tbuckley/cabot-search huggingface dataset:
Response to afatinib in patients with advanced NSCLC previously treated with reversible EGFR inhibitors in a mono-institutional experience.
Authors: Chiara Bennati, Maria Francesca Currà, Rita Chiari, Verena De Angelis, Vincenzo Minotti, Giulio Metro, Simona Duranti, Carmen Molica, Chiara Scafati, Luca Paglialunga, Lorenza Pistola, Antonella Flacco, Francesca Romana Tofanetti, Annamaria Siggillino, Elisa Baldelli, Vienna Ludovini, Lucio Crinò
Journal: Journal of Clinical Oncology (2012)

e18101 Background: All mutated non-small cell lung cancer (NSCLC) patients (pts) previously treated with an EGFR reversibile inhibitor, develop, soon or later, resistance. Afatinib is a potent irreversible HER family inhibitor, with preclinical data suggesting activity against the resistance mutation EGFR T790M. From August 2005 to January 2011, in a retrospective observational study at our Division of Medical Oncology, we have evaluated 22 advanced NSCLC pts, who have been treated with Afatinib, after disease progression with Erlotinib or Gefitinib. Methods: 22 advanced NSCLC pts who have previously received a reversible EGFR-TKI (gefitinib or erlotinib), and subsequently have been treated with Afatinib in a different setting of their medical history, were included in the analysis. Afatinib was provided in an expanded access program by Boehringer. Results: Patients characteristics: median age 64 ys (34-85); PS 0-1; most of pts were never smokers (82%) with non-squamous histology. 12 pts (54%) had multi-metastatic sites at diagnosis, 4 of which (33%) had brain lesions. Nineteen pts (86%) were found to be EGFR mutated (15 patients with EGFR-sensitizing mutations at exon 19 and 21). No one was K-RAS mutated. Eighteen pts (82%) received Afatinib in a second line TKI setting and 4 pts (18%) in a third line. Overall, 4 pts (18%), 2 of which had a multi-metastatic disease at diagnosis, had a partial response to Afatinib and 11 pts (50%) achieved a stable disease. Of the 16 pts evaluable for response in the second line setting, median progression-free survival (PFS) was 5,2 months. Diarrhea and skin rash were the most common adverse events but a dose-limiting toxicity was observed in only three patients. Conclusions: Our experience confirmed Afatinib clinical activity in patients with acquired resistance to prior reversible TKI. The treatment has been well tolerated and there were no new or unexpected safety findings.
Concurrent therapy with immune checkpoint inhibitors and TNFα blockade in patients with gastrointestinal immune-related adverse events
Authors: Yousef R. Badran, Justine V. Cohen, Priscilla K. Brastianos, Aparna R. Parikh, Theodore S. Hong, Michael Dougan
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Immune checkpoint inhibitors (ICI) have demonstrated remarkable efficacy as&nbsp;cancer therapeutics, however, their use remains limited due to the development of immune related adverse events (irAEs). Immune related enterocolitis (irEC) is among the most common severe irAEs leading to the discontinuation of ICIs. Inhibitors of tumor necrosis factor alpha (anti-TNFα) have been used to treat irEC. Recent animal studies have shown that concurrent treatment with anti-TNFα and ICIs improves tumor responses and decreases colitis severity. This approach has not yet been studied in prospective trials in humans. Here we describe, for the first time, the outcomes of patients who were treated concurrently with anti-TNFα and one or two ICIs. <h3>Case presentations</h3> Five patients with different primary malignancies were treated with&nbsp;ipilimumab/nivolumab (2 patients), pembrolizumab (1 patient), ipilimumab (1 patient), or cemiplimab (1 patient). All patients developed irEC within 40 days of their first ICI dose. The patients presented with a combination of upper and lower gastrointestinal symptoms and subsequently underwent upper endoscopy and/or lower endoscopy. Endoscopy results demonstrated a spectrum of acute inflammatory changes across the gastrointestinal tract. Steroid therapy was used as first line treatment. To prevent prolonged steroid use and recurrence of gastrointestinal inflammation after resumption of cancer therapy, patients were treated concurrently with infliximab and ICI. Patients tolerated further ICI therapy with no recurrence of symptoms. Repeat endoscopies showed resolution of acute inflammation and restaging imaging showed no cancer progression. <h3>Conclusions</h3> Concurrent treatment with anti-TNFα and ICI appears to be safe, facilitates steroid tapering, and prevents irEC. Prospective clinical trials are needed to assess the outcomes of this treatment modality.
A T cell–myeloid IL-10 axis regulates pathogenic IFN-γ–dependent immunity in a mouse model of type 2–low asthma
Authors: William J. Branchett, Helen Stölting, Robert A. Oliver, Simone A. Walker, Franz Puttur, Lisa G. Gregory, Leona Gabryšová, Mark S. Wilson, Anne O'Garra, Clare M. Lloyd
Journal: Journal of Allergy and Clinical Immunology (2019)
ALT-GIST: Randomized phase II trial of imatinib alternating with regorafenib versus imatinib alone for the first-line treatment of metastatic gastrointestinal stromal tumor (GIST).
Authors: Desmond Yip, John Raymond Zalcberg, Jean-Yves Blay, Mikael Eriksson, David Espinoza, Timothy Jay Price, Sandrine Marreaud, Antoine Italiano, Neeltje Steeghs, Kjetil Boye, Craig Underhill, Sayeda Naher, Martinus Oostendorp, Val Gebski, John Simes, Hans Gelderblom, Heikki Joensuu
Journal: Journal of Clinical Oncology (2019)

11023 Background: Imatinib (IM) is the standard first-line treatment for advanced GIST and regorafenib (REG) is approved for third line therapy. We studied if an alternating regimen of two tyrosine kinase inhibitors, IM and REG, delays resistance to IM and improves outcomes. Methods: ALT-GIST (NCT02365441) is a randomised non-comparative phase II trial to investigate the efficacy of an alternating regimen (ALT) of 21-25 days of IM 400mg orally daily followed by a 3-7-day gap for washout followed by 21 days of REG 160 mg orally daily and a 7-day gap for washout. The control arm was continuous IM 400mg daily. Delayed recruitment led to revised endpoints of activity and safety. To assess clinical activity, the best objective tumor response (OTR) at 9 months was deemed to be an appropriate endpoint in the revised protocol. Results: Seventy-six eligible patients (ALT 40, IM 36) enrolled from June 2015 to September 2018 were evaluable for the OTR. The patients (pts) were predominately male (n = 51, 67%). Median age was 58 (range, 24-81) in the ALT arm and 65 (range, 35-82) in the IM arm. KIT was mutated in 63, PDGFR in 2, and wildtype in 5 tumors. Relative dose intensity in the ALT arm 102% for IM and 82% for REG and was 93% in the IM arm. Median follow-up time was 19.3 months (range 6.0-40.0).The best responses to the ALT and IM treatments were similar at 9 months, 1 vs 0 pts had complete response, 23 vs 23 partial response, 15 vs 13 stable disease, and the OTR was 60% (95% CI, 45-74%) and 64% (95% CI, 48-78%), respectively. Seven (18%) pts in ALT arm and 10 (28%) in IM arm discontinued treatment due to progressive disease. Seven pts (18%) in the ALT arm stopped protocol therapy due to unacceptable toxicity, and none in the IM arm. Fifteen (38%) pts in the ALT arm and 14 (38%) in the IM arm had serious adverse events, mostly grade 3. Progression free survival (PFS) at 1 year was ALT 0.86 (95%CI:0.69,0.94) and IMI 0.83 (95% CI 0.65-0.92), p logrank = 0.57. Conclusions: There was no meaningful difference in the primary endpoint of OTR and in PFS between the groups in this first analysis of ALT-GIST, and no unexpected safety signals. The study is ongoing and other endpoints will be reported in due course. Clinical trial information: ACTRN12614000950662.
Comparison of genomic changes between tumors detected by screening mammography versus other methods
Authors: T. E. Becker, R. E. Ellsworth, D. L. Ellsworth, B. Deyarmin, J. A. Hooke, C. D. Shriver
Journal: Journal of Clinical Oncology (2006)

10033 Background: The prognosis in patients with breast cancer detected by screening mammography has been found to be significantly better than those with similar-sized tumors detected by other methods (e.g. physical examination). (Joensuu, et al. 2004). Given the similar pathological characteristics, outcome differences may be explained by molecular differences within the tumors. To address this question, the relationship between genomic instability and methods of detection was assessed using allelic imbalance (AI) in similarly sized primary breast tumors from patients with breast cancer identified by screening mammography versus other methods. Methods: Patients with stage I breast cancer identified by screening mammography (n=50) versus other methods (n=50) were selected. Samples were matched between the two groups for clinical information. DNA was extracted from pure populations of tumor cells obtained by laser microdissection. Referent DNA was obtained from blood or disease-free skin samples from each patient. A panel of 52 microsatellite markers from 26 chromosomal regions commonly altered in breast cancer was used to assess AI, determined by the peak height ratio (≤0.35) between alleles from tumor and referent samples. Fisher’s exact test and Student’s t-tests were used to test for significant differences in levels of AI. Results: When clinical parameters such as age, ethnicity, menopause and status of tumor hormone receptors or HER2 were examined between tumor groups, no significant differences were detected. The overall frequency of AI between tumors detected by screening mammography (21.8%) versus other methods (22.3%) was similar (P=0.93). When patterns of AI were examined, none of the 26 chromosomal regions detected here showed a significant difference in AI events between the two groups. Conclusions: In this study, we have shown that global chromosomal differences are likely not the cause for the difference in tumor detection and prognosis between patients whose tumors were detected mammographically versus those whose were not. Prognostic factors known to correlate with disease aggressiveness and recurrence (e.g. hormone receptor or HER2 status) were also shown to not be associated with this difference in tumor detection among our patients. No significant financial relationships to disclose.
Pexidartinib for advanced tenosynovial giant cell tumor (TGCT): Long-term efficacy and safety from the phase 3 ENLIVEN and phase 1 PLX108-01 (TGCT cohort) studies.
Authors: Hans Gelderblom, William D. Tap, Emanuela Palmerini, Silvia Stacchiotti, Zev A. Wainberg, Jayesh Desai, John H. Healey, Michiel van de Sande, Nicholas M. Bernthal, Charles Peterfy, Dale Edward Shuster, Qiang Wang, Henry Hsu, Andrew J. Wagner
Journal: Journal of Clinical Oncology (2019)

11042 Background: TGCT is a rare, locally aggressive neoplasm of the joint/tendon sheath linked to colony-stimulating factor 1 (CSF1) overexpression. Pexidartinib (pex), a selective inhibitor of CSF1 receptor, KIT, and FLT3-ITD, had a compelling tumor response rate in the TGCT cohort of a phase 1 study (NCT01004861) and significant tumor response vs placebo by RECIST v1.1 (39% vs 0%, P&lt; 0.0001) and tumor volume score (TVS) (56% vs 0%, P&lt; 0.0001) in the randomized, 2-part, crossover phase 3 ENLIVEN study (NCT02371369). Updated efficacy and safety with longer treatment are reported. Methods: Patients (pts) were ≥18 y with TGCT that was inoperable or for which surgery would likely be associated with worsening functional limitation or severe morbidity. Best overall response (complete or partial [CR/PR]) and duration of response (DOR) by RECIST and TVS were assessed by independent central review. Data cutoff was Jan 31, 2018, 16-67 mo after pts’ first dose. Results: In both studies 130 pts received pex, 61 ongoing at data cutoff. Median treatment duration was 17 mo (1, 60+). CR/PR rates were high and consistent and, together with DOR, improved with prolongation of treatment (Table). Most frequent adverse events were hair color change (75%), fatigue (60%), nausea (45%), arthralgia (38%), AST increase (30%), and diarrhea (30%). In ENLIVEN part 1, 3 of 61 (5%) pts had reversible ALT and AST ≥3 × ULN with TBil and ALP ≥2 × ULN; all started in the first 8 weeks of treatment, and no new cases emerged with continuation of treatment. Conclusions: Tumor response rate increased with continuation of pex treatment. The safety profile remained similar, with no new mixed or cholestatic hepatotoxicity. Clinical trial information: NCT01004861 and NCT02371369. [Table: see text]
First Treatment for Rare Autoimmune Neuromyelitis
Authors: Feyza Sancar
Journal: JAMA (2019)

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Identifying resistance biomarkers against five clinically approved tyrosine kinase inhibitors in 45 cell lines.
Authors: Zsófia Pénzváltó, Bálint Tegze, Attila Marcell Szasz, Reinhold Schäfer, Balazs Gyorffy
Journal: Journal of Clinical Oncology (2012)

e21005 Background: Clinical studies show low overall response rates of 10-47% to targeted cancer therapeutics. Our aim was to identify new biomarkers for predicting sensitivity against five already approved tyrosine kinase inhibitors. Methods: Sensitivity to sunitinib, erlotinib, lapatinib, sorafenib and gefitinib were tested in 45 cancer cell lines, and a resistance index was calculated for each cell line. The gene expression profiles (data were obtained by interrogating the raw microarray data of the caArray database) in the subset of resistant vs. sensitive cell lines were compared for each drug. Feature selection was carried out using significance analysis of microarrays and rank products. The results were validated by qPCR in the cell lines and - in case of four sunitinib resistance associated genes - in clinical samples by immunohistochemistry. Results: A set of 63 genes was identified as associated with resistance against the examined drugs. Overall classification accuracy of the prediction was 92.8% in a leave-one-out cross validation using prediction analysis of microarrays. The expression of the genes was validated by qPCR in the cell lines. The results confirmed 45/63 of the microarray-based resistance associated genes and 7/32 of literature based genes. All together 48 sunitinib-treated metastatic renal cell carcinomas were collected. The immunohistochemical analysis in these confirmed the correlation of the expression of RAB17, LGALS8, and EPCAM with overall survival. Conclusions: We identified new predictive biomarker candidates for five tyrosine kinase inhibitors, and validated a set of sunitinib resistance associated genes in an independent patient cohort.
Risk of Secondary Hematological Malignancies in Patients with Follicular Lymphoma: A Retrospective Analysis of 1045 Patients Treated in the Rituximab Era
Authors: Roosa Enni Inkeri Prusila, Marc Sorigue, Aleksi Postila, Petteri Salmi, Taru Tanhua, Susanna Tikkanen, Sakari Kakko, Hanne Kuitunen, Marjukka Pollari, Ilja Nystrand, Milla Kuusisto, Kaija Vasala, Esa Jantunen, Eija Korkeila, Peeter Karihtala, Taina Turpeenniemi-Hujanen, Outi Kuittinen
Journal: Blood (2018)
A global overview of pleiotropy and genetic architecture in complex traits
Authors: Kyoko Watanabe, Sven Stringer, Oleksandr Frei, Maša Umićević Mirkov, Christiaan de Leeuw, Tinca J. C. Polderman, Sophie van der Sluis, Ole A. Andreassen, Benjamin M. Neale, Danielle Posthuma
Journal: Nature Genetics (2019)
Plasma Cell Leukemia - a Single Center Experience
Authors: Diana Mota, Adriana Roque, Ana Luísa Pinto, Catarina Geraldes, Jose Pedro Carda, Marília Gomes, Emília Cortesão, José Carlos Almeida, Luis Francisco Araújo, Ana Isabel Espadana, Maria Leticia Ribeiro
Journal: Blood (2018)
Maintenance therapy in AML: The past, the present and the future
Authors: Matteo Molica, Massimo Breccia, Roberto Foa, Elias Jabbour, Tapan M. Kadia
Journal: American Journal of Hematology (2019)

Abstract Curative treatment in acute myeloid leukemia (AML) depends on successful induction therapy to achieve a complete remission (CR), and subsequent post‐remission therapy to prevent relapse. High relapse rates after consolidation therapy and after allogeneic stem cell transplant contribute to suboptimal outcomes in AML patients, and continue to represent a difficult challenge. Effective maintenance therapy could play an important role in prolonging the remission interval in the post‐consolidation setting, especially in high risk AML patients. Maintenance treatment approaches based on conventional chemotherapy, immunotherapy, hypomethylating agents, and targeted small molecules have been explored in this setting, but no data so far have been convincing enough to establish this approach as the standard of care. However, ongoing and future studies including novel targeted therapies may demonstrate promising efficacy that could facilitate incorporation of maintenance therapy into clinical practice. In this review we summarize previous and ongoing approaches of maintenance therapy in AML and discuss the most promising strategies.
Hsa-mir-31-3p effects on gene expression in colorectal cancer cell lines and patients.
Authors: Raphaële Thiébaut, Marc Vincent, Celine Vazart, Virginie Decaulne, Delphine Le Corre, Karine Fontaine, Berengere Genin, Jerome Carayol, Francis Rousseau, Francois Liebaert, Pierre Laurent-Puig
Journal: Journal of Clinical Oncology (2013)

e14600 Background: Recently, hsa-miR-31-3p was found to be up-regulated in some tumors of metastatic colorectal cancer (mCRC) patients and was proposed as a prognostic marker for anti-EGFR therapy in KRAS wild-type (WT) patients. The aim of this study was to identify the target genes of hsa-miR-31-3p in a CRC context. Methods: Three different KRAS WT CRC cell lines, Caco-2, Colo205 and Colo320HSR were transfected with hsa-miR-31-3p mimic or control mimic. After 24h, cells were harvested and total RNA was extracted for an expression array analysis. Linear models for micro-arrays analysis from R package was used to analyze the results. A miRNA predictive target database including 6 available databases (microRNA.org, MicroCosm, TargetScan, PicTar, PITA, miRDB) was created. Validation of the identified target genes was performed on tumors sample of 39 patients treated with panitumumab and irinotecan as third line. Results: After transfection of the 3 cell lines with hsa-miR-31-3p mimic, an expression profile analysis was done. Results obtained in each cell lines were first compared in a pair wise analysis and secondly tested with eBayes procedure without matching. Fifty –four genes were down-regulated (fold change: fc≤0.77, p&lt;0.05). Using the predictive target database, hsa-miR-31-3p was the second most common miRNA as it targeted putatively 25 out the 54 genes, among which STAT3. To identify indirect target genes, we then studied the genes up-regulated by hsa-miR-31-3p over-expression in the 3 different cell lines and identified 27 genes. As expected all but one were not predicted to be direct target genes of hsa-miR-31-3p using the predictive target database. Interestingly, the proto-oncogene MET was up regulated by the over expression of hsa-miR-31-3p. Validation of the 25 putative targets and of the 27 genes up-regulated genes was done with RT qPCR on tumor samples of patients treated with anti-EGFR and some of the direct and undirected target genes were confirmed. Conclusions: This study shows that hsa-miR-31-3p, which expression level was shown to be correlated with prognosis of mCRC patients treated with anti-EGFR, plays an important role in CRC by regulating genes involved in cancer like STAT 3 and MET.
Hypoplastic MDS with PNH clone treated successfully with eculizumab.
Authors: Sonia John, Hiral D. Parekh, Osama M. Qubaiah, George Basil Selby, Jennifer L. Holter
Journal: Journal of Clinical Oncology (2012)

e17010 Background: Myelodysplasia (MDS) is a myeloid clonal disorder characterized by dysplastic and ineffective hematopoiesis. Hypoplastic MDS is a rare variant found in &lt;15 % of MDS patients.Severe aplastic anemia (SAA) is defined as &lt;10% marrow cellularity associated with pancytopenia. Paroxysmal nocturnal hemoglobinuria (PNH) an acquired clonal hematopoietic disorder presenting as chronic intravascular hemolysis, venous thrombosis, deficient hematopoiesis and can be found in both SAA and MDS. PNH can be diagnosed by measuring the surface markers for phosphatidylinositolglycan (PIG),CD59, CD55 and CD14. In clinical practice, these three diagnoses have significant overlap with unclear thresholds for the level of clone for which therapy should be directed. Methods: We present a 69 year old patient who was found to have hypoplastic MDS/SAA by bone marrow biopsy and flow cytometry with no chromosomal abnormalities.Treatment with Anti-thymocyte globulin (ATG) and cyclosporine (CSA) was initiated. He achieved transfusion independence and was in complete remission for 6 months. He developed recurrent thrombocytopenia and was retreated with ATG &amp; CSA with minimal improvement. He remained transfusion dependent.Repeat BM biopsy showed persistent hypoplastic MDS/SAA. PNH evaluation showed a small clone of PIG deficient cells quantified as 0 % red cell, 2% granulocytes and 0.9% monocytes which was negative at initial diagnosis. Eculizumab was instituted weekly for the last 18 months.Transfusion independence was obtained within 2 months with significant improvement in all cell lineages. BM biopsy performed 4 months after therapy showed hypercellular marrow. Patient continues to be treated with eculizumab and has maintained a complete remission for over 18 months. Results: The diagnosis hypoplastic MDS/aplastic anemia is usually highly sensitive to therapy with ATG and CSA. Although our patient initially responded to ATG, retreatment was not successful. Eculizumab has documented a significant and sustained response in this patient’s treatment. . Conclusions: We report a patient with less than 1% PNH clone that achieved complete transfusion independence with eculizumab and full resolution of hypoplastic MDS/SAA by marrow histology.