tbuckley/cabot-search huggingface dataset:
Lynch-like syndrome in endometrial cancer: Features of a growing population.
Authors: Sushmita Gordhandas, Ryan Kahn, Brandon Paul Maddy, Becky Baltich Nelson, Gulce Askin, Paul J. Christos, Kevin Holcomb, Thomas A. Caputo, Eloise Chapman-Davis, Melissa Kristen Frey
Journal: Journal of Clinical Oncology (2019)

5585 Background: Current guidelines recommend screening all endometrial cancers (EC) and colorectal cancers (CRC) for defects in DNA mismatch repair (MMR). Tumor screening combined with germline genetic testing can categorize patients into three groups: intact-MMR, Lynch syndrome (LS), and Lynch-like syndrome (LLS). Our objective was to describe features of the growing population of patients with LLS in EC and compare to existing CRC literature. Methods: A systematic search of databases between 1990-2018 identified studies of EC patients with tumor testing (MMR immunohistochemistry or microsatellite instability) and germline assessment for LS. Data on clinicopathologic features was abstracted when available. Associations between LS, LLS, and intact-MMR were analyzed using descriptive statistics. Results: The comprehensive search produced 3,427 publications; 29 met inclusion criteria. Abstracted data and features of each group are presented in the table. Conclusions: In EC, LLS closely resembles LS with younger age at diagnosis, more advanced stage and higher grade as compared to patients with intact-MMR. LLS in EC is similar to intact-MMR in regard to histology, and family history of LS-associated cancer. The CRC literature is limited, but reports LS and LLS have similar stage, grade and histology. In CRC, LS and LLS are diagnosed at a younger age, and are more likely to have family history of LS-associated cancers than intact-MMR. Features of EC with intact-MMR, LLS, and LS. [Table: see text]
FGFR2: A pan-genomic target.
Authors: Russell Madison, Ethan Sokol, Alexa Betzig Schrock, Adrienne Johnson, Dean Pavlick, Julia Andrea Elvin, Jo-Anne Vergilio, Nhu Ngo, Jonathan Keith Killian, Douglas I. Lin, Shakti Ramkissoon, Eric Allan Severson, Amanda Hemmerich, Daniel Duncan, Siraj Mahamed Ali, Prasanth Reddy, Kimberly McGregor, Brian Alexander, Vincent A. Miller, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2019)

3099 Background: FGFR2 genomic alterations (GA) have been described in a variety of solid tumors and emerged as biomarkers for investigational agents undergoing clinical trials. Methods: 201,766 primarily relapsed/refractory malignancies were evaluated with a hybrid-capture based sequencing assay Tumor mutational burden (TMB) was determined on 0.8-1.1 Mbp of sequenced DNA and reported as mut/Mb. Microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3 antibody). Results: FGFR2 GA were detected in 2,993 (1.5%) cases featuring short variant (SV) mut (42%), copy number changes (27%), rearrangements/fusions (28%) and multiple GA (3%). The most frequent SV GA were S252W, N549K, C382R, P253R, Y375C, K659E and R664W. A small cohort (2%) of tumors featured the V564I and V564L GA that are associated with resistance to TKI drugs. The FGFR2-altered cases were 69% female/31% male with median age of 61 yrs. Most frequent GA in FGFR2 altered cancers: TP53 (47%), PIK3CA (22%), PTEN (20%), ARID1A (18%), CDKN2A/2B (18/14%) and MYC (12%). FGFR2 SVs most common in endometrial, breast carcinomas (ca) and CUP. FGFR2 amplification most common in breast, gastroesophageal and lung ca. FGFR rearrangement/fusions most common in cholangioca (37%), CUP (15%), pancreatobiliary (12%) and breast ca (6%). The FGFR2- BICC1 was the most frequent fusion followed by fusions with TACC2, AHCYL1, CCDC6, VCL, and KIAA1217. MSI-High status present in 6.8% of evaluable FGFR2 altered cases (63% in endometrial ca). Median TMB was 3.5 mut/Mb with 21.8% featuring ≥ 10 mut/Mb and 12.0% featuring ≥ 20 mut/Mb. Only 63% of MSI-High FGFR2 mut tumors had TMB ≥ 20 mut/Mb. 12.7% FGFR2 mut+ had &gt; 1% PD-L1 staining with 3.4% &gt; 50% staining. 29% of PD-L1 IHC+ cases in NSCLC. FGFR mut ca’s responding to anti-FGFR2 therapies will be presented. Conclusions: FGFR2 GA are most frequent in cholangioca, breast, GI tract, lung ca and CUP, with enrichment of FGFR2 fusions in biliary tract ca. Cases with FGFR2 GA typically do not feature other kinase driver GA and are associated with mut in the MTOR/PIK3CA/AKT pathways. Finally, in contrast with RTK driver GA in EGFR (5.7%) and ERBB2 (7.9%), at 12.0%, across all tumor types, FGFR2 mut cancers may have higher frequency of TMB ≥ 20 mut/Mb suggesting potential immunotherapy responsiveness.
Is in vivo reflectance confocal microscopy a useful assessment tool in chemotherapy-induced peripheral neuropathy (CIPN)?
Authors: Sabrina Ramnarine, Roman Rolke, Patrick M. Dougherty, Linda J Williams, Christi Alessi Fox, Andrew Coleman, Marie T Fallon
Journal: Journal of Clinical Oncology (2019)

e23088 Background: The lack of standardized diagnostic or assessment tools in CIPN pose an unmet need for objective and reliable measures. Advances in non-invasive, in vivo reflectance confocal microscopy (RCM) offer a painless method to identify markers of peripheral neuropathy such as loss of Meissner’s corpuscles (MC). This study aims to investigate the feasibility of RCM in CIPN by assessing MC density in healthy controls compared to cancer patients. Methods: RCM imaging (Vivascope 1500) was performed on the fingertip (digit V) to evaluate MC density in 45 healthy controls and 9 cancer patients prior to starting chemotherapy. Quantification was completed by two reviewers, one being blinded to achieve unbiased identification as the maximum MC count/6x6 mm image. Quantitative Sensory Testing (thermal and mechanical detection thresholds) along with the grooved pegboard test (sensorimotor function) were conducted for comparison with MC density. Spearman’s correlation coefficients were used to determine associations. Results: In healthy controls (25 females, 20 males; mean age 58.9, range 24-81 years), females exhibited a greater mean MC density compared with males (49.9 ± 7.1 MC vs 30.9 ± 4.2 MC; p = 0.03). Variances were observed across age range by decade (p &lt; 0.0001). MC density was inversely correlated with mechanical detection (ρ = -0.51) and warm detection thresholds (ρ = -0.47) in contrast to cold pain threshold (ρ = 0.49). All correlations were significant (p &lt; 0.01). Time to complete the grooved pegboard test correlated with MC density in the dominant hand (p = 0.02) and non-dominant hand (p &lt; 0.01). Compared with age and gender matched controls, cancer patients had reduced MC density (22.0 ± 9.3 vs 35.4 ± 14.1; p = 0.03), mirroring deficits in cold detection threshold and the grooved pegboard test. Inter-rater reliability of MC density count showed an intraclass correlation of 0.96 (p &lt; 0.0001). Conclusions: The findings from this study support the clinical utility of RCM in CIPN. Assessment of MC density using RCM may provide meaningful markers of sensory loss, sensorimotor function and an ability to detect possible subclinical deficits in patients at risk of CIPN prior to initiating chemotherapy.
KEYNOTE-811 pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction cancer (mG/GEJc): A double-blind, randomized, placebo-controlled phase III study.
Authors: Hyun Cheol Chung, Yung-Jue Bang, Charles S. Fuchs, Shukui Qin, Taroh Satoh, Kohei Shitara, Josep Tabernero, Eric Van Cutsem, Maria Alsina, Z. Alexander Cao, Xinqun Chen, Pooja Bhagia, Chie-Schin Shih, Yelena Yuriy Janjigian
Journal: Journal of Clinical Oncology (2020)

TPS463 Background: Combination therapy with the anti-HER2 antibody trastuzumab plus fluoropyrimidine and platinum is the current standard of care for patients with HER2+ mG/GEJc. We hypothesize that combination anti–PD-1 and anti-HER2 therapy will result in T-cell activation, augment antibody-dependent, cell-mediated cytotoxicity, and potentiate antitumor immune response in HER2+ patients. A phase 2 study in HER2+ mG/GEJc demonstrated the safety and preliminary efficacy of trastuzumab/pembrolizumab/chemotherapy; the objective response rate was 87%, and the disease control rate was 100% (Janjigian YY, ASCO GI 2019). KEYNOTE-811 (ClinicalTrials.gov, NCT03615326), a global, multicenter, randomized, placebo-controlled, phase 3 study, is underway. Methods: Key eligibility criteria are age ≥18 years; previously untreated unresectable or metastatic HER2+ (centrally confirmed IHC 3+ or IHC 2+/ISH &gt; 2.0) G/GEJ cancer; life expectancy &gt; 6 months with RECIST v1.1 measurable disease; and adequate organ function and performance status (ECOG PS of 0 or 1). Patients will be randomly assigned 1:1 to receive chemotherapy with pembrolizumab 200 mg intravenously (IV) or placebo with trastuzumab 6 mg/kg (after 8 mg/kg load) every 3 weeks (Q3W) up to 2 years or until intolerable toxicity or disease progression. Investigator-choice chemotherapy will include day 1 cisplatin 80 mg/m 2 IV and 5-fluorouracil 800 mg/m 2 /day IV (days 1-5) or oxaliplatin 130 mg/m 2 IV and capecitabine 1000 mg/m 2 BID days 1-14 (Q3W). Primary end points are progression-free survival and overall survival. Secondary end points are objective response rate, duration of response, and safety and tolerability. Adverse events are graded per CTCAE v4.0 and will be monitored for 30 or 90 days after treatment. Patients will be followed up for survival. Planned enrollment is approximately 692 patients. Clinical trial information: NCT03615326.
Genetic mutation analysis of plasma circulating tumor DNA by ultra-deep sequencing in breast benign lesions and cancers.
Authors: Qian Wu, Wenjing Jian, Xumei Yao, Xintong Xie, Hanjie Fang, Shengkai Geng, Shufeng Song, Haiyan Sheng, Xia Liu, Fangsheng Cheng, Wenling Xie, Shixin Lu, Yanhui Wang, Longhui Deng, Xiaohua Li, Xianming Wang, HW Zhang, Chuanbo Xu
Journal: Journal of Clinical Oncology (2019)

e14572 Background: Mammography screening for breast cancer results in large number of impalpable lesions without clear determination of the malignancy. Analysis of breast cancer related gene mutations in blood circulating tumor DNA (ctDNA) may provide clarification. This analysis aims to provide insights into the feasibility of the approach. Methods: The clinical trial was conducted at top tier teaching hospitals in China to recruit patients with breast diseases for surgery. Eligible patients were consented and the breast lesions were pathologically diagnosed. Peripheral blood was collected prior to surgical resection. For breast cancer patients, samples of resected tissue were also collected. The samples were analyzed using our proprietary NGS technique called systematic error correction sequencing (Sec-Seq) (detailed in Abstract ##e23057, ASCO 2018). Results: In total, 69 patients with breast lesions (57 malignant and 12 benign) were included in this analysis. Tumor gDNA and plasma ctDNA were analyzed by deep NGS sequencing using a panel of 62 breast cancer-associated genes. The average sequencing depth is 35000. After deduplication, the average number of unique reads is 1500. Detection limit for mutant allele frequency was set at 0.2% for ctDNA and 1% for tumor tissue. For ctDNA mutation detection, 2 out of 12 patients with benign diseases were found with mutations while 10 out of 55 breast cancer patients had no mutations, resulting in an overall sensitivity of 82% and specificity of 83%. By cancer stage, the two Stage 0 (carcinoma in situ) patients had no mutation, and the range of mutations detected is between 53% to 75% from Stage I to III. The tumor tissue samples have higher rate of mutations (only 2 cancer patients, 1 Stage 0 and 1 Stage 2, had no mutations). 15% patients have at least one common mutation detected in both the tumor tissue and ctDNA, and 27% patients have mutations in the same genes in the two matching samples. The concordance increases as the clinical stage advances. The most commonly mutated genes are previously reported breast cancer drivers of PIK3CA (79% of tumor and 18% of ctDNA samples), TP53 (56% and 39%), and BRCA1 (6% and 15%). Conclusions: In this hypothesis generating analysis, we showed the feasibility of plasma ctDNA sequencing for gene mutation detection in early stage breast cancer and differentiation from the benign breast diseases. Although with limited number of samples, the data encourage further improvement of the gene panel and the validation of ctDNA assay as a non-invasive approach to the cancer screening. Clinical trial information: ChiCTR1800017345.
Model-driven metronomic vinorelbine in heavily pre-treated metastatic NSCLC and PM patients: Results of a phase I/II study.
Authors: Joseph Ciccolini, Elissa Cousin, Laure Deyme, Diane-Charlotte Imbs, Sylvanie Bonnet, Raphael Serre, Matthieu Barbolosi, Laurent Greiller, Pascale Tomasini, Melissa Galloux, Bruno Lacarelle, Dominique Barbolosi, Fabrice Barlesi
Journal: Journal of Clinical Oncology (2019)

e20505 Background: A phase I/II trial (NCT02555007) of oral metronomic Vinorelbine derived from a mathematical model was performed in heavily pretreated metastatic Non-Small Cell Lung Cancer or Pleural Mesothelioma patients. Progression free survival, toxicity and PK/PD endpoints were the main objectives. Methods: Metronomic scheduling was selected using a simplified phenomenological model to identify the best continuous scheduling and dosing of oral vinorelbine with a total dose of 150 mg QW. Patients were monitored on a weekly basis, efficacy was evaluated by CT scans (RECIST). Toxicity was monitored using standard CTCAE criteria. Total tumor size (TTS) was the sum of diamaters of all lesions. Computation of individual PK parameters was done with Monolix software using population approach. Results: The PK/PD model proposed the following schedule: 60 mg D1, 30 mg D2, 60 mg D4. A total of 36 patients (30 evaluable) were enrolled (22M, 13F, 24 NSCLC, 11 mesothelium, median age 69.5, range 33-85.2). Patients were all heavily pre-treated (median 3 lines, range 1-9). Grade 3+ Neutropenia was observed in 30% patients. Median PFS was 11 weeks (range: 6-16.9). Best responses included 4 PR (13%) and 18 SD (60%). Baseline total tumor size was associated with reduced PFS (HR: 1.09, p = 0.026). A large variability in drug exposure (AUC 53 %, range 26 – 501 ng.h/ml) and PK parameters (Cl 82 %, range 45-605 l/h) was observed among patients. Exposure was not associated with efficacy, apart in patients with larger TTS (i.e., &gt; 70 mm) who seemed to have longer PFS (125 days VS. 40 days, p = 0.057). Vinorelbine exposure tended to be associated with higher risk for grade 2+ neutropenia, especially in patients with BSA &lt; 1.8 m² (60% VS. 25.5%, p = 0.055). A non-significant trend towards baseline NLR and PFS was observed (i.e., NLR &lt; 4: 80 days, NLR &gt; 4: 60 days, p = 0.077). Conclusions: Metronomic vinorelbine was characterized by huge variability in drug exposure among patients. However and despite being all heavily pre-treated, 60% of stable disease and 13% of PR were achieved in these patients. Plasma exposure yielded conflicting results depending on the initial tumor burden, suggesting that patients should be carefully selected prior to be scheduled for metronomic regimen. Possible role NLR could play as a predictive marker is intriguing and should be confirmed in larger cohort.
Sacubitril/valsartan eligibility and outcomes in the ESC‐EORP‐HFA Heart Failure Long‐Term Registry: bridging between European Medicines Agency/Food and Drug Administration label, the PARADIGM‐HF trial, ESC guidelines, and real world
Authors: Chris J. Kapelios, Mitja Lainscak, Gianluigi Savarese, Cécile Laroche, Petar Seferovic, Frank Ruschitzka, Andrew Coats, Stefan D. Anker, Maria G. Crespo‐Leiro, Gerasimos Filippatos, Massimo F. Piepoli, Giuseppe Rosano, Luisa Zanolla, Carlos Aguiar, Jan Murin, Przemyslaw Leszek, Theresa McDonagh, Aldo P. Maggioni, Lars H. Lund
Journal: European Journal of Heart Failure (2019)
Combination of niraparib and bevacizumab versus niraparib alone as treatment of recurrent platinum-sensitive ovarian cancer: A randomized controlled chemotherapy-free study—NSGO-AVANOVA2/ENGOT-OV24.
Authors: Mansoor Raza Mirza, Elisabeth Avall-Lundqvist, Michael J. Birrer, Rene dePont Christensen, Gitte-Bettina Nyvang, Susanne Malander, Maarit Anttila, Theresa Louise Werner, Bente Lund, Gabriel Lindahl, Sakari Hietanen, Ulla Peen, Maria Dimoula, Henrik Roed, Anja Or Knudsen, Louisa Boufercha, Synnove Staff, Anders Krog Vistisen, Line Bjorge, Johanna Unelma Maenpaa
Journal: Journal of Clinical Oncology (2019)

5505Background: Standard treatment of platinum-sensitive recurrent ovarian cancer (PSROC) is platinum based combination chemotherapy ± bevacizumab. However, this treatment modality is hardly curati...
Multidisciplinary approach to immune related adverse events as a potential biomarker: Single institution experience in non-small cell lung cancer.
Authors: Sooyoung Martin, Kai Laukamp, Amit Gupta, Kianoush Ansari-Gilani, Elias Kikano, Daniel Arnold Smith, Afshin Dowlati, Nikhil H. Ramaiya
Journal: Journal of Clinical Oncology (2019)

e14124 Background: Immune checkpoint inhibitor (ICI) has emerged as a novel systemic treatment for advanced cancers. As ICI modulates immune signaling pathways by targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1) or its ligands (PD-L1), a number of immune related adverse events (IRAE) have been reported. Whether IRAE can be a predictor for treatment response has remained controversial and we evaluated the association between IRAE and outcome. Methods: Retrospective chart and Computed Tomography (CT) review of patients with stage IV NSCLC treated with single agent Nivolumab or Pembrolizumab was performed. Any abnormalities in lab values, imaging finding or clinical signs to suggest pneumonitis, thyroiditis, hepatitis, nephritis, pancreatitis, colitis, pleural/pericardial effusion, arthritis or myositis between the start of the therapy and six months after the end of the therapy were recorded in a binary fashion. Abnormality in the setting of baseline abnormal values or due to clear cause other than IRAE has been excluded. Overall survival as well as best response based on RECIST 1.1 was also recorded. Results: 88 patients treated between January 2012 and March 2017 were identified. 62 patients, 42 patients and 50 patients demonstrated abnormalities in lab values, CT and clinical signs, respectively. When each subcategory was correlated with OS using ANOVA, thyroid function test abnormality (n = 15) and liver function test abnormality (n = 36) were associated with increased OS (p = 0.021, p = 0.038, respectively). Interestingly, elevated C-reactive protein was associated with decreased OS (p = 0.01). Initially, each score was given depending upon the number of abnormal categories (lab, imaging or clinical signs), ranging from score 0 (n = 7), 1 (n = 19), 2 (n = 33) and 3 (n = 17). Increased score was associated with increased OS (p = 0.03). For more detailed analysis, we came up with scoring system which sums up each score given for any abnormality in each subcategory. On Multivariate analysis, there was significant positive correlation between higher score and increased OS (p = 0.001). Conclusions: We have identified several IRAE parameters that were associated with increased OS. Furthermore, scoring system used in the study which encompassed clinical, radiologic and laboratory aspect, showed positive association with increased OS, indicating IRAE’s potential role as a biomarker.
Lowell S Levin: guardian of public health
Authors: Franklin Apfel, Ilona Kickbusch, Erio Ziglio
Journal: BMJ (2019)

Lowell Levin, professor emeritus of the Yale School of Public Health, was an inspirational source and mentor for many public health students, practitioners, managers, and leaders in the World Health Organisation, academia, and communities around the world.

Lowell focused much of his research, consulting, and teaching on promoting the importance of citizen participation in healthcare, health promotion, self care, and the control of iatrogenic complications in medical care.

> “Listen to the community: it’s defining its own problems, and may well know what to do about them.” 1
> 
> “There is a hidden healthcare system with clear definitions and roles. Eighty five per cent of healthcare takes place in a big pool without the ‘benefit’ of ‘medical clergy.’” 2

His research and work as a consultant throughout the world have often challenged established public health beliefs and practices. Committed to health promotion, in the 1960s he pioneered the citizen participation movement, focusing on health communication and the social and behavioural factors affecting health ( Self Care: Lay Initiatives in Health , 1976). In the 1970s and early 1980s, with the first publication of The Hidden Health Care System and other works, Lowell brought to public health’s attention the role of non-professional resources in strengthening personal capacity for health and wellbeing, primarily self care. In the 1980s Lowell pressed for improvement in the quality of medical care, notably as a co-author of Medicine on Trial: The Appalling Story of Ineptitude, Malfeasance, Neglect, and Arrogance —a 1988 groundbreaking book documenting the extent of medical mistakes and other widespread medical scandals. Lowell inspired people in different disciplines and with …
Evaluation of androgen receptor expression in core needle biopsies and clinico-pathological factors in primary breast cancer.
Authors: Nobuyuki Arima, Reiki Nishimura, Tomofumi Osako, Yasuhiro Okumura, Masahiro Nakano, Mamiko Fujisue
Journal: Journal of Clinical Oncology (2019)

e12023 Background: Immunohistochemistry (IHC) is used to determine breast cancer subtypes and to evaluate the ER, PgR, and HER2 expressions and the Ki-67 index value. The androgen receptor (AR) is frequently expressed in breast cancer but has not been standardized. IHC is recommended when using preoperative biopsy specimens to determine biomarker expressions. In this study, the differences in AR expression between core needle biopsy and matched surgical samples were investigated. The AR expression was evaluated as a predictor for neoadjuvant chemotherapy and grade of malignancy. Methods: Primary breast cancer patients (n = 363) who underwent surgery between March 2017 and December 2018 were divided into 3 groups; the core needle biopsy and matched surgical comparison group (n = 167), the neoadjuvant chemotherapy group (n = 54), and the without neoadjuvant chemotherapy group (n = 309). The AR expression was evaluated using IHC and the expression was divided into the negative, low ( &lt; 10%) and high (≥10%) groups. Breast cancer subtypes were categorized using the IHC data derived from ER/PgR, HER2 and Ki-67 (cutoff 20%) values. Results: 1. There was no difference between the ER, PgR and HER2 expressions in the comparison group. AR was significantly lower in the surgical specimens. 2. The pCR rate was significantly higher in the ER and PgR negative cases. AR and the Ki-67 value did not correlate with pCR. 3. The AR positive rate was 61.2% in invasive carcinoma cases. Apocrine carcinoma showed a 100% positive rate. 4. AR expression significantly correlated with positive ER and PgR, a lower Ki-67 value, negative p53, and a lower nuclear grade. Luminal A type showed a higher AR rate (78.2%) than the TN and HER2 types. The AR rate was significantly lower (17.1%) in the TN type cases. Conclusions: discordance in the AR expression between the core needle biopsies and matched surgical specimens was found. AR expression using IHC should be evaluated in core needle biopsies.