tbuckley/cabot-search huggingface dataset:
Investigation of anaplastic lymphoma kinase (ALK) translocations in gastric and esophageal signet ring cell carcinomas.
Authors: Jill Miller, Zhihua Peng, Rebecca Wilcox, Mark Evans, Kumarasen Cooper, Steven Ades, Claire F. Verschraegen
Journal: Journal of Clinical Oncology (2013)

e15106 Background: Anaplastic lymphoma kinase (ALK) fusion oncogenes are present in multiple cancer types. The inversion of echinoderm microtubule associated protein like 4 (EML4) and ALK genes on chromosome 2 is present in a subset of non-small cell lung cancer (NSCLC) patients. ALK mutated lung cancers demonstrate a significantly higher incidence of signet ring cell histology than compared to ALK-negative tumors. Based on the histological similarities of ALK positive NSCLC and signet ring cell carcinomas (SRCC) of the GI tract, we hypothesized that gastric and/or esophageal SRCC may also harbor ALK translocations. Methods: Thirty-five formalin-fixed, paraffin-embedded (FFPE) tissue specimens of SRCC originating from esophageal, GE junction or gastric locations were obtained from the Fletcher Allen Healthcare (Burlington, Vermont) tissue bank following Internal Review Board guidelines. Confirmation of SRCC or adenocarcinoma with signet ring cell features was confirmed by a board certified, gastrointestinal pathologist. SRCC specimens were analyzed by fluorescence in situ hybridization (FISH) analysis using an ALK (2p23) break-apart probe (Kreatech Diagnostics). Results: The FISH analysis revealed no evidence of ALK translocation: all thirty-five (100%) SRCC specimens showed intact (yellow) ALK FISH signals. Conclusions: These data indicate that despite histological similarities between SRCC of the GI tract and ALK positive NSCLC, ALK translocations are unlikely to be a significant contributor to gastric and esophageal SRCC molecular etiology. Further genomic investigations are on-going. This study was performed with funding received from the Lake Champlain Cancer Research Organization.
Mixed pathologies and neural reserve: Implications of complexity for Alzheimer disease drug discovery
Authors: David A. Bennett
Journal: PLoS Medicine (2017)

Alzheimer disease (AD) is among the most common causes of dementia worldwide.Approved medications for the symptoms of AD dementia have marginal benefit, and no new therapies have been approved in more than a dozen years.There are no approved treatments for the prevention of AD dementia.The lack of robust therapeutics comes despite intense efforts by the public and private research community to discover them.There have been about 450 failed clinical trials on www.clinicaltrials.govsince the last drug approval by the Food and Drug Administration [1].With changing demographics forecasting a marked increase in the number of persons with AD and other dementias worldwide, and with extraordinary attendant costs of care and toll on individuals and families, countries around the globe are investing substantial capital to stimulate basic and translational research in the hopes of developing new therapeutics for the treatment and prevention of AD and other dementia.Clinical-pathologic findings, many from community-based studies that incorporate brain autopsy, are shedding light on the complexity of the AD dementia phenotype.This complexity, largely the result of mixed dementia and neural reserve, has important implications for clinical trial design and drug discovery.
Outcomes and treatment of patients with POEMS syndrome experiencing progression or relapse after first line treatment.
Authors: Taxiarchis Kourelis, Robert A. Kyle, Shaji Kumar, Morie A. Gertz, Martha Lacy, Prashant Kapoor, Francis Buadi, Ronald S. Go, John Anthony Lust, Suzanne R. Hayman, Vincent Rajkumar, Steven R. Zeldenrust, Stephen J. Russell, David Dingli, Yi Lin, Nelson Leung, Angela Dispenzieri
Journal: Journal of Clinical Oncology (2015)

8594 Background: While clinical improvement is almost universal with first line chemotherapy and/or radiation therapy in patients with POEMS syndrome, outcomes and management of patients who relapse or progress (R/P) after first line treatment have not been described. Methods: We identified 291 patients with POEMS syndrome treated at the Mayo Clinic from 1974-2014. Median follow-up for survival and R/P were 68 months and 51 months, respectively. Results: For the 78 documented R/P patients (27%), 2ndline treatments included: novel agents, n = 16 (21%), chemotherapy, n = 23 (30%), radiation, n = 15 (19%), ASCT, n = 12 (15%), other, n = 5 (6%) and uncertain type of therapy, n = 5 (6%). The 5 year PFS for the 291 patients was 68%. For patients with documented R/P, median time to R/P was 42 months (range 3-327 months). The 5 year OS for patients with and without an R/P was 85% vs 77%, p = NS. Excluding 9 patients with refractory disease, 47 (60%) patients experienced a clinical R/P and 22 (28%) R/Ps were identified by a combination of worsening VEGF, hematologic or radiographic evaluations. Eighteen (23%) patients relapsed with symptoms that were not present at diagnosis. Outcomes after second line treatment are shown in the table. Thirty patients (30%) went on to experience a second R/P (R/P-2) at a median of 17 months from the end of second line treatment/diagnosis of the first R/P (range 0-96 months). Conclusions: One quarter of patients with POEMS had a documented R/P after first line chemo-or radiation therapy, some of whom with symptoms not present at initial diagnosis. The vast majority of patients with R/P responded to subsequent therapy. Types of relapses/progressions with respective second responses. Type of relapse/progression N=78 2nd responses N (%) CR PR NR NE Hematologic (VGPR included) 23 39% 17% 26% 17% PET 44 16% 23% 7% 55% VEGF 26 62% 15% 8% 15% N Response Mixed response or stable disease Progression NE Neuropathy 39 41% 26% 10% 23% Fluid overload 27 48% 15% 30% 7% Erythrocytosis/ Thrombocytosis 12 67% 8% 8% 17% Endocrinopathy 20 15% 40% 5% 40% Skin Changes 20 45% 10% 15% 30% Lung function 16 38% 6% 13% 44% Organomegaly/ Lymphadenopathy 15 53% 20% 0 27% Papilledema 9 56% 0 0 44% Other 6 67% 0 17% 17%
Stomach cancer risk following radiotherapy for testicular cancer.
Authors: Lindsay M Morton, Sophie D. Fossa, Marilyn Stovall, Flora E. van Leeuwen, Tom B. Johannesen, Preetha Rajaraman, Berthe M Aleman, Graca Dores, Ethel S. Gilbert, Per Hall, Eric J. Holowaty, Heikki Joensuu, Magnus Kaijser, Charles Lynch, Eero Pukkala, Hans H Storm, Susan A Smith, Joseph F Fraumeni, Lois B. Travis, Michael Hauptmann
Journal: Journal of Clinical Oncology (2013)

4536 Background: Testicular cancer (TC) is a highly curable malignancy occurring most commonly among men aged 15-34 years. Survivors are at increased risk for adverse late effects of therapy. Previous studies have reported more than 4-fold risks of stomach cancer after TC, although the potential role of radiotherapy and chemotherapy for TC in these associations is unclear. Methods: We evaluated stomach cancer risk in an international cohort of 23,982 men diagnosed with TC during 1959-1987. Using detailed radiotherapy records, doses to the stomach tumor location were estimated for 92 stomach cancer patients and 180 individually matched controls. Chemotherapy drugs and doses also were recorded. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. Results: Fifty-seven percent of patients with stomach cancer were diagnosed with TC before age 40 years, 65% had seminoma, 95% had stage I or II disease, and 37% were diagnosed with stomach cancer ≥20 years after TC diagnosis. Patients who received radiotherapy [87 (95%) cases, 151 (84%) controls] had a 5.9-fold (95%CI 1.6-21.3) increased risk of stomach cancer compared with patients who did not receive radiotherapy. Risk increased with increasing radiation dose to the stomach (P-trend&lt;0.001), with ORs of 3.6 (95%CI 1.3-10.6), 4.4 (1.2-16.4) and 13.3 (2.5-70.0) after 20-39.9 Gy, 40-49.9 Gy, and ≥50 Gy radiation to the stomach, respectively, compared with &lt;10 Gy. Radiation-related stomach cancer risk did not vary by calendar year of treatment, age at exposure, or TC histology. The OR for having received any chemotherapy was 1.3 (14 cases, 23 controls, 95% CI 0.6-2.8). Stomach cancer risk was not significantly elevated among patients given cisplatin-based chemotherapy (7 cases, 10 controls, OR=1.7, 95% CI 0.6-5.1). Conclusions: Patients administered radiotherapy for TC in the past are at increased risk of developing stomach cancer, particularly those who received ≥20 Gy to the stomach. The study results warrant consideration in radiation risk assessment and long-term follow-up. Future studies should further investigate a possible role for chemotherapy in stomach cancer risk.
A phase I study of DMOT4039A, an antibody-drug conjugate (ADC) targeting mesothelin (MSLN), in patients (pts) with unresectable pancreatic (PC) or platinum-resistant ovarian cancer (OC).
Authors: Colin D. Weekes, Laetitia E. Lamberts, Mitesh J. Borad, Johannes Voortman, Robert R. McWilliams, Jennifer Robinson Diamond, Elisabeth De Vries, Henk M.W. Verheul, Christopher Hanyoung Lieu, Huibin Yue, Yulei Wang, Suzie Scales, Divya Samineni, Katie Wood, Flavia Brunstein, Daniel J. Maslyar, George P. Kim
Journal: Journal of Clinical Oncology (2014)

2529 Background: MSLN is a tumor antigen over-expressed in PC and OC. The ADC DMOT4039A is a humanized IgG1 anti-MSLN monoclonal antibody and anti-mitotic agent, MMAE, that shows anti-proliferative activity in xenograft models. Methods: This study evaluated safety, PK, and activity of DMOT4039A (0.2-2.8 mg/kg) given every 3 weeks (q3w) to pts with PC or OC. A traditional 3+3 design was used for dose escalation followed by expansion by disease (2nd line in PC) at the recommended Phase 2 dose (RP2D). Anti-tumor response was evaluated per RECIST 1.1, and serum CA19-9 or CA125. Tumor MSLN expression was determined in archival tissue by immunohistochemistry (IHC). Results: As of 5 Dec 2013, 49 pts have enrolled (30 PC; 19 OC), median age 63 (range 39-75), PS 0-1, median number of prior regimens 2 (1-7) in PC, and 5 (1-16) in OC. Pts received a median of 3 (range 1-14) cycles of DMOT4039A. The MTD was 2.4 mg/kg, with 2 DLTs at the maximum dose level of 2.8 mg/kg: hyperglycemia (G3) and hypophosphatemia (G3). The most common related AEs (all grades) were fatigue (49%), nausea (37%), diarrhea (29%), vomiting (27%), decreased appetite (22%), abdominal pain, and constipation (both 20%). The majority of AEs were G1-2. Seven related SAEs (fatigue, hyperglycemia, hypophosphatemia, infection, pyrexia, tachycardia, and vomiting) were observed in 2 pts. ADC exposure was dose-proportional over all dose levels. Four pts (8%) had a confirmed partial response (PR), including 1/19 PC (no IHC sample) and 3/10 OC pts (IHC 2+/3+) treated at the RP2D of 2.4 mg/kg q3w. One PC pt without RECIST response showed > 50% decrease from baseline in CA19-9 levels; 7 OC pts showed > 50% decrease in CA125. MSLN expression was IHC 2+/3+ in 64% of in the PC cohort (25 pts), and 91% in the OC cohort (23 pts), in part due to diagnostic selection for enrollment in expansion cohorts. IHC assessment was unavailable for 2 pts with PC with RECIST / CA19-9 response; all patients with OC with RECIST/CA125 responses were IHC 2/3+. Conclusions: DMOT4039A administered at 2.4 mg/kg q3w has a tolerable safety profile and encouraging anti-tumor activity in both PC and OC, supporting further evaluation in these diseases. Clinical trial information: NCT01469793.
Evolution of resistance in ALK-positive patients treated with ALK tyrosine kinase inhibitors (TKIs).
Authors: Justin F. Gainor, Luc Friboulet, Ryohei Katayama, Mark M Awad, Elizabeth L. Lockerman, Katherine Schultz, Sidra Mahmood, Makoto Nishio, Noriko Yanagitani, Lecia V. Sequist, Mari Mino-Kenudson, Jeffrey A. Engelman, Alice Tsang Shaw
Journal: Journal of Clinical Oncology (2014)

8031 Background: Lung cancers harboring ALK rearrangements are sensitive to treatment with ALK TKIs. Ceritinib (LDK378) is a novel, highly potent ALK TKI that has shown promising anti-tumor activity in crizotinib-resistant patients (pts); however, resistance invariably develops. Methods: To determine molecular mechanisms of resistance to ceritinib, we identifiedpts with ALK-positive lung cancer who underwent biopsies of progressing lesions following treatment with ceritinib. Specimens underwent ALK FISH and sequencing of the ALK tyrosine kinase domain. Similar analyses were performed in a subset of pts with pre-ceritinib/post-crizotinib biopsy specimens available. Biopsies were performed under an IRB-approved protocol. Results: We identified 10 ALK-positive pts who underwent biopsies at the time of resistance to ceritinib. Median duration of treatment (DOT) on ceritinib was 7.5 months (range 2.5 – 15.4 months). Nine of 10 pts had previously received crizotinib with a median DOT of 8.1 months (range 2.8 – 35.1 months). Pre-ceritinib/post-crizotinib biopsies were available for comparison in 8 pts. ALK resistance mutations were identified in 5/11 (45%) post-ceritinib biopsies (1 pt had 2 separate procedures performed). Resistance mutations included: G1202R (3), F1174C (1) and F1174V (1). Notably, 2 pts had ALK resistance mutations (S1206Y and G1269A) identified in pre-ceritinib/post-crizotinib samples. These mutations were no longer present in ceritinib-resistant biopsies performed at the same anatomic sites; however, the G1202R mutation emerged in both pts. One of these pts was also found to have an F1174V mutation at a separate post-ceritinib biopsy site. ALK FISH was positive for ALK rearrangement in 8/8 ceritinib-resistant specimens, but ALK gene amplification was not identified, including in 1 pt with high-level ALK amplification in a pre-ceritinib/post-crizotinib biopsy. Additional genetic data will be presented at the meeting. Conclusions: Mechanisms of acquired resistance are heterogeneous and may evolve dynamically in response to different ALK TKIs. Consistent with preclinical data, ALK mutations in two residues, G1202 and F1174, can mediate resistance to ceritinib in the clinic.
A phase II study of preoperative chemotherapy and chemoradiation for localized gastric and gastroesophageal junction adenocarcinoma (LGCA).
Authors: Elena Elimova, Roopma Wadhwa, Kazuki Sudo, Hironori Shiozaki, Rebecca Slack, Hsiang-Chun Chen, Brian D. Badgwell, Aurelio Matamoros, Jeffrey H. Lee, Brian Weston, Manoop S. Bhutani, Mariela A. Blum, Jeannelyn Estrella, Prajnan Das, Jaffer A. Ajani
Journal: Journal of Clinical Oncology (2014)

4053 Background: For patients with LGCA, adjunctive therapies improve the 5-year survival rates by ≈10% over surgery alone. We studied preoperative oxaliplatin/5-FU-based chemotherapy followed by chemoradiation. Methods: Patients with LGCA with baseline eusT2-T3 any N, M0 (M stage by laparoscopy and imaging) were eligible. Patients received ≤4 doses of oxaliplatin and infusional 5-FU q 2 weeks then oxaliplatin and infusional 5-FU with 45 Gy of conformal radiation in 25 fractions. 5-6 weeks after chemoradiation, patients underwent an attempted D2 dissection and were followed. Results: Between Feb. 2004 and Nov. 2010 a total of 58 patients were enrolled. Most patients were men (66%) and had clinical stage IIIA cancer (52%). 14% (95%CI: 6%, 25%) of patients achieved a pathCR. With a median follow-up of 37.4 months, the median survival was 39.4 (95%CI: 27.6, NR) months. The 5-yr OS was 44% and the 5-yr PFS was 42%. 72% of patients proceeded to surgery and 86% of these had an R0 resection. The 5-yr OS for patients who had surgery was 56%. 44.8% of patients experienced grade 3 and/or 4 toxicities (commonly, fatigue, anorexia and insomnia) due to induction chemotherapy. 58.6% experienced grade 3 and/or 4 toxicities due to chemoradiation (commonly, fatigue, myelosuppression, vomiting, and dysphagia). No treatment-related death occurred. Conclusions: The 5-yr OS for all patients treated on this study was 44%. Our data show that if LGCA patients can complete the described therapeutic strategy (i.e., including surgery), their outcome may be excellent. Therefore, we must refine patient selection for future trials based on clinical variables and biomarkers. This will help in identifying patients who are likely to respond to pre-operative treatment versus those who are not. Biomarker studies (with mTOR, Gli-1, Sox9, ALDH-1, and Shh, etc.) are underway and will be presented. Clinical trial information: 2003-0769.
National predictors and trends for androgen deprivation therapy use in low-risk prostate cancer.
Authors: David Yang, Vinayak Muralidhar, Brandon Arvin Virgil Mahal, Michelle Daniel Nezolosky, Marie Vastola, Shelby Labe, Peter F. Orio, Neil E. Martin, Martin T. King, Quoc-Dien Trinh, Christopher Sweeney, Toni K. Choueiri, Paul L. Nguyen
Journal: Journal of Clinical Oncology (2017)

50 Background: Androgen deprivation therapy (ADT) is not recommended for low-risk prostate cancer due to its known harms and lack of benefits. We evaluated the incidence and predictors of ADT use in men with low-risk prostate cancer. Methods: We identified 197,980 patients in the National Cancer Database (NCDB) with low-risk prostate cancer (Gleason 3+3 = 6, PSA &lt; 10ng/mL, and cT1-T2a) diagnosed from 2004 to 2012 with complete demographic and treatment information. We determined the incidence of ADT use and utilized multiple logistic regression to evaluate predictors of ADT use. Results: ADT use in low-risk prostate cancer patients declined steadily from 2004 to 2012 (17.6% vs. 3.5%). 80.6% of these patients underwent radiation, and 10.0% received ADT as primary therapy. Among 82,354 low-risk disease patients treated with radiation, demographic and treatment factors associated with increased likelihood of ADT use include older age (adjusted odds ratio [AOR] 1.04 per year, p &lt; 0.001); Hispanic vs. non-Hispanic white ethnicity (18.9% vs. 17.8%, AOR 1.26, p &lt; 0.001); having Medicare at age &lt; 65 (15.3%, AOR 1.14, p = 0.008) or Medicare at age ≥ 65 (21.5%, AOR 1.11, p &lt; 0.001) vs. private insurance (13.9%); having bottom quartile vs. top quartile income (19.4% vs. 16.3%, AOR 1.26, p &lt; 0.001); being treated in a community cancer program (22.0%, AOR 1.60, p &lt; 0.001) or a comprehensive community cancer program (18.7%, AOR 1.38, p &lt; 0.001) vs. an academic/research cancer program (13.9%); and receiving brachytherapy vs. external beam radiation therapy (19.3% vs. 15.5%, AOR 1.32, p &lt; 0.001). Increasing distance from the treatment facility was associated with decreased likelihood of receiving ADT (AOR 0.97 for every 100 miles, p = 0.001). Conclusions: Among men with low-risk prostate cancer, increasing age, Hispanic ethnicity, Medicare insurance, lower income level, treatment in a non-academic/research cancer program, and brachytherapy use were all associated with increased odds of receiving ADT. Given the lack of evidence supporting ADT use in low-risk disease and increasing evidence of its many side-effects, it is critical to understand why low-risk prostate cancer patients are still receiving ADT so that this practice may be reduced.
Defining quality and value in a prospective study of an emergency department (ED) febrile neutropenia pathway (FNP).
Authors: Michael Kenneth Keng, Elaine A. Thallner, Paul Elson, Christine Ajon, Jennifer Sekeres, Candice M. Wenzell, Erika M. Gallagher, Catherine M. Weber, Marc A. Earl, Sudipto Mukherjee, David James Seastone, Brad L. Pohlman, Eric Cober, Beth Rodgers, Virginia B. Foster, Joy Yuhas, Matt E. Kalaycio, Brian James Bolwell, Mikkael A. Sekeres
Journal: Journal of Clinical Oncology (2014)

6632 Background: Febrile neutropenia (FN) is an oncologic emergency and delays in antibiotic (ABX) administration lead to worse outcomes. We instituted a FNP in the Cleveland Clinic (CC) ED to reduce ABX delays. Methods: This is a prospective study comparing ED FNP patients (pts) (06/12-06/13) to historical (H) pts (02/10-05/12) and direct admit (DA) FN pts (06/12-06/13). Interventions included: providing pts with FN ID cards, recognizing FN as a distinct chief complaint, revising ED triage level for FN, creating ED-specific electronic FN order sets, administering ABX prior to return of neutrophil count, and relocating all FN ABX to ED automated drug dispensing machines. The primary goal of the FNP was empiric broad-spectrum ABX administration within 90 minutes of ED presentation. Group comparisons were made using the chi-square and Kruskal-Wallis tests, as appropriate. Results: In total, 276 consecutive FN episodes in 217 FNP pts occurred during the 12 month study period, 107 episodes in 87 pts and 114 episodes in 101 pts in the H and DA cohort respectively. All ED FN pts were triaged and treated using the ED FNP, but use of the specific FN order set was variable: episodes were classified as treated per order set (n=103) or not (n=173). In addition to hospital stay, the ED FNP improved all identifiable metrics (all p <.0005), depicted in Table 1. Other factors increasing hospital stay were primary hematologic malignancy and degree of neutropenia (p <.05). Conclusions: The CC ED FNP is a significant quality initiative, and was able to demonstrate value by decreasing time to ABX administration and length of hospital stay compared to both H and DA controls in cancer pts presenting to the ED with fever. ICU admission rate and ICU length of stay were also decreased. Usage of the ED FNP FN order set further improved these metrics. ED FNP H DA p value Episodes (n) Total, 276 Order set, 103 No order set, 173 107 114 Time to (median minutes) Physician evaluation 43 43 43 73 57 <.0001 ABX order 35 35 48 141 72 <.0001 ABX administration 81 68 96 235 168 <.0001 Admission 263 252 276 360 <.0001 Length of stay (median days) Hospital stay 3.3 3.1 3.4 4.3 5.6 .0005 ICU admission rate (n(%)) 18(6%) 4(4%) 14(8%) 8(8%) 5(4%) .39 ICU stay 1.9 3.1 1.8 2.2 4.4 .19