sample size: An increase in the proportion of pathological complete responses by &gt; 25% (from 10% to 35%) will be considered clinically important. Power = 90%, α = 0.05, 41 pts are required– an additional 4 pts to allow for drop-out. Total sample size = 45pts. Treatment: All pts to receive standard LCCRT (50.4Gy RT plus 5FU [225mg/m 2 /day/CI] or Capecitabine [825mg/m 2 BID on RT days] over 5.5 weeks). Post LCCRT (prior to surgery), pts receive 4 cycles Avelumab (10mg/kg, q2 weeks). Surgical resection 10-12 weeks post LCCRT. Fresh tumour biopsy and ctDNA sampling pre LCCRT, pre Cycle 1 Avelumab and at surgery. Response by FDG PET and pelvic MRI pre surgery. Pts to be followed up for 2 years. Major Inclusion Criteria: Pts with LARC, MRI stage T3b-4/N1-2/M0, planned for LCCRT followed by curative resection, tumoural lower border within 12cm from the anal verge, measurable disease (RECIST1.1), ECOG 0-1, adequate organ function and no contraindications to Avelumab therapy. Current Enrolment: 11 of the planned 45 patients enrolled. Clinical trial information: NCT03299660.
Phase Ib study: Selective histone deacetylase (HDAC) inhibitor ACY-241 + nivolumab (Nivo) in advanced non-small cell lung cancer (NSCLC).
Authors: Mark M. Awad, Yvan Le Bruchec, Brian Lu, Julieann Miller, Calin Dan Dumitru, Alexander I. Spira
Journal: Journal of Clinical Oncology (2019)

9029 Background: Identification of new regimens for patients (pts) with relapse/refractory NSCLC is an ongoing need. HDAC inhibitor monotherapy has cytostatic activity in pts with NSCLC. The HDAC6 inhibitor ACY-241 has immunomodulatory activity and may synergize with immune checkpoint inhibitors (ICI). This phase Ib study investigated ACY-241 + nivo in metastatic NSCLC. Methods: Previously platinum-treated, ICI-naïve pts with advanced NSCLC and ECOG PS ≤ 1 were eligible. In 3 + 3 dose-escalation, pts received ACY-241 (180, 360, or 480 mg PO; d 1-28) + nivo 240 mg on d 15 of cycle 1 and d 1,15 subsequently in 28-d cycles. Primary outcomes: safety and RP2D. Secondary outcome: antitumor activity. Exploratory outcome: biomarker analyses; peripheral blood samples and tumor biopsies were collected pre- and on-treatment. Results: As of Jan 17, 2019, 18 pts were treated. Median age 66 y; 56% male, 78% PS 1, 93% stage IV, 28% PD-L1–negative, and 89% adenocarcinoma (11% squamous). No DLTs were observed at ACY-241 180 or 360 mg, and 2 DLTs were observed at 480 mg (gr 3 nausea lasting &gt; 72 h despite medication; gr 5 cardiac arrest); 360 mg was declared RP2D. Common all-grade AEs: fatigue (22%), arthralgia (17%), and cough (17%); 1 gr 3 cerebrovascular accident (related to brain metastasis unrelated to study drug) and 1 additional gr 5 AE (myasthenia gravis, possibly related to ACY-241 and nivo) occurred. Of 13 response-evaluable pts, 8 had clinical benefit (1 CR, 3 PR [1 PD-L1–negative], 1 unconfirmed PR [tumor shrinkage followed by new lesion], 3 SD); 5 had PD. At data cutoff, treatment was ongoing in 5 pts (12 – 30 cycles). Histone and tubulin acetylation levels were transiently increased after treatment. Circulating IL-2, IL-1β, MMP-9, and IL-10 levels increased, with undetectable TNF-α and IFN-γ modulation. Treatment-related changes in tumor-infiltrating T reg , MDSC, T CM , and macrophages varied between pts but revealed a trend of increased infiltrating cytotoxic T and NK cells. Conclusions: The ACY-241 + nivo combination is feasible and can be considered for further research as a potential NSCLC treatment option. Biomarker analyses may help identify an optimal population for the combination. Clinical trial information: NCT02635061.
AcSé-ESMART: European Proof of Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors in Children and Adolescents–Arm D: Olaparib and irinotecan.
Authors: Susanne Andrea Gatz, Jonathan Rubino, Caroline Rossoni, Nicolas Andre, Isabelle Aerts, Estelle Thebaud, Souad Nebchi, Windy Rondof, Daniel Hübschmann, Peter G. Mortimer, Xavier Paoletti, Gilles Vassal, Birgit Geoerger
Journal: Journal of Clinical Oncology (2019)

10047 Background: AcSé-ESMART is a proof-of-concept, phase I/II, multicenter, prospective basket trial designed to explore targeting agents in a molecularly enriched cancer population; treatment arms with targeted agents as single agent or in combination regimens are explored independently. Arm D explores the PARP inhibitor olaparib (ola) in combination with irinotecan (iri). The design is based on the hypothesis that in pediatric cancer pathogenic BRCA alterations are extremely rare and proliferative capacity is high requiring a chemotherapy sensitisation approach. Preclinical data in pediatric cancer suggest PARP inhibitor activity in other genomic alterations impairing homologous recombination (HR) and demonstrate synergy with iri. We here report the results of the Phase I part of the trial. Methods: Children and adolescents with relapsed/refractory cancer and comprehensive molecular profiling (whole exome and RNA sequencing) at relapse were eligible. Dose-escalation followed a continuous reassessment method design of pre-specified dose combinations of oral ola and iv iri. Plasma for pharmacokinetics (PK) was collected. Results: From Oct 2016 to April 2018, 27 pts (19 sarcomas, 3 brain tumors, 5 other) with a median age of 15 y (range 4;22) were enrolled over 4 dose levels. Dose limiting toxicities occurred in 7 of 24 evaluable pts (gastrointestinal (n = 4), febrile neutropenia (n = 1), thrombocytopenia (n = 2)). The RP2D was defined as ola 90 mg/m2 BID day 1-10 and iri 20 mg/m2 day 4-8. Twenty-three pts evaluable for response received a median of 2 cycles (range 1-27+). Confirmed PRs were seen in one osteosarcoma, one pinealoblastoma and one neuroblastoma; time to progression was 22.4, 50 and 89+ weeks, respectively. Eight pts experienced disease stabilization (median 14.8 weeks, range 9;42.3). PK and biomarker analysis (ie. HR alterations, DNA and gene expression signatures) is ongoing to identify factors associated with clinical benefit and data will be presented. Conclusions: The RP2D of the combination is ola 90 mg/m2 BID day 1-10 and iri 20 mg/m2 day 4-8. Preliminary activity led to the ongoing Phase II part of the arm. Clinical trial information: NCT02813135.
Human cleaving embryos enable robust homozygotic nucleotide substitutions by base editors
Authors: Meiling Zhang, Changyang Zhou, Yu Wei, Chunlong Xu, Hong Pan, Wenqin Ying, Yidi Sun, Yun Sun, Qingquan Xiao, Ning Yao, Wanxia Zhong, Yun Li, Keliang Wu, Gao Yuan, Shoukhrat Mitalipov, Zi-jiang Chen, Hui Yang
Journal: Genome biology (2019)

Base editing installs a precise nucleotide change in specific gene loci without causing a double-strand break. Its efficiency in human embryos is generally low, limiting its utility in functional genetic studies. Here, we report that injecting base editors into human cleaving two-cell and four-cell embryos results in much higher (up to 13-fold) homozygotic nucleotide substitution efficiency as opposed to MII oocytes or zygotes. Furthermore, as a proof-of-principle study, a point mutation can be efficiently corrected by our method. Our study indicates that human cleaving embryos provide an efficient base editing window for robust gene disruption and correction.