tbuckley/cabot-search huggingface dataset:
Identification and validation of actionable mutations in solid tumors.
Authors: Amelia S. Zessin, Adrian Randall, Shannon McCall, Michael B. Datto, Shiaowen David Hsu
Journal: Journal of Clinical Oncology (2014)

e22149 Background: Although the use of genomic sequencing to guide cancer patients into clinical trials is being developed, much needs to be done before this becomes the standard of care. First, small panels of cancer related genes are thought to be more cost effective for directing patients into proper treatment groups, as it is currently too costly and cumbersome to perform full exome or genome sequencing. Thus, gene selection for these targeted sequencing platforms remains a challenge. Second, as most mutations are not targetable, in vivo testing must be performed to identify actionable mutations. Methods: To identify actionable mutations in solid tumors, we began by sequencing 50 genes in 12 matched patient tumor samples and their corresponding patient derived xenografts using the Ion AmpliSeq Cancer Hotspot Panel. To screen for additional actionable mutations, we utilized the Ion AmpliSeq Comprehensive Panel in 4 additional matched samples, screening for mutations in over 400 genes. We sorted through data to identify previously described and novel actionable mutations as a model for guiding patient therapy. Mutations were then characterized in vivo using a patient derived xenograft model. Results: Using the Hotspot Panel, we identified mutations in 8 of 12 samples, four of which were potentially actionable mutations. We tested two of these mutations in vivo, IDH1 R132C in a cholangiocarcinoma sample, and ERBB2 G776V in a colon cancer sample. We found IDH1 R132C to be effectively targeted by an IDH1 R132 mutant inhibitor, but ERBB2 G776V to be untargetable. After sequencing with the Comprehensive Cancer Panel, we further identified potentially actionable mutations in all 4 samples, including 2 samples that had no actionable mutations using the Hotspot Panel. Conclusions: The Hotspot Panel covers commonly mutated genes in cancer and may provide information for guiding therapy. However, in most samples, no actionable mutations were found to direct therapy options. Therefore, the Comprehensive Cancer Panel is a better option for use in the clinic for determining appropriate therapeutic targets. Finally, validation of novel mutations found in cancer panels in vivo using matched patient derived xenografts can help better guide patient therapy.
Abstract 17296: Remote Ischemic Postconditioning Improves Myocardial Dysfunction in a Rat Model of Severe Hemorrhagic Shock
Authors: Zhengfei Yang, Qinyue Guo, Dawei Xu, Jennifer Bradley, Mary Ann Peberdy, Joseph P Ornato, Wanchun Tang
Journal: Circulation (2017)

Introduction: Severe hemorrhagic shock frequently leads to death. Previous studies have found that remote ischemic postconditioning (RIPostC) improved the outcomes of circulatory shock significantly. Objective: In this study, we investigate the effects of RIPostC on myocardial function in a rat model of hemorrhagic shock. Methods: Twenty-four male rats weighing between 450-550g were randomized into three groups: Sham, Control, and RIPostC. Hemorrhagic shock was induced by removing 45% of the estimated total blood volume in 60 min and maintained for 40 min. Resuscitation was then attempted by infusion of shed blood for 40min. In RIPostC group, RIPostC was induced by four cycles of 5 min of limb ischemia followed by reperfusion for 5 min during resuscitation. Myocardial function was measured by echocardiography. Results: All animals were resuscitated successfully. An increased cardiac output (CO) level was observed in the RIPostC group compared to that of control animals (p <0.05). Ejection fraction (EF) wa...
Comparative effectiveness of contemporary adjuvant chemotherapy among older rectal cancer patients.
Authors: Jennifer Leigh Lund, Til Sturmer, Hanna Kelly Sanoff
Journal: Journal of Clinical Oncology (2014)

3579 Background: Guidelines for stage II and III rectal cancer in the US recommend neoadjuvant chemoradiation therapy (CRT), curative resection, and adjuvant chemotherapy. This paradigm is based on early trials without neoadjuvant CRT and extrapolations from colon cancer. Recent trials have called into question whether adjuvant chemotherapy improves overall survival (OS) among patients treated with neoadjuvant CRT. We sought to examine whether chemotherapy improves OS in patients treated with neoadjuvant CRT or radiation therapy (RT) and surgery in real world settings. Methods: We identified a population-based cohort of 1,431 older (65+ years) non-metastatic rectal cancer patients diagnosed from 2004-2009 using the Surveillance, Epidemiology and End Results program (SEER)-Medicare data, who underwent neoadjuvant CRT or RT and curative resection. We described patterns of adjuvant chemotherapy using binomial regression models and evaluated the comparative effectiveness of: 1) any adjuvant chemotherapy vs. no adjuvant chemotherapy and 2) adjuvant oxaliplatin+5-fluorouracil (5-FU)/capecitabine vs. 5-FU/capecitabine on OS using Cox proportional hazards regression models and propensity score (PS) matching to adjust for measured covariates. Results: In total, 744 patients (52%) received adjuvant chemotherapy; most received oxaliplatin (53%). Older age, lower pathologic stage, and being widowed were associated with a lower likelihood of receiving adjuvant chemotherapy. Unadjusted and PS adjusted survival was superior in patients treated with chemotherapy (adjusted hazard ratio (aHR)=0.71, 95% confidence interval (CI): 0.57, 0.89). Among patients receiving adjuvant therapy, older age, earlier year of diagnosis, lower stage, and higher census tract poverty level were associated with a lower likelihood of receiving oxaliplatin. The addition of oxaliplatin to 5-FU/capecitabine did not improve OS after PS matching (aHR=1.15, 95% CI: 0.78, 1.70). Conclusions: Our results suggest that older non-metastatic rectal cancer patients benefit from adjuvant chemotherapy; however, the addition of oxaliplatin to 5-FU/capecitabine may not provide any incremental benefit.
Abstract 18017: Metabolic Modulation as a Novel Therapy for Chemotherapy-Induced Cardiotoxicity
Authors: Bruno Saleme, Vikram Gurtu, Adam Kinnaird, Aristeidis E Boukouris, Cory Wagg, Gary Lopaschuk, Gopinath Sutendra
Journal: Circulation (2017)

Introduction: Chemotherapy Induced Cardiotoxicity (CIC) is a serious complication that results in early termination of cancer therapies, despite responsive tumours. There are no therapies that prevent CIC, as our understanding of the mechanisms in this condition is limited. Intriguingly, similar metabolic processes (increased glycolysis) has been described in heart failure and cancer, suggesting metabolic therapies may be beneficial against both diseases. One challenge in designing CIC therapies is protecting the heart against apoptosis without hindering chemotherapy-mediated tumour apoptosis. An intriguing difference between the myocardial and tumour microenvironments is the former is normoxic (oxidized) and the latter hypoxic (reduced), suggesting that targeting metabolic redox-sensitive proteins induced by chemotherapy agents in the heart may provide selectivity against CIC, without compromising tumour suppression. Hypothesis: We hypothesized that therapeutically targeting the metabolic redox-sensitive...
Feasibility and Benefit of Molecularly-Informed Enrollment into Personalized Therapies or Early Phase Trials for Patients with Relapsed or Refractory Multiple Myeloma
Authors: Tarek Assi, Jean-Marie Michot, Toni Ibrahim, Fabien Le Bras, Karim Belhadj, Julien Lazarovici, David Ghez, Julien Rossignol, Veronique Vergé, Julia Arfi-Rouche, Sophie Cotteret, Christophe Massard, Jean-Charles Soria, Alina Danu, Vincent Ribrag
Journal: Blood (2018)
EGFR T790M mutation testing within a phase I study with AZD9291.
Authors: Simon Patrick Dearden, Helen Brown, Rebecca Cole, Suzanne Jenkins
Journal: Journal of Clinical Oncology (2014)

e19051 Background: EGFR tyrosine kinase inhibitors (TKIs) have demonstrated clinical benefit in patients (pts) with advanced EGFR mutation-positive NSCLC. Eventually pts develop acquired resistance and disease progression, most commonly associated with the EGFR T790M mutation in 50-60% of tumors. AZD9291 is a potent, oral, third-generation, irreversible inhibitor of EGFR sensitising (EGFRm) and resistance (T790M) mutations with a reduced potency against the wild-type EGFR. Within the current phase I AURA study (NCT01802632), patients who have progressed following an EGFR-TKI are enrolled into expansion cohorts based on T790M mutation status. Determination of T790M and EGFRm mutation status were performed either at a central testing laboratory (lab), or at a local lab with central lab confirmation of the result. Methods: Currently, 3 central labs are performing T790M testing using the Roche Molecular Diagnostics cobas EGFR Mutation test. Local testing was performed using a variety of mutation detection methods. Testing is performed on fresh biopsy material taken following progression on the latest line of therapy. In order to maximise assay success rates, the sample area is used to estimate the number of tissue sections required for analysis. As of DCO, 135 samples had been tested centrally; of these 102 had both central and local results. Results: 97% (131/135) of samples were analysed successfully despite biopsy samples being small, with a median area of 12mm2. A median of five 5mm sections were used for DNA extraction. The prevalence of centrally tested T790M mutations in this study was 67% (88/131) with no meaningful difference between Asian (67% [57/85]) and Caucasian (68% [31/46]) patients. Overall, concordance between central and local testing was 91% (93/102). Conclusions: Despite limited sample material, the cobas EGFR test proved to be a reliable testing platform in our study. The prevalence of T790M mutations in post EGFR-TKI patients was 67%, and were consistent between Asian and Caucasian subgroups. Whilst local lab testing was largely concordant with the central result, the variability in the sensitivity of local testing methods led to some inconsistencies when compared with the central result. Clinical trial information: NCT01802632.
Distribution and Prognostic Significance of Left Ventricular Global Longitudinal Strain in Asymptomatic Significant Aortic Stenosis
Authors: Julien Magne, Bernard Cosyns, Bogdan A. Popescu, Helle G. Carstensen, Jordi Dahl, Milind Y. Desai, Leighton Kearney, Patrizio Lancellotti, Thomas H. Marwick, Kimi Sato, Masaaki Takeuchi, Concetta Zito, Anne-Claire Casalta, Dania Mohty, Luc Piérard, Gilbert Habib, Erwan Donal
Journal: JACC. Cardiovascular imaging (2019)
Causes for hospitalizing patients at a university hospital cancer clinic.
Authors: Bjørn Henning Grønberg, Marte Bjorkvoll, Cecilie Lund Mathisen, Jo-Asmund Lund, Stein Kaasa
Journal: Journal of Clinical Oncology (2014)

e17515 Background: The number of beds in our ward was reduced from 68 in 2008-9 (A) to 36 in 2012-13 (B). The aim was to increase our capacity by treating more patients on an outpatient basis. To plan future organization of our clinic, we analyzed why patients were admitted to our ward in these periods. Methods: Patients were identified from our administrative system and data were collected from the medical records. Results: In period A, 4,154 patients had 15,372 consultations at our outpatient clinic and 1,418 patients had 2,423 hospital stays. Corresponding numbers in B were 5,273, 24,650, 1,218, and 1,996. We analyzed 995 admissions (39 %) / 498 pts (35 %) in period A; and 915 admissions (46 %) / 499 pts (41 %) in B. Mean no. of admissions per patient was similar (A: 1.71, B: 1.64; p=.4). Admissions per patient were 1: 57 %; 2: 20 %; 3+: 23 %. Mean length of hospital stays were A: 6.5 and B: 6.4 days; proportions of beds occupied were A: 83 % and B: 93 %. Emergency admissions increased from A: 25 % to B: 48 % (p<.001). Re-admissions within 30 days after discharge increased from A: 7 % to B: 15 %. Age, gender, marital status and Charlson Comorbidity Index were similar in both periods. Lymphomas (19 %), breast (12 %) and prostate (9 %) were the most common cancers admitted. More patients in A had metastatic disease (A: 72 %, B: 66 %; p=.04). Admissions for staging or planning therapy decreased from A: 30 % to B: 7 % (p<.001). 29 % was admitted for treatment in both periods (68 % chemo- and 28 % radiotherapy). Admissions due to poor performance status (PS) and severe symptoms increased from 325 (34 %) to 538 (60 %) (p<.001). The largest increases were for infections (A: 36 [4 %], B: 104 [10 %]; p<.001) and neutropenic fever (A: 40 [4 %], B: 67 [7 %]; p=.004). Mean PS at admission increased from 1.8 to 2.0 (p<.001). Conclusions: The number of patients admitted due to poor PS, severe symptoms and treatment-toxicity increased significantly – and more than the number of patients treated. There were no obvious differences in patient characteristics, suggesting that the reason might be that patients now in general receive more therapy than only a few years ago. With the expected development of new therapies and an increasing incidence of cancer, it seems that more resources are needed to provide sufficient supportive care.
Patterns of failure analysis after radical nephrectomy for renal cell carcinoma.
Authors: Sameer G. Jhavar, Gregory P. Swanson
Journal: Journal of Clinical Oncology (2014)

e15606 Background: This is a single institution patterns of failure analysis after radical nephrectomy (RN) for renal cell carcinoma (RCC) over a 14 year period to determine the incidence of loco-regional failure (LRF) and distant failure (DF) and to assess the risk of failure with clinic-pathological variables. Methods: From 1998 to 2012, 259 of 379 patients who underwent RN for presumed RCC met all of our inclusion criteria which were a) clear or non-clear cell renal cell carcinoma; b) no metastatic disease at presentation; and c) at least one year of follow-up. The median age at diagnosis was 65 years (range 4 to 88). Stage I, II, III and IV disease was found in 60%, 15%, 25% and 0.003% respectively. 91% had clear cell histology. 3% had node positive disease. Grade 1, 2, 3 and 4 disease was seen in 8%, 71%, 17%, and 2% patients respectively. 8% patients had lympho-vascular invasion (LVI). Results: The median follow-up was 5 years (range 1-18) for the entire cohort. The patterns of failure are detailed in the table below. Conclusions: LRF alone after radical nephrectomy for RCC in our series was not uncommon. Patients with advanced stage, high grade, positive lymph nodes and presence of LVI had a considerable risk for LRF with or without DF. These findings warrant further investigation. Total failures (%) LRF only (%) LRF plus DF (%) DF only (%) Stage I 6 0 3 3 Stage II 45 5 11 26 Stage III 51 15 15 20 Positive lymph nodes 89 33 33 22 LVI 52 10 14 29 No LVI 20 4 7 9 Grade 1 18 0 14 5 Grade 2 17 3 5 9 Grade 3 45 14 11 20 Grade 4 50 25 0 25 Extension into peri-nephric fat not beyond Gerota’s fascia and not in adrenal gland 54 16 16 23 Renal vein invasion 50 11 11 28
Coroners warn health secretary of clozapine deaths
Authors: Clare Dyer
Journal: BMJ (2018)

Coroners have alerted the health and social care secretary for England to two deaths from side effects of the antipsychotic clozapine and asked what action he intends to take to prevent future deaths.

Two coroners have sent “regulation 28” letters to Matt Hancock and two NHS trusts after the deaths of Julia MacPherson and Tom Jackson, amid concerns that healthcare staff may not be sufficiently aware of the drug’s serious side effects.

Coroners have a duty to send such letters if information emerges during an inquest that could be used to prevent other people from dying in the future.

MacPherson, who …
Pharmacokinetic (PK) assessment of dacomitinib (D) in patients with locoregionally advanced head and neck squamous cell carcinoma (LA SCCHN) following administration through gastrostomy feeding tube (GT).
Authors: Joanne Wing-Yan Chiu, Kelvin K. Chan, Lillian L. Siu, Eric Xueyu Chen, Albiruni R. A. Razak
Journal: Journal of Clinical Oncology (2014)

e17049 Background: D is an irreversible oral pan-HER tyrosine kinase inhibitor with antitumor activity demonstrated in patients (pts) with recurrent/metastatic (RM) SCCHN (Razak et al, Ann Oncol 2013). A Phase I trial of D with standard therapy in LA SCCHN is ongoing (NCT01737008). As enteral feeding is needed for many SCCHN pts, this study investigated the PK properties of D when administered via GT. Since pts with GT are difficult to recruit, this study also determined the feasibility of PK assessments using a unique design in LA SCCHN pts with GT, by giving a single dose of drug during their radiotherapy (co-administration with chemotherapy avoided). Methods: Eligible pts were given a single dose of crushed D at 45mg in water suspension via GT. All doses were administered in fasting state and supine position. PK samples were drawn prior to dose (t=0), 30 minutes and 1, 2, 3, 4, 6, 12, 24, 48, 72, 96, 144, 168, 192 and 216 hrs post-dose, and analyzed by HPLC-MS/MS. PK parameters (mean [CV%]) of this study were compared with those of D given orally using Student t test. Results: Six patients with LA SCCHN patients were enrolled. The median age of patients was 54 years. Two different types of GT were used: 14F Cope-loop tube (n=3), 20F PEG/disc retention tube (n=3). PK study showed t1/2 of 58 hours [22%], Cmax of 17 ng/ml [33%], Tmax of 8 hours, AUC0-inf of 1185 ng*hr/ml [30%], Vd/F of 3310 L [24%] and CL/F of 41 L/hr [32%]. Compared with oral dosing of intact immediate release (IR) tablets, GT administration resulted in 34% reduction in Cmax and 33-44% decrease in AUC (all p<0.05) (Janne et al, Clin Cancer Res 2011). Such difference was not detected when compared with PK of D administered orally in aqueous suspension (Bello et al, Cancer Chemother Pharm 2013). Conclusions: Administration of D via GT resulted in reduced drug absorption compared with oral dosing of intact IR tablets. The difference may be attributed to aqueous suspension of D. Caution should be taken with GT administration of orally active small molecule targeted therapy. This study also demonstrated that PK trials in GT patients are feasible using novel designs. Clinical trial information: NCT01484847.
Clinical, Immunophenotypic and Genomic Findings of Acute Undifferentiated Leukemia and Comparison to AML with Minimal Differentiation: A Study from the Bone Marrow Pathology Group
Authors: Olga K Weinberg, Robert P. Hasserjian, Ezra Baraban, Chi Young Ok, Julia T Geyer, John KSS Philip, Jason H. Kurzer, Heesun J. Rogers, Valentina Nardi, Richard M. Stone, Jacqueline S. Garcia, Eric D. Hsi, Adam Bagg, Sa A. Wang, Attilio Orazi, Daniel A. Arber
Journal: Blood (2018)
Stage migration and survival in DLBCL patients before and after the approval of positron emission tomography (PET) scan: Population-based analysis using the U.S. National Cancer Data Base (NCDB).
Authors: Anusha Reddy Madadi, Ronald S. Go, Mohammed Al-Hamadani
Journal: Journal of Clinical Oncology (2014)

8561 Background: PET scan was approved by the US Medicare for diagnosis and staging of NHL in July 2001. We studied the DLBCL stage distribution and overall survival (OS) before and after introduction of PET scan. Methods: We identified DLBCL patients diagnosed in 1998 to 2011 from the NCDB. We obtained data pertaining to stage and OS. We grouped patients into 2 cohorts: pre (1998-2001) and post (2002-2005) PET approval. To minimize bias in improvement of OS due to new treatments, year 2005 cut-off was chosen as rituximab was approved by the US Food and Drug Administration for treatment of B-cell NHL in 2006. Results: There were 202,294 patients with DLBCL. Of these, 30.5% had extra-nodal disease presentation. The stage distribution over time is shown in table 1. Overall, early stage disease (I/II) remained relatively stable over time (35.1% in 1998 to 38.3% in 2011). Advanced stage disease (III/IV) increased from 30.7% to 51.8%. In contrast, patients with unknown stage decreased from 34.2% to 9.4%. We observed similar stage migration in both nodal and extra-nodal DLBCL subgroups.The median OS was significantly better (all P values < 0.001) in the post-PET approval era for all stages: combined (64.5 vs. 38.4 months), I/II (not reached (NR)[mean 103.8 months]) vs. (NR [mean 75.3 months]), III/IV (28.2 vs. 13.0 months), and unknown (57.2 vs. 39.9 months). Conclusions: Since the approval of PET scan for NHL diagnosis and staging in 2001, there has been a substantial change in the stage distribution among DLBCL patients. This is predominantly due to a migration from unknown stage into advanced stage disease. The OS has improved across all stages but most marked among patients with advanced stage disease. The latter may be in part due to stage migration. Stage (%) 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 I 20.2 21.7 21 20.2 19.8 21.6 20.9 20.3 19.9 19.4 21 20.9 20.7 20.9 II 14.9 14.9 15.3 15.4 15.8 16.4 17 17 16.2 16.6 17.8 18.4 18.1 17.3 III 10.6 10.6 11 11.3 11.7 13.2 13.6 14.8 14.8 14.9 16.6 16.8 17 17.9 IV 20.1 21 21.4 21.6 22.7 26.8 26.9 27.9 28.2 28.3 31.3 32.5 33.5 34.5 Unknown 34.2 31.8 31.3 31.5 30 22 21.6 20 20.9 20.8 13.3 11.4 10.7 9.4
Splenectomy-only approach for the first-line treatment of splenic marginal zone lymphoma.
Authors: Muhit Ozcan, Guldane Cengiz Seval, Pervin Topcuoglu, Onder Arslan, Gunhan Gurman, Isinsu Kuzu
Journal: Journal of Clinical Oncology (2014)

e19543 Background: The aim of this retrospective single-center study was to evaluate the clinical characteristics and response to treatment of splenic marginal zone lymphoma (SMZL), a rare B-cell malignancy with no standard treatment.Methods: Between January 2005 and October 2013, we analyzed a total of 24 patients with SMZL in our clinic. There were 17 (70.8%) female and 7 (29.2%) male patients.Median age was 60.4 years (range, 37-84 years).The median time of follow-up was 18.4 months (range, 3-96 months).Results: The presence of splenomegaly (95.2 %) was recorded as the most frequent finding at the diagnosis.Twenty-one patients (87.5%) had bone marrow involvement, 7 had (26.2%) lymph nodes involvement.Tumor involvement of peripheral blood (defined as more than 5.0x109/L of absolute lymphocyte count) was detected in 6 patients (25%).The presence of hypogammaglobulinemia was observed in 10 patients (41.7%).Splenectomy was the first line treatment in 21 patients.Five patients (20.8%) received additional CHOP-like chemotherapy because of physician’s choice based mostly on the presence of symptoms.The number of patients reaching clinical complete hematological response or partial response after splenectomy only or followed by chemotherapy was 16 (85.7%) and 3 (14.3%), respectively. Four of 21 (19%) patients who achieved a response after splenectomy ultimately relapsed at a median of 27 months (range, 4-72 months) (Table-1).No treatment related mortality was seen.The probability of 5 year-relapse-free and overall survival was 71.0 %±13.4 % and 90.9 %±8.7 % , respectively.When we analyzed the patients underwent splenectomy only (n=16) the probability of relapse-free and overall survival was estimated as 63.8 %±19.8 and 87.5 %±11.7%, respectively.The comparison of survivals was not effected on the type of treatment (p>0.05).Conclusions: In conclusion, although the options of new treatment modality in SMZL have been debated today, splenectomy seems to be safe and effective in controlling long-term disease.