tbuckley/cabot-search huggingface dataset:
Clinical, pathological and prognostic features of rare BRAF mutations (MTs) in metastatic colorectal cancer (mCRC): A bi-institutional retrospective analysis (REBUS study).
Authors: Brunella Di Stefano, Maria Alessandra Calegari, Michele Basso, Armando Orlandi, Alessandra Boccaccino, Fiorella Lombardo, Ina Valeria Zurlo, Maria Bensi, Floriana Camarda, Raffaella Vivolo, Alessandra Cocomazzi, Maurizio Martini, Alessandra Auriemma, Carmelo Pozzo, Emilio Bria, Lisa Salvatore, Giampaolo Tortora
Journal: Journal of Clinical Oncology (2019)

3554 Background: Recently, 3 classes of BRAF MTs have been described. BRAF V600 MTs, which identify mCRC with poor prognosis and not benefitting from anti-EGFR drugs, belong to class 1. Class 2 and 3 include BRAF non-V600 MTs, which occur in about 1-2% mCRC and are associated to favourable prognosis and specific clinicopathologic features. Class 2 and 3 differ in kinase activity and sensitivity to anti-EGFR: class 2 are activated and RAS-independent MTs; class 3 are kinase-dead and sensitive to inhibition of This study aims to retrospectively evaluate features and prognostic role of rare BRAF non-V600 compared to BRAF V600E MTs in mCRC pts treated at 2 Italian Institutions. Methods: mCRC pts harboring BRAF MTs, assessed by means of NGS, pyrosequencing or RT-PCR, treated between Jan-13 and Dec-18 at 2 Italian Institutions, were retrospectively analyzed. Clinico-pathological and treatment characteristics and survival data were collected. Results: 55 pts bearing BRAF MTs were identified. Of those, 46 (84%) harbored a V600E and 9 (16%) a non-V600 MT. Within the non-V600 group, 3 MTs (K601E, G469A, G469R) belonged to class 2, while 5 MTs (G466E, G466A, 2 D594G, D594N), belonged to class 3. One pt harboured a T599I MT, whose kinase activity is unknown. Compared to BRAF V600E mCRC, BRAF non-V600 mCRC were more frequently left-sided ( p .017) and displayed a lower grade ( p .045). In addition, non-V600 mCRC pts had a lower tumor burden (involving one metastatic site) ( p .026) and underwent more frequently to resection of metastases with radical intent (77.7 vs 18%; p .000175). mOS was significantly longer in the non-V600 compared to the V600E group (61.3 vs 20.4 m; HR 0.41, 95%CI 0.18-0.93; p .05). No difference in activity and efficacy of anti-EGFR agents was observed between class 2 and 3. Conclusions: Despite the small size of our retrospective analysis, the results were consistent with previous evidences. BRAF non-V600 MTs identified a subgroup of mCRC, differing both in terms of clinicopathologic characteristics and prognosis from BRAF V600 mCRC. Interestingly, the better prognostic features allowed more frequently radical resection of metastases, positively impacting on survival.
Dynamic of molecular subtypes of high‐grade serous ovarian cancer in paired primary and relapsed biopsies.
Authors: Elena Ioana Braicu, Hagen Kulbe, Felix Dreher, Eliane T Taube, Frauke Ringel, Gabriele Welsch, Silvia Darb-Esfahani, Carlotta Keunecke, Thomas Kessler, Christoph Wierling, Paul Jank, Carsten Denkert, Hedwig Lammert, Michael Hummel, Jalid Sehouli
Journal: Journal of Clinical Oncology (2019)

e17091 Background: Previously four molecular subtypes of high grade serous ovarian cancer (HGSOC) with distinct biological features and clinical outcome have been described: C1 (mesenchymal), C2 (immunoreactive), C4 (differentiated), and C5 (proliferative). Using Nanostring technique and a minimal signature of 39 classifier genes could reproduce the subtypes identified by microarray gene expression profiling (Leong HS et al. Australian Ovarian Cancer Study. J Pathol. 2015). Methods: We characterized paraffin embedded tissue samples from 279 HGSOC patients for molecular subtypes, utilizing the 39 classifier signature and 9 control genes by Nanostring nCounter Analysis System. From 16 patients paired primary and relapsed samples were available. Only chemonaive primary HGSOC patients were included in the study. FFPEs and clinical data were provided by TOC ( www.toc-network.de ). For each sample, probability scores for the four molecular subtypes (C1, C2, C4, and C5) were calculated. The highest calculated score determined the most likely subtype of the tumor. Results: Of all analyzed primary tumor samples, 88 (31.5%) were classified as C1, 83 (29.8%), 53 (19.0%) and 55 (19.7%) as subtypes C2, C4 and C5, respectively. Our results confirmed data by the AOCS study, which described the distribution of HGSOC with 40.2% (C1), 22.5% (C2), 20.1% (C4) and 17.2% (C5), respectively. Within the paired samples, for 12 of the 16 patients dynamic changes in the molecular subtypes between primary and relapse occurred, while in the remaining 4 patients the phenotype was stable. Conclusions: Molecular subtypes of HGSOC using Nanostring technology with a small panel of classifier genes can be confirmed. Furthermore, the data showed that a change of the established molecular subtype might occur during the evolution of the disease, and therefore translate in a different clinical outcome.
TTF1 negative in non small cell lung cancer adenocarcinoma: A prognostic factor.
Authors: Juan Felipe Cordoba, Serafin Morales, Joel Veas Rodriguez, Álvaro Rodriguez Galindo, Antonia Salud
Journal: Journal of Clinical Oncology (2019)

e20004 Background: Patients with thyroid transcription factor 1 (TTF1) negative lung adenocarcinoma (ADC) have been reported to have a worse prognosis and to lack epidermal growth factor receptor (EGFR) mutations. This study describes a series of sample tumors from patients with clinically confirmed lung cancer. Methods: In all lung cancer patients diagnosed in the University Hospital of Lleida from January 2011 to December 2016, a real world data study of TTF1-negative ADC was performed, using TTF1 clone 8G7G3/1(DAKO). Each patient’s clinical history, pathology specimens and molecular results were noted. Two hundred and thirty one patients with TTF1 positive lung ADC formed the control group. Results: Twenty seven (27) patients were identified with ADC TTF1 negative (74% males). The media age was 66 years. The smoking history was as follows: 55,5% former, 29,6% ex smokers and 14,8% never smokers. The clinical stages were as follows: stage I or II (n = 3 [11%]), stage III (n = 4 [14,8%]) and stage IV (n = 20 [74%]). Patients’ mean survival was 7,6 vs 24,4 months in ADC TTF1 negative patients (P = 0,00001). Three hundred and thirty four (334) patients with ADC were found, TTF1 results were available in 258 (77,2%) cases, of them twenty-seven cases (10,4%) had TTF1 negative; when they were compared with the control group, TTF1 negative patients had overall shorter survival (P = 0,00001), regardless of whether patients were treated with radical or palliative intent: 34,4 vs 10, months P = 0,00001 (radical treatment) and 14,6 vs 6,7 months P = 0,007 (palliative intent). EGFR mutations were less frequent (P = 0,046) in TTF-negative tumors 5,5% vs 25,3%. Conclusions: Patients with TTF1 negative NSCLC ADC, have worse overall survival regardless of treatment intention and a lower frequency of EGFR mutations.
ENGOT-OV44/FIRST study: A randomized, double-blind, adaptive, phase III study of platinum-based therapy with dostarlimab (TSR-042) + niraparib versus standard-of-care (SOC) platinum-based therapy as first-line treatment of stage 3/4 non-mucinous epithelial ovarian cancer (OC).
Authors: Anne-Claire Hardy-Bessard, Kathleen N. Moore, Mansoor Raza Mirza, Bernard Asselain, Andres Redondo, Jacobus Pfisterer, Sandro Pignata, Diane M. Provencher, David Cibula, Anna K.L. Reyners, Lubomir Bodnar, Rosalind Margaret Glasspool, Christos A. Papadimitriou, Rami Eitan, Sileny Han, Linda R. Duska, Bj Rimel, Sebastien Hazard, Jian Chen, Eric Pujade-Lauraine
Journal: Journal of Clinical Oncology (2019)

TPS5600 Background: Despite surgery and SOC therapy (paclitaxel and carboplatin ± bevacizumab[bev]), 5-year survival rates remain low for patients (pts) with FIGO stage 3/4 OC. Niraparib (ZEJULA) is the first selective poly(ADP-ribose) polymerase inhibitor (PARPi) approved in the US and Europe for maintenance treatment in pts with recurrent OC regardless of BRCAmut status. Preclinical data suggest synergy with PARPi + anti-PD-1 blockade. Niraparib + pembrolizumab has shown clinical efficacy in pts with platinum-resistant or secondary refractory OC regardless of biomarker status. Dostarlimab is an anti–PD-1 humanized monoclonal with clinical activity as monotherapy in early phase trials. The primary objective of the currently enrolling FIRST trial is to compare PFS (per RECIST v1.1) in pts treated with SOC + dostarlimab + niraparib to SOC. Methods: Eligible pts (up to 912) are FIGO stage 3 (with residual disease, CC0 high risk, or planned neoadjuvant therapy) or stage 4, non-mucinous epithelial OC and ECOG score &lt; 2. After 1 cycle of SOC, pts are stratified by concurrent bev use, BRCAmut/HRR status, and disease burden then randomized as 1:1:2 to 1 of 3 arms (Table). An innovative feature of ENGOT-OV44/FIRST (NCT03602859; EUDRACT 2018-000413-20) is the pre-planned adaptive study design to adapt the control arm to the evolving SOCs in OC, allowing pts in the control arm to receive up to date SOC. These adaptations will occur when practice-changing data are released. Following publication of SOLO1 results, BRCAmut pts will only be randomized to arm 2 or 3 to ensure they receive niraparib. Further adaptations may be incorporated as new data become available, leading to stop randomization in arm 1 or 2 of pts based on their biomarker status. Clinical trial information: NCT03602859. [Table: see text]
Surgery of the Biliary Tract
Authors: Marshall K. Bartlett, William C. Quinby, Gordon A. Donaldson
Journal: New England Journal of Medicine (1956)

THE purpose of this paper is to present the experience at the Massachusetts General Hospital in the treatment of acute cholecystitis from 1943 to 1953 inclusive. During this time the concepts and methods of treatment of this disease have been relatively uniform, and it was believed that valuable information could be obtained from an analysis of this experience. A comparison of the mortality and morbidity resulting from surgical treatment of the acute phase of cholecystitis with that attending similar surgical procedures in the chronic or interval phase of the disease is also given.MaterialAll 716 patients with acute cholecystitis . . .
Social deprivation is associated with poor kidney transplantation outcome in children
Authors: Bénédicte Driollet, Florian Bayer, Valérie Chatelet, Marie-Alice Macher, Rémi Salomon, Bruno Ranchin, Gwenaelle Roussey, Annie Lahoche, Florentine Garaix, Stéphane Decramer, Elodie Mérieau, Marc Fila, Ariane Zaloszyc, Georges Deschênes, Linda Valeri, Ludivine Launay, Cécile Couchoud, Karen Leffondré, Jérôme Harambat
Journal: Kidney International (2019)
Economic impact of post-progression treatment in gastroenteropancreatic neuroendocrine tumor (GEP-NET) patients previously treated with octreotide monotherapy.
Authors: David Ray, Marko Zivkovic, Michael Gargano, Heloisa P. Soares
Journal: Journal of Clinical Oncology (2019)

e18366 Background: For unresectable, well-differentiated, advanced GEP-NET patients somatostatin analogs octreotide LAR (OCT) and lanreotide depot (LAN) are recommended as first-line systemic therapy. Recent evidence suggests that GEP-NET patients may benefit from LAN after OCT prior to modifying treatment class. The goal of this analysis is to quantify treatment escalation costs among patients who progress on OCT. Methods: A decision-tree model was used to assess the cost of treating GEP-NET patients over a 6-month time horizon after they progress on OCT. Drug acquisition (Wholesale Acquisition Costs), administration, grade 3/4 adverse event (AE) management, and patient monitoring costs were considered. Patients could utilize either OCT escalation (30 mg every 3 weeks or 40 or 60 mg every 4 weeks), OCT + peptide receptor radionuclide therapy (PRRT), OCT + liver directed therapy (e.g. transarterial chemoembolization (TACE)), everolimus, or LAN 120mg every 4 weeks. Administration and monitoring test costs were based on CMS physician and laboratory fee schedules, respectively. AE management costs were determined from the CMS Inpatient prospective payment system based on reimbursements corresponding to the associated DRG codes. Results: LAN ($44,462) was found to be cost-saving versus alternatives when used post-OCT. OCT escalations to 30mg every 3 weeks, 40mg every 4 weeks, and its use with liver directed therapy were 2nd, 3rd, and 4th lowest cost treatment options ($52,873, $53,041, and $72,152, respectively); all three had higher drug acquisition and AE management costs. Drug acquisition costs for everolimus were more than twice those of LAN and for PRRT + OCT nearly 4 times that amount. GA-68 Dotatate PET/CT imaging greatly increased the monitoring costs of PRRT + OCT, which were $3,682 higher than the nearest alternative. Conclusions: LAN was the lowest cost treatment option over a 6-month interval for GEP-NET patients who progressed on OCT, however clinical appropriateness must be considered when transitioning patients. Evidence for the appropriate clinical strategy of sequencing of patients is still needed.
Case 11-1988
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, James H. Jandl, Zareh N. Demirjian
Journal: New England Journal of Medicine (1988)

Presentation of CaseA 44-year-old woman was seen at this hospital because of thrombocytosis.She was well until six months earlier, when anorexia developed and she lost 4.5 kg in weight.Two months before entry evaluation elsewhere showed that the hematocrit was 30.6 percent; the white-cell count was 9900, with 39 percent neutrophils, 2 percent band forms, 38 percent lymphocytes, 6 percent atypical lymphocytes, 6 percent monocytes, 5 percent eosinophils, and 4 percent basophils. The mean corpuscular volume (MCV) was 80 μm3 per cell, the mean corpuscular hemoglobin (MCH) 24.4 pg per red cell, and the mean corpuscular hemoglobin concentration . . .
Comprehensive genomic profiling (CGP) of upper-tract (UTUC) and bladder (BUC) urothelial carcinoma reveals opportunities for therapeutic and biomarker development.
Authors: Andrea Necchi, Sumanta K. Pal, Jeffrey S. Ross, Russell Madison, Neeraj Agarwal, Guru Sonpavde, Monika Joshi, Ming Yin, Vincent A. Miller, Petros Grivas, Jon Chung, Siraj Mahamed Ali
Journal: Journal of Clinical Oncology (2019)

4581 Background: To understand the genomic landscape and inform the therapeutic development of UC, 2463 cases were analyzed by CGP for genomic alterations (GAs) and for genome wide signatures. Methods: 479 UTUC and 1984 BUC FFPE tissues (77%/70% primary [PT] and 23%/30% metastatic tumors [MT] from unmatched patients [pts]) underwent hybrid-capture based CGP to evaluate all classes of GA. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Targetable GA and signatures were assessed according to the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT). Results: 48% of UC pts overall harbored ≥1 tier 1-2 GA suggesting benefit from approved or investigational targeted therapies (TT). Additionally, 17% had a tier 3 GA that provides a strong rationale for clinical trial consideration. Non- FGFR3 kinase fusions were observed in 1% of pts (0.6% UTUC v 1.1% BUC), including BRAF/RAF1 fusions in 0.5%. BRAF mut/fusions were observed in 2% (49/2463) of cases and were mutually exclusive with FGFR3 GA (p = 0.002). In comparing UC from anatomic sites, there were no differences of TMB-H (≥20 mut/mb)/MSI-H for PT and MT but UTUC was enriched for MSI-H (3.4%) relative to BUC (0.77%, p &lt; 0.001, all TMB-H). Excluding MSI-H pts, UTUC has lower median TMB (4.35 mut/mb) than BUC (6.96 mut/mb). FGFR3 GA (26% v 19%, p &lt; 0.05) and specifically short variants (SV) (20% v 13%) were enriched in UTUC vs BUC. HRAS SV were also enriched in UTUC vs BC (7.3% v 3.0%), attributed to an enrichment in renal pelvis UC (10.1%) v ureteral UC (1.8%, p &lt; 0.05). RB1 GA were more frequent in BUC vs UTUC (21% v 7.8% p &lt; 0.001). Conclusions: Against a background of 50% actionability in UC with opportunities for immunotherapy, TT, or combinations thereof, the UTUC cohort is enriched for FGFR3 and HRAS SV relative to BUC, with the observation of HRAS mutations predominantly in UC of the renal pelvis, that warrants further investigation into the distinct modes of oncogenesis for UC as stratified by anatomic origin. These results argue strongly for the routine incorporation of CGP prior to systemic therapy initiation in metastatic UC.
Mature, real world progression-free survival (PFS) and overall survival (OS) milestones in stage IV, non-squamous, non-small cell lung cancer patients (nsqNSCLC) treated with first line pemetrexed(Pem)/platinum(Plat) followed by pem+/-bevacizumab(Bev) maintenance.
Authors: Parva Kiran Bhatt, Ibtihaj Fughhi, Sanjib Basu, Mary J. Fidler, Jeffrey Allen Borgia, Philip D. Bonomi, Marta Batus
Journal: Journal of Clinical Oncology (2019)

e20721 Background: Pemetrexed maintenance therapy is associated with superior survival in stage IV nsqNSCLC patients. We have observed long term disease control in some patients treated with at least one cycle of Pem/Plat with potential for maintenance pem. There are no reports of data regarding long term PFS and OS in patients treated with Pem regimens. The objectives of our retrospective analysis are to determine the frequency of long term disease control on Pem maintenance and to identify parameters associated with longer PFS/OS. Methods: We included all patients with Stage IV nsqNSCLC who received at least one cycle of pem/plat between May 2010 and Nov 2013. We identified 240 patients from our database and analyzed their demographics, lab values, dates of therapy, and dates of progression. PFS/OS was estimated by the Kaplan-Meier method and associations with patient characteristics were assessed by log-rank tests and Cox proportional hazards analysis. The shortest potential follow up was 5 years. Results: Median age was 66 years, 60% were female, and 72% were Caucasian. Baseline ECOG performance status was 0(22%), 1(50%) and ≥ 2(22%). Median PFS was 6.2 months. At 1, 2, 3, 4, and 5 years of follow up absence of disease progression was seen in 33%, 14%, 7.5%, 4%, and 3%, respectively. Additionally, in terms of OS at 1-5 years, we observed 54.5%, 35%, 21%, 14%, and 11%. Lower baseline neutrophil: lymphocyte ratio (NLR) was strongly associated with improved PFS when using NLR≤5 vs &gt; 5 (median PFS 13.2 mo vs 5.6 mo) Additionally, baseline Hemoglobin (mean = 12.03 g/dL, HR = .904, p = .0046) and Albumin (mean 3.3 g/dL, HR = .7722, p = .024) were associated with better PFS. Conclusions: The similarity in median PFS in our patients (6.2 mo) and clinical trial data suggests that our group of real world patients did not have uniquely favorable baseline characteristics. However, the patients most likely to reach long PFS/OS milestones had favorable baseline prognostic indicators suggesting that this patient subset might also be most likely to benefit from the recently approved regimen which combined Pembrolizumab with Pemetrexed/Carboplatin.
Mutational profile of dysplastic lesions evolving to laryngeal cancer.
Authors: Santiago Cabezas-Camarero, Vanesa García-Barberán, Diana Hernanpérez-Hidalgo, Melchor Saiz-Pardo-Sanz, David De Pablo Velasco, Victor Lorca, Mari Cruz Iglesias, Pedro Pérez-Segura
Journal: Journal of Clinical Oncology (2019)

e17551 Background: Few studies have addressed the carcinogenic process of laryngeal cancer from its premalignant phases. Our aim was to compare mutational status of laryngeal dysplasias (LD) evolving to laryngeal cancer (ELC) and not evolving to LC (NELC). Methods: Retrospective study of LD diagnosed between 2007 and 2011. A customized 15-gene NGS panel (DICER, IRF6, NOTCH1, NOTCH2, NOTCH3, NOTCH2NLA, PIK3CA, PTEN, RB1, RIPK4, SYNE1, SYNE2, TP53, TP63, CASP8) was used for mutational analysis with Truseq Custom Amplicon (Illumina) performed in FFPE LD samples and results compared between LD-ELC and LD-NELC. Results: Sixty-four patients (pts) with LD were identified. LD-ELC (N = 23) and LD-NELC (N = 41) were scored as mild (N = 40; NELC: 32 / ELC:8), moderate (N = 8; NELC: 4/ ELC: 4) and severe (N = 16; NELC:5 / ELC: 11). Prior or current moderate-to-heavy tobacco smoking ( &gt; 10 pack-year): 53/64 (83%). Males: N = 50 (ELC: 21; NELC: 29); Female: N = 14 (ELC: 2; NELC: 12). Median time to cancer among 23 LD-ELC: 8 m (range: 0-46). Forty-seven gene variants were detected in ELC not found in NELC, of which 27 were pathogenic/likely pathogenic: Frameshift: 8 (1 in NOTCH2, 1 in PTEN, 2 in RB1, 2 in SYNE1 y 2 in SYNE2); Stop-gained: 3 (1 in NOTCH2NL, 2 in SYNE2); Splicing: 3 (1 in RB1, 1 in RIPK4 y 1 in TP53); Missense: 12 (1 in IRF6, 2 in NOTCH1, 1 in RB1, 2 in RIPK4, 6 in SYNE1). Conclusions: LD from pts ELC showed a different mutational profile than LD-NELC. These results show promise for identifying pts at higher risk for developing LC and should be validated in a larger, prospective study.
The complex of MCMV proteins and MHC class I evades NK cell control and drives the evolution of virus-specific activating Ly49 receptors
Authors: Jelena Železnjak, Vanda Juranić Lisnić, Branka Popović, Berislav Lisnić, Marina Babić, Anne Halenius, Anne L’Hernault, Tihana Lenac Roviš, Hartmut Hengel, Florian Erhard, Alec J. Redwood, Silvia M. Vidal, Lars Dölken, Astrid Krmpotić, Stipan Jonjić
Journal: The Journal of Experimental Medicine (2019)

CMVs efficiently target MHC I molecules to avoid recognition by cytotoxic T cells. However, the lack of MHC I on the cell surface renders the infected cell susceptible to NK cell killing upon missing self recognition. To counter this, mouse CMV (MCMV) rescues some MHC I molecules to engage inhibitory Ly49 receptors. Here we identify a new viral protein, MATp1, that is essential for MHC I surface rescue. Rescued altered-self MHC I molecules show increased affinity to inhibitory Ly49 receptors, resulting in inhibition of NK cells despite substantially reduced MHC I surface levels. This enables the virus to evade recognition by licensed NK cells. During evolution, this novel viral immune evasion mechanism could have prompted the development of activating NK cell receptors that are specific for MATp1-modified altered-self MHC I molecules. Our study solves a long-standing conundrum of how MCMV avoids recognition by NK cells, unravels a fundamental new viral immune evasion mechanism, and demonstrates how this forced the evolution of virus-specific activating MHC I–restricted Ly49 receptors.