tbuckley/cabot-search huggingface dataset:
High-throughput parallel amplicon sequencing of common driver mutations from FFPE lung cancer samples in molecular pathologic routine diagnostics for a regional health care provider network.
Authors: Reinhard Buettner, Katharina Koenig, Martin Peifer, Katrin Stamm, Marc Christiaan Allardt Bos, Lucia Nogova, Thomas Zander, Masyar Gardizi, Sabine Merkelbach-Bruse, Thomas Henkel, Juergen Wolf, Lukas Carl Heukamp
Journal: Journal of Clinical Oncology (2013)

e12517 Background: Treatment paradigms for non–small-cell lung cancer have shifted from histology based towards incorporation of molecular subtypes involving particular genetic alterations such as mutations in EGFR or translocations of ALK. The list of targetable lesions is rapidly increasing including mutations in genes such as EGFR, HER2, KRAS, ALK, BRAF, PIK3CA, AKT1, ROS1, NRAS, FGFR1 and MAP2K1. Analysis of these potential targets is becoming a challenge in terms of work load, tissue availability as well as cost. Within the Network Genomic Medicine Lung Cancer (NGM), a regional molecular screening network of the Center for Integrated Oncology Köln Bonn, we aimed to improve the sequential analysis of a set of 9 target amplicons by Sanger sequencing using bench top ultra-deep parallel sequencing platforms. We aimed to reduce 1) the time requirement for comprehensive molecular diagnostics, 2) the minimal amount of formalin fixed paraffin embedded (FFPE) derived input DNA, 3) while at the same time increasing the number of target regions analysed. Methods: We established a multiplex PCR to amplify up to 640 lung cancer relevant target regions from at least 20ng of FFPE derived tumor DNA. The amplicon libraries were ligated to adapters encompassing medical identifier sequences that allowed multiplexing of up to 48 patients. The resulting libraries were sequenced on a benchtop Illumina platform (MiSeq). Mutations identified by parallel sequencing were confirmed by Sanger sequencing. Results: 330 patients were analyzed by traditional Sanger sequencing of 9 amplicons and the newly established parallel sequencing protocol. The time needed to complete the mutation screening was significantly reduced to 7 working days from previously 21 days. A total of at least 300ng of DNA was needed to complete the analysis of 9 amplicons by Sanger sequencing compared to 20 to 100ng of DNA needed for up to 640 amplicons analyzed by parallel sequencing. Conclusions: Newly multiplex PCR based parallel sequencing allows rapid comprehensive mutation testing in routine molecular pathological diagnostics even on small transbronchial biopsies.
Efficacy and safety of liposomal irinotecan (nal-IRI) + 5-fluorouracil and leucovorin (5-FU/LV) in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC) who previously received gemcitabine (gem)-based therapy: Post-hoc analysis of the NAPOLI-1 trial.
Authors: Li-Tzong Chen, Andrea Wang-Gillam, Shan Yanshen, Teresa Macarulla, Jean-Frédéric Blanc, Richard Hubner, Chang-Fang Chiu, Gilberto Schwartsmann, Jens T. Siveke, J. Marc Pipas, Bruce Belanger, Floris de Jong, Khalid Mamlouk, Daniel D. Von Hoff
Journal: Journal of Clinical Oncology (2017)

303 Background: nal-IRI+5-FU/LV is approved in the United States and Taiwan for pts with mPDAC previously treated with gem-based therapy based on the NAPOLI-1 study which showed that nal-IRI+5-FU/LV improved overall survival (OS) vs 5-FU/LV (6.1 vs 4.2 mo; HR, 0.67; 95% CI, 0.49-0.92; P = 0.012; Wang-Gillam et al, Lancet. 2016). This post hoc analysis evaluated the efficacy and safety of nal-IRI+5-FU/LV in subgroups of pts defined by prior gem regimen including gem monotherapy and gem combinations (combo). Methods: This analysis (data cutoff, Nov 2015) focuses on the 236 pts assigned to nal-IRI+5-FU/LV q2w (n = 117) or 5-FU/LV qw for weeks 1-4 q6w cycle (n = 119). Pts previously received gem-based therapy in a neoadjuvant, adjuvant, locally advanced, or metastatic setting. Results: Of 117 pts in the nal-IRI+5-FU/LV arm, 53 (45%) previously received gem monotherapy and 64 (55%) previously received gem combo including erlotinib (n = 9) or nab-paclitaxel (n = 20). Of the 119 pts in the 5-FU/LV arm, 55 (46%) previously received gem monotherapy and 64 (54%) previously received gem combo including erlotinib (n = 17) or nab-paclitaxel (n = 11). Nal-IRI+5-FU/LV improved median OS, median PFS, and ORR vs 5-FU/LV, regardless of prior therapy (Table). Grade ≥3 treatment-emergent adverse events were not influenced by prior treatment. Clinical trial information: NCT01494506. Conclusions: These resultsshow consistent benefit of nal-IRI+5-FU/LV treatment across subgroups of pts who previously received gem therapy and support the ASCO guidelines recommending nal-IRI+5-FU/LV for this pt population. These analyses may be limited by the small sample size of treatment arms.[Table: see text]
Impact of histologic subtype on bladder cancer outcome.
Authors: Samuel L Washington, Thomas Sanford, Michael S. Leapman, Maxwell V. Meng, Sima P. Porten
Journal: Journal of Clinical Oncology (2017)

391 Background: Variant histology is increasingly recognized but its impact on outcomes is less well known compared to urothelial carcinoma (UC). We aim to evaluate the impact of variant histology on bladder cancer outcomes using the National Cancer Database (NCDB), a U.S. population-based cohort capturing approximately 70% of newly diagnosed cancer cases. Methods: We identified patients with bladder cancer from 2004 to 2013 treated with radical cystectomy. We compared clinical and pathologic characteristics between those with UC and those with variant histology. Chi-square test was utilized for categorical variables and Independent Samples t-test for continuous variables. Multivariable Cox regression was used with hazard ratios (HR) and 95% confidence intervals (CI) to identify independent predictors of overall survival. Results: A total of 40,918 patients were identified with mean age 67 years, with male (75%) and Caucasian (90.9%) predominance. Median follow-up was 36.9 months (IQR 16.1-67.5). Squamous cell carcinoma (4.4%), small cell carcinoma (1.6%) and micropapillary (0.9%) were the most common variant histologies. Variant histology was found more commonly in women (35.6% vs 23.4%, p &lt; 0.05), black (8.8% vs 5.6%, p &lt; 0.05), stage pT3 or T4 (67% vs 50.2%, p &lt; 0.05) and node positive (30.8% vs 26.9%, p &lt; 0.05). In adjusted models squamous cell carcinoma (HR 1.3, 95% CI 1.2-1.4), small cell carcinoma (HR 1.6, 95% CI 1.5-1.8) and black ethnicity (HR 1.2, 95% CI 1.1-1.2) were independent predictors of increased mortality risk while micropapillary was associated with decreased risk (HR 0.8, 95% CI 0.7-1.0) after controlling for age, gender, surgical margin status, pathologic T stage, pathologic N stage and history of chemotherapy. All associations remained statistically significant (p &lt; 0.05). Conclusions: Non-urothelial histology was associated with worse overall survival in patients with bladder cancer treated with radical cystectomy; however, contrary to some previous reports, micropapillary variant was associated with lower risk of death. In addition, black ethnicity was associated with worse survival. Further investigation is needed to explore the impact of variant histology as well as other socioeconomic factors on survival after cystectomy.
Spanish national hereditary pancreatic cancer registry (PanFAM).
Authors: Carmen Guillen-Ponce, Evelina Mocci, Julie Earl, Carmen T Guerrero, Maria Celia Calcedo, Maria Teresa Salazar, MJ Molina-Garrido, Mirari Marquez, Cristina Gonzalez Gordaliza, Enrique Vazquez Sequeiros, Ana Custodio, Francisco X Real, Nuria Malats, Alfredo Carrato
Journal: Journal of Clinical Oncology (2012)

e12033 Background: Inherited predisposition to Pancreatic Cancer (PC) corresponds 10% of all cases and includes members of families affected with hereditary cancer syndromes as Familial Pancreatic Cancer (FPC), Peutz-Jeghers, familial melanoma, hereditary breast and ovarian cancer, hereditary pancreatitis. An inherited predisposition in early onset PC (≤ 50 years) has also been suggested. We report preliminary data on PanFAM patients and screening of high risk individuals. Methods: PamFAM is a part of the European PANGEN PC case/control study of hereditary PC, co-ordinated by the Ramón y Cajal (RC) hospital and the Spanish National Cancer Research Center, with 16 participating hospitals. All families with clinical evidence of an inherited PC syndrome were recruited and multi-generational pedigrees were constructed. Cancer diagnoses were confirmed, when possible, by review of medical records. Blood samples and epidemiological data were collected for all participating family members. A screening program for early detection of PC, based on endoscopic ultrasound (EUS), CT and circulating tumour cells (CTCs) was offered to high risk individuals. Results: Of 505 Spanish PCs collected by PANGEN, 31 (~6%) were FPC cases; 18 (58%) revealed only PC and the remaining showed clustering with other tumor types, gastric cancer was the most common (13%). Among FPC families, 3 had 3 cases of PC and the remaining had 2 cases. The mean age of diagnosis was 67 years (range 47-85), 20 male and 11 female. Four FPCs were previously diagnosed with cancer (Hodgkin lymphoma, breast and prostate cancer) and 3 with acute pancreatitis. 37 PCs with no family history of cancer were diagnosed at the age of 50 years or earlier (mean 45, range 30-50), 18 male and 19 female. Other 27 eligible families were recruited by RyC hospital, 8 (30%) with FPC and 3 (11%) with PC ≤ 50 years. A cohort of 61 high risk individuals participes in the screening study: 3 had abnormal EUS, 1 a benign pancreatic node and 1 a renal angiolipoma; one young man had 2 CTCs. Conclusions: PanFAM is the first registry in Spain collecting hereditary PC cases and it represents an important resource to identify underlying gene defects and to the development of screening methods precursor lesions detection in high risk individuals.
Single-agent bortezomib in previously untreated multiple myeloma (MM): Results of a phase II multicenter study
Authors: K. Anderson, P. Richardson, A. Chanan-Khan, R. Schlossman, N. Munshi, A. Oaklander, L. Heffner, H. Hassoun, D. Avigan, A. Amato
Journal: Journal of Clinical Oncology (2006)

7504 Background: Bortezomib is effective in relapsed and/or refractory MM. This trial evaluated its efficacy and safety as monotherapy in previously untreated MM. Methods: Pts with untreated, symptomatic MM were eligible, with pts receiving concomitant steroids, platelet count &lt; 30 × 10 9 /L, or grade &gt; 2 peripheral neuropathy [PN] excluded. Endpoints included response rate (RR) [Bladé criteria], time to progression, safety, incidence/severity of PN, and effect of dose modifications on PN. Pts received bortezomib 1.3 mg/m 2 (d1, 4, 8, 11 every 21d) for 8 cycles. Comprehensive neurologic evaluation including electrophysiologic testing [NCS] and skin biopsy was performed in a subset of pts (n = 34). Results: Sixty-six pts (47% with stage III MM) were treated and 60 pts are evaluable for response, with an overall RR of 38% (CR 10%, PR 28%). PN was reported in 55% (36/65) pts (23 grade 1, 12 grade 2). One pt with grade 3 PN was discontinued. Other common treatment-associated adverse events reported to date include grade 1–2 fatigue in 21% (6/29), and rash in 17% (5/29) pts. Preliminary analysis shows PN improved or resolved in 75% (6/8 pts, with available follow-up data) with dose reduction. At baseline, small-fiber neuropathy (SFN) was seen in 52% (17/33) and large fiber axonal neuropathy (LFN) occurred in 9% (3/34) pts by NCS. SFN worsened in 41% (7/17) pts with baseline SFN. After completion of treatment, new SFN was seen in 33% (8/24) pts and LFN in 17% (4/24) pts by NCS. Conclusion: Single agent bortezomib is active in newly diagnosed MM pts (CR 10%), has manageable toxicity and offers a steroid-sparing approach. Underlying SFN appears more common in MM than previously appreciated and can also develop during bortezomib therapy, with symptomatic PN improving with dose modification. [Table: see text]
Erratum to: A case report of Grover’s disease from immunotherapy-a skin toxicity induced by inhibition of CTLA-4 but not PD-1
Authors: Marc Uemura, Faisal Fa’ak, Cara Haymaker, Natalie McQuail, Elizabeth Sirmans, Courtney W. Hudgens, Lydia Barbara, Chantale Bernatchez, Jonathan L. Curry, Patrick Hwu, Michael T. Tetzlaff, Adi Diab
Journal: Journal for ImmunoTherapy of Cancer (2017)

[This corrects the article DOI: 10.1186/s40425-016-0157-6.].
The integration of cancer survivorship training in the curriculum of hematology/oncology fellows and radiation oncology residents.
Authors: Michelle Shayne, Eva Culakova, Michael T. Milano, Sughosh Dhakal, Louis S. Constine
Journal: Journal of Clinical Oncology (2013)

e20667 Background: The population of cancer survivors is steadily increasing. Cancer specialists require an understanding of survivors’ needs to insure optimal delivery of post-treatment care. Residency and fellowship training traditionally focus on cancer therapy, while survivorship care is often not emphasized. As a paradigm shift in our training programs, we instituted a Cancer Survivorship Workshop. Methods: In academic year 2011-2012 a Cancer Survivorship Workshop course was held at the James P. Wilmot Cancer Center/University of Rochester, a comprehensive cancer center with accredited training programs in Hematology Oncology (HO) and Radiation Oncology (RO). Course objectives included 1) learning about survivorship from patient, primary care physician, and oncologist perspectives using an evidenced-based curriculum; 2) designing treatment summaries (TS) and survivorship care plans (SCP) for 5 malignancies (lung, breast, prostate, colon, lymphoma) for integration into the electronic medical record and dissemination to patients; 3) establishing collaboration between HO and RO trainees by working together in assigned teams. Course impact was assessed pre- and post- training with a 13 question survey. Questions were answered using a 10 point scale, with a pre-defined rating system for each question. Results: Significant differences in responses to several survey questions were observed comparing pre- and post-course experience. Improvement in comfort level when discussing survivorship issues with patients (median pre-course score=6, post-course=8; p=.001), reported knowledge of survivorship care for 5 types of cancer (5 to 7; p=.002), confidence in ability to explain a SCP to a patient (5 to 8; p=.001), and comfort discussing late effects of treatment with patients (5 to 8; p=.001). The number of articles read regarding cancer survivorship increased. Five unique sets of TS and SCP’s were completed. Conclusions: This study demonstrates the feasibility of implementing cancer survivorship education into the curriculum of HO and RO training. This represents, to our knowledge, the first documented educational undertaking of its kind nationally in HO and RO Programs.
Preclinical activity of ofatumumab (OFA) in mantle cell lymphoma (MCL) in vitro, ex vivo, and in vivo models.
Authors: Matthew John Barth, Gopichand Pendurti, Cory Mavis, Natalie Czuczman, Jospeh J. Skitzki, Francisco J. Hernandez-Ilizaliturri, Myron Stefan Czuczman
Journal: Journal of Clinical Oncology (2012)

e18537 Background: MCL is characterized by an aggressive clinical course and inevitable development of refractory disease despite early intervention that often includes: immunotherapy (e.g., rituximab), multi-agent induction chemotherapy and consolidation with high dose chemotherapy and autologous stem cell transplant in first remission. OFA is a fully human anti-CD20 mAb targeting a novel membrane-proximal epitope on CD20. To characterize the activity of ofatumumab in MCL, we conducted pre-clinical studies in cell lines, primary tumor cells derived from MCL patients and a MCL bearing severe combined immunodeficiency (SCID) mouse model. Methods: Antibody-dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) assays were performed in 51 Cr labeled Mino, Jeko, Rec-1 and Z-138 cells comparing RTX or OFA. Primary tumor cells were exposed ex vivo to OFA or RTX with human serum, differences in cell viability were determined by Cell Titer Glo assay. Expression of CD20 and complement inhibitory proteins (CIPs) CD55 and CD59 was determined by Imagestream analysis and Western blot. SCID mice were inoculated SQ with 10x10 6 Z-138 cells. Once tumors were established, mice were assigned to observation versus 4 doses of either OFA or RTX, and anti-tumor activity was measured by changes in tumor volume. Results: OFA induced higher CDC than RTX in all MCL cell lines tested (Mino: 65.9% vs. 0.5% ; Jeko 43.9% vs. 13.3% ; Rec-1 25.4% vs. 4.7% ; Z-138: 56.4% vs. 0.65%). No differences in ADCC were noted between OFA and RTX. In primary tumor cells, OFA and RTX demonstrated similar activity. CD20 levels were similar in all MCL cell lines tested. Of interest, CIP expression in MCL cell lines was higher when compared to other NHL cell lines, explaining differences observed between OFA and RTX. In vivo OFA was more effective in slowing tumor progression than RTX. Conclusions: Our data suggest OFA is more potent than RTX against MCL pre-clinical models. In addition and as expected, OFA exhibits potent CDC despite high expression of CIP. Our results support the evaluation of ofatumumab in future prospective clinical trials for patients with MCL.
Optimizing induction and pretransplant consolidation for myeloma: Results of Myeloma XI, a phase III trial comparing different IMiDs.
Authors: Charlotte Pawlyn, Faith E Davies, David A. Cairns, Walter Gregory, Ana Quartilho, Jacqueline Ouzman, Helen C Howard, Corinne Collett, Jindriska Lindsay, Gordon Cook, Donald Milligan, Claire Chapman, David Allotey, Roger G. Owen, Mark Drayson, Nigel Russell, Graham H. Jackson, Gareth J Morgan
Journal: Journal of Clinical Oncology (2014)

8537 Background: Treatment with immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) has dramatically increased response rates and survival for myeloma patients over the last decade. Triplet drug combinations are more effective than doublets or single agents. The more recently developed IMiD lenalidomide, with a different spectrum of effects to thalidomide, is an excellent option for induction therapy due to its oral administration and lack of significant peripheral neuropathy (PN) when compared with bortezomib and thalidomide. Methods: Myeloma XI, a phase III randomised trial for newly diagnosed patients of all ages, compared induction treatment with cyclophosphamide/lenalidomide/dexamethasone (CRD) to cyclophosphamide/thalidomide/dexamethasone (CTD) given to max. response or intolerance. To evaluate the role of pre-transplant consolidation with a PI we randomised patients achieving <VGPR to additional cyclophosphamide/bortezomib/dexamethasone (CVD) vs nothing. Fit patients went on to receive melphalan+ASCT. Recruitment is now complete. Results: Results are available for a total of 1939 patients, 1104 intensive pathway (540 CRD vs 564 CTD, median age 61 yrs, range 28-75) + 835 non-intensive (411 CRDa vs 424 CTDa, median 74 yrs, range 51-89). 274 patients received additional bortezomib. The pre-planned ITT analysis of combined CR+VGPR rates shows a significant difference between CRD and CTD treatment on multivariate analysis in favour of CRD with odds ratio 1.27 (95% CI 1.06-1.52, p = 0.009). This is due to different CR rates (CRD: CR 25%, VGPR 30%, PR 26% vs CTD: CR 15%, VGPR 33%, PR 31%). Additional bortezomib therapy for those with a suboptimal response upgraded response in 51% demonstrating that PI therapy can be effective in patients intrinsically resistant to IMiDs. Treatment with both IMiDs was well tolerated. Patients on lenalidomide had lower rates of PN (≥ grade II CRD 1.9% vs CTD 6.3%, p<0.001) but higher rates of grade III/IV cytopenias. Conclusions: We have demonstrated an important difference in response between the IMiDs thalidomide and lenalidomide however further follow up is required to see whether this translates into prolonged PFS and OS. Clinical trial information: NCT01554852.
Second primary malignances (SPMs) in patients with gastrointestinal stromal tumors (GIST): The potential influence of imatinib treatment.
Authors: Anna Estival, Laia Espasa, Olatz Etxaniz, Ignacio Blanco, Jose Luis Cuadra-Urteaga, Maria de los Llanos Gil, Carmen Balana, Isabel Ojanguren, Alberto Indacochea, Sara Ahlal, Laia Vila, Enric Carcereny, Erika Mijangos
Journal: Journal of Clinical Oncology (2014)

10552 Background: GISTs are relatively uncommon and predominantly sporadic tumors of the gastrointestinal tract. The high incidence of SPMs observed in patients (p) with GIST (13-20 %), has suggested a possible cause-and-effect relationship between treatment with imatinib and SPMs. Whether this concomitant occurrence is a causal association or a coincidence is not yet resolved. Methods: We have retrospectively analyzed the incidence of synchronous and metachronous SPMs, in all p diagnosed with GIST and treated at a single institution between 1997 and 2012. Results: A total of 95p were diagnosed with GIST, 18 (19%) of whom developed SPMs. For these 18p, the median age at GIST diagnosis was 61.7 years (range, 27-75). The GIST was located in the stomach in 10p (52.6%) and in the small bowel in 8 (47.4%). The SPMs were more frequent in the colon (4p), breast (4), kidney (3), esophagus (2), lymphoproliferative disease (2), bladder (2), adrenal gland (1), prostate (1), pancreas (1), vocal cord (1) and oligodendroglioma (1). 3p had more than one SPM and only one p had the diagnosis of Neurofibromatosis as a genetic sydrome. Of 14p with metachronous SPMs, GIST was the first tumor in 8p, with a median time of 53.9m (range, 4-169) between tumors. GIST was the second tumor in the remaining 6p, with a median time to diagnosis of 34.3m (range, 5-98). Only 4 of our 18p (22.2 %) received imatinib, two of whom were diagnosed with SPMs after having been treated with Imatinib. Conclusions: We have observed SPMs in 19% of p with GIST. The cause of this association is difficult to determine but it seems unrelated to imatinib treatment. The potential non-random association between GIST and other malignances merits further investigation.
Retraction
Journal: Journal of Clinical Oncology (2012)

The majority of the authors wish to retract this article because they have identified several instances of misalignment of genomic and clinical outcome data.Although a reanalysis of correctly aligned data still demonstrated a capacity to predict patient response to platinum-based therapy, the accuracy of these predictions has been reduced from 77.8% to 72.2%, and as a result, the original conclusions have been compromised.