tbuckley/cabot-search huggingface dataset:
Association of genetic variants involved in drug metabolism and transport with efficacy and toxicity of chemotherapeutic treatment in osteosarcoma patients.
Authors: Hanneke I. Vos, Marieke J.H. Coenen, Hans Gelderblom, Tahar van der Straaten, Eveline S.J.M de Bont, Winette T.A. Van Der Graaf, H.W.B. Schreuder, Frank N. van Leeuwen, Henk-jan Guchelaar, Dunja Maroeska W.M. Te Loo
Journal: Journal of Clinical Oncology (2014)

10038 Background: Despite multiagent chemotherapeutic treatment, osteosarcoma patients relapse frequently and survival has reached a plateau in the past decades. A poor response to chemotherapy seems to be the predominant risk factor for an unfavorable outcome. We have previously identified several genetic polymorphisms in genes in the metabolic pathways of cisplatin and doxorubicin which might be used for risk stratification of patients in relation to treatment response. However, as the complex metabolism of drugs used in the treatment of osteosarcoma involves a broader range of genes, we have performed a DMET analysis including 1,936 genetic variants in 231 genes known to be involved in drug metabolism and transport. Methods: We used a two-stage design, including 135 osteosarcoma patients in the discovery stage. Germline DNA was genotyped using the DMET Plus array. Associations between the presence of genetic variants and histological response (HR) to preoperative cisplatin and doxorubicin based chemotherapy, 5-year Disease Free Survival (DFS) and ototoxicity (SIOP grade 1-3) were assessed by logistic regression models in PLINK. In the replication cohort 185 osteosarcoma patients will be included. Results: 734 markers and 131 patients passed quality control (call rates > 0.9, minor allele frequency > 0.01) in the discovery cohort. A total of 21 markers showed association (p < 0.05) with HR and 20 markers with 5-year DFS, with overlap of associated markers in the transporter SLCO4A1 and Phase I enzyme CYP8B1 genes. In addition, 21 markers were significantly associated with ototoxicity, the majority was located in cytochrome p450 genes. Conclusions: To the best of our knowledge, the present pharmacogenetic study is the first in osteosarcoma patients using the DMET analysis. Significant associations of treatment response and ototoxicity with genes previously unknown to impact cisplatin and doxorubicin metabolism and transport were explored. Following replication and validation in functional studies and in larger prospective studies, these markers are of potential interest for the development of new treatment strategies and optimizing current therapy.
Brain metastasis in melanoma patients: Associations with BRAF status and age.
Authors: Chiara Martinoli, Emilia Cocorocchio, Sara Gandini, Elisabetta Pennacchioli, Giulio Tosti, Giuseppe Spadola, Massimo Mosconi, Federica Baldini, Salvatore Alfieri, Maria Di Leo, Concetta Riviello, Massimo Barberis, Alessandro Testori, Pier Francesco Ferrucci
Journal: Journal of Clinical Oncology (2014)

e20037 Title: Brain metastasis in melanoma patients: associations with BRAFstatus and age. Background: Somatic BRAF mutations are found in 40-50% melanoma patients. While associations with patient demographics and tumor features have been established, the prognostic value of BRAF mutations is less clear. The aim of this study was the evaluation of associations of BRAFmutations with clinico-pathological characteristics, disease progression and outcome of metastatic melanoma patients. Methods: Advanced melanoma patients tested for BRAF mutations in a single Institution (n=271) were retrospectively analyzed. Wild-type and V600-mutant BRAF patients with a primary cutaneous or occult melanoma were compared (n=232). Associations of V600 BRAFmutations with patient’s characteristics, site and time of visceral progression, and survival, were evaluated. Results: V600 BRAF mutations were found in 53% patients, and were associated with younger age at diagnosis and primary tumor site. V600-mutant patients had an higher incidence of brain but not of other visceral metastasis. A significant interaction of BRAF status with age for the development of brain metastasis (B-Met) was detected. In young patients, wild-type and V600-mutant BRAF had a comparable incidence of B-Met, but wild-type BRAF was associated with a shorter B-Met free interval. In older patients, V600-mutant BRAF had higher frequency of B-Met and a shorter B-Met free interval. The interaction was confirmed in the subgroup of V600E-mutant patients. BRAF mutation per sehad no clear impact on overall survival. Treatment with BRAF inhibitors positively affected overall survival. Conclusions: Prognostic value of BRAF mutations for brain metastasis depends on patient’s age. BRAF mutations do not affect development of other visceral metastasis.
Somatostatin signaling in squamous cell carcinoma of the lung.
Authors: Jonathan Lehman, Megan Hoeksema, Clay Callison, Pierre P. Massion
Journal: Journal of Clinical Oncology (2014)

e13563 Background: Squamous cell carcinoma of the lung (SCC) is a subset of lung cancer responsible for ~ 25% of non small cell lung carcinoma. Unfortunately, targeted therapies in SCC have not to date been as successful as in adenocarcinoma of the lung. Somatostatin receptors (SSTR) are G protein-coupled receptors with multiple direct and indirect effects on cell cycling, angiogenesis, apoptosis, and growth factors which signal by inhibition of adenylate cyclase, increased p53 activity, and act through downstream MAPK and Akt as well as other downstream kinases. The cancer genome atlas data suggests SSTR signaling expression changes in ~ 20% of SCCs. We sought to evaluate SSTR2 as a potential target for therapeutic intervention in a subset of SCCs of the lung. Methods: We developed and validated an antibody for SSTR2 in a rabbit model via affinity purification and use of a blocking peptide to verify binding. SSTR2 expression was evaluated by IHC staining and western blotting of multiple cell lines and tissues. This was followed by the construction of shRNA based stable SSTR2 knockdown cell lines. These lines were evaluated for changes in proliferation and colony formation in vitro and tumor growth in vivo via a nude mouse xenograft model. Significance(p<0.05) by student’s t test or Wilcoxon testing. Results: High expression of SSTR2 was found in multiple neuroendocrine lung carcinoma lines and a subset of SCC cell lines. SSTR2 knockdown in H520 (an SSTR2 expressing SCC line) led to a 37% (p<0.05) reduction in proliferation in vitro. We followed this data in vivo which showed dramatically reduced ki67 staining and significantly reduced tumor weight and growth curves. Ki67 IHC showed dramatically reduced proliferation from ~99% staining to ~30% staining. Western blotting of tumor xenografts suggested decreased pAKT and increased pERK signaling with SSTR2 knockdown. Conclusions: SSTR2 knockdown led to significant changes in cell proliferation in vitro and in vivo in a SCC cell line. A potential mechanism is due to reduction in pAKT. This data challenges the existing dogma that SSTR signaling is solely growth inhibitory and raises the question that SSTR2 may be a viable target for therapy in a subset of SCC. The above study was funded by a VA Merit Review Grant awarded to PPM.
Analysis of CAR-T and Immune Cells within the Tumor Micro-Environment of Diffuse Large B-Cell Lymphoma Post CAR-T Treatment By Multiplex Immunofluorescence
Authors: Pei-Hsuan Chen, Mikel Lipschitz, Kyle Wright, Philippe Armand, Caron A. Jacobson, Zachary J. Roberts, John M. Rossi, Adrian Bot, William Y. Go, Scott J Rodig
Journal: Blood (2018)
Evaluation of Romyelocel-L Myeloid Progenitor Cells to Decrease Infections in De Novo AML Patients Receiving High-Dose Ara-C-Based Induction Therapy
Authors: Farhad Ravandi, Camille N Abboud, Luke Paul Akard, Saar I. Gill, Jack W. Hsu, Suman Kambhampati, Irum Khan, Delong Liu, Wendy Stock, Janice W Brown, Asad Bashey, Gautam Borthakur, Courtney D. DiNardo, H. Kent Holland, Tapan M. Kadia, Hagop M. Kantarjian, Lawrence E Morris, Scott R Solomon, Richard David Mamelok, Swapna Panuganti, Rod Van Syoc, Alicia Wong, Deborah Zimmerman, Melhem Solh
Journal: Blood (2018)
Breast cancer screening in younger women.
Authors: Nina Beri, Kevin Houck, Victor Villagra, Stephanie B. Wheeler, Jeffrey M. Peppercorn
Journal: Journal of Clinical Oncology (2014)

1502 Background: The 2009 US Preventative Services Task Force (USPSTF) guidelines for breast cancer screening have proven controversial. Previously, annual screening was recommended for women over 40, but new guidelines recommend screening only for high risk women under 50. Other guidelines still recommend annual screening for young women on the basis of reduction in breast cancer mortality. In a population of rural insured women we sought to determine which younger women received mammograms, and the factors that motivate them to do so. Methods: Surveys were mailed to 1,000 randomly selected women between the ages of 40 and 49, insured by the National Rural Electric Cooperative Association (NRECA). A study specific survey evaluated screening patterns, knowledge of guidelines, and sociodemographic information. Results: Overall, 639 women responded (response rate 63.9%). Median age was 45, 92% were white, 75% resided in rural areas, and 34% reported 4 year college education. The majority (67%) had a screening mammogram within the past year. 81% had their mammograms paid for by NRECA and 66% reported no out of pocket costs. 43% had a family history of breast cancer and 69% had friends with the disease. 71% felt that they understood current guidelines, though less than 1% reported that mammograms for women under 50 were not routinely recommended. 15% were aware that expert recommendations vary. 58% believed that annual mammograms are recommended for women <50. Less than 1% reported that the media coverage of expert recommendations made them less likely to obtain screening, while 44% felt it had no effect. Reported barriers to screening included: lack of time (29%), fear of test (5.6%), fear of diagnosis (4.2%), and discomfort (12%). Women with friends or family with breast cancer were more likely to report screening within the past year (70% vs 54%, p 0.003). Education and geographic residence did not correlate with screening. Conclusions: The majority of younger insured women in rural America are not aware of USPSTF guidelines and continue to undergo screening mammography. However, modifiable barriers persist and there is a need for consensus and education regarding the current evidence for screening so that younger women can make informed choices about early detection of breast cancer.
Preliminary evaluation of the tolerability and feasibility of combining 5-amino-levulinic acid (5-ALA) with carmustine wafers (Gliadel) in the surgical management of primary glioblastoma.
Authors: Colin Watts, Paul Smith, Katharian Wanek, Nicolas Counsell
Journal: Journal of Clinical Oncology (2014)

2081 Background: Fluorescence-guided resection of glioblastoma improves surgical cytoreduction, which may improve therapeutic benefit from intra-operative carmustine wafers. The objective of this study was to establish the safety and tolerability of combining fluorescence‐guided surgical resection (5-ALA) with intra‐operative chemotherapy (carmustine wafers) in patients with primary glioblastoma (GBM) prior to standard treatment with radiotherapy and temozolomide. Methods: A single arm design with the following inclusion criteria: Age 18+ years; patient reviewed at a specialist neuro-oncology MDT; imaging evaluated by a neuro-radiologist and judged to be a GBM; radical resection judged to be realistic by the neurosurgeons (i.e. NICE criteria for the use of Carmustine wafers can be met); and WHO performance status 0 or 1 on clinical review Results: Seventy-two patients were recruited from 8 UK sites between July 2011 and May 2013; 64 patients received carmustine wafer implants and 59 patients were found to be eligible after surgery. Thirteen patients were ineligible due to wafers not inserted (n=8); GBM not diagnosed post-operatively (n=4); simultaneous diagnosis of cutaneous sebaceous carcinoma (n=1). There were 8 surgical complications reported in 6 patients: wound infections in 5 patients (8%) and cerebrospinal fluid leakage in 3 patients (5%). One patient was unable to begin chemoRT (1/33, 3%), and 4 patients (4/33, 12%) were not able to begin chemoRT within 6 weeks of surgery, due to surgical complications. After a median follow-up of 10.8 months, 25 patients (42%) are alive without progression, 16 patients (27%) are alive having progressed and 18 patients (31%) have died. Thirty-three patients (56%) have reported 68 adverse events of grade 3 or higher, 5 of these were reported as being ‘possibly’ related to the combination of 5-ALA and carmustine wafers: sepsis (n=2), wound infection (n=2), seizure (n=1). Conclusions: The combination of 5-ALA and carmustine wafers is safe and tolerable in the surgical management of primary glioblastoma. A phase III randomised controlled trial is being designed to confirm efficacy Clinical trial information: 77105850.
Schizophrenia, Dopamine and the Striatum: From Biology to Symptoms
Authors: Robert A. McCutcheon, Anissa Abi-Dargham, Oliver D. Howes
Journal: Trends in Neurosciences (2019)

The mesolimbic hypothesis has been a central dogma of schizophrenia for decades, positing that aberrant functioning of midbrain dopamine projections to limbic regions causes psychotic symptoms. Recently, however, advances in neuroimaging techniques have led to the unanticipated finding that dopaminergic dysfunction in schizophrenia is greatest within nigrostriatal pathways, implicating the dorsal striatum in the pathophysiology and calling into question the mesolimbic theory. At the same time our knowledge of striatal anatomy and function has progressed, suggesting new mechanisms via which striatal dysfunction may contribute to the symptoms of schizophrenia. This Review draws together these developments, to explore what they mean for our understanding of the pathophysiology, clinical manifestations, and treatment of the disorder.
SOAPsnv: An integrated tool for somatic single-nucleotide variants detection with or without normal tissues in cancer genome.
Authors: Yujian Shi
Journal: Journal of Clinical Oncology (2014)

e22086 Background: Among genetic alterations causing oncogenesis, acquired somatic mutations are the most fundamental ones in the analysis and interpretation. In the search of the genetic traits in the oncogenesis, current studies apply next-generation sequencing to investigate the somatic variants in an unbiased manner comparing variants in tumor tissue against the background reference from normal tissues. Methods: To further accurately predict the SNV in cancer, even in the situation lacking of matched normal samples, we develop the SOAPsnv program, fishing the potential somatic mutations comprehensively and screening stringently by all the reads, and affiliated with a mode calling SNV in normal-absent condition. Results: We applied SOAPsnv in the 88-pair hepatocellular carcinoma study, and it effectively identified the druggable somatic mutations from tumor/normal pairs. 497 somatic mutations were randomly selected for validation using SequenomiPLEX Mass Array system, and 480 hits are translated to 96.5% specificity. Without normal control, SOAPsnv still predicted the high confident SNVs. After alignment and pileup, the possible germline variants, 85-90% of total, are filtered out through public databases (dbSNP137, 1000 Genomes and ESP coding regions) and BGI in-house Asia databases (>17504samples). Then the left SNP set is taken as the targeted pool for machine-learning based somatic SNVs prediction. With the same HCC data set, SOAPsnv predicted 15,431 tentative SNVs, and more than 80% accuracy is achieved according to previous validation based on tumor/normal pairing results. With the benefit of RNA-Seq data, we setup and test the in silicon cross validation strategy, and 88 out of 107 variants on transcriptome level can be confirmed as consistent with corresponding variants on DNA level according to the Sequenom genotyping result, indicating 82% sensitivity. Conclusions: Our results suggest that SOAPsnv program achieves high sensitivity and specificity, even at relative lower coverage to other programs, and thus enables the prediction of somatic mutations even in the absence of normal controls.
Effect of the novel galectin-3 blocker, Gal3M, on the efficacy and reduction of toxicity of proteasome inhibitors for the treatment of multiple myeloma.
Authors: Jehanzeb Riaz, Rashmi Verma, Leonardo Mirandola, Jose A. Figueroa, Everardo Cobos, Diane Duyen Thuy Nguyen, Amardeep Singh Aulakh, Venu Konala, Marjorie Jenkins, Yuefei Yu, Saba Radhi, Kayley Trotter, Lukman Aderoju Tijani, Fred Hardwick, Nicholas C. D'Cunha, Michela Colombo, Scott Dahlbeck, Fabio Grizzi, Maurizio Chiriva-Internati
Journal: Journal of Clinical Oncology (2014)

e19581 Background: Multiple myeloma (MM) is a neoplastic plasma cell disorder which results in multiple organ failure. Anemia, hypercalcemia, renal failure and skeletal lesions are the most relevant morbidities associated with MM. The treatment of MM includes chemotherapy, hematopoietic stem cell transplantation, immune modulating treatments and proteasome inhibitors. Carfilzomib is a new proteasome inhibitor that also has anti osteoclastogenic effects. Treatment with Carfilzomob is associated with both cardiac and renal toxicity, mostly mediated by fibrotic tissue damage. Galectin-3 hyper-expression has also been implicated in development of congestive heart failure and acute renal failure. We aimed to test the efficacy of combined therapy with a novel dominant-negative inhibitor of Galectin-3, namely Gal3M, and Carfilzomib for MM. Methods: We used the 5TGM1 murine syngeneic model of MM. In order to monitor tumor growth in vivo in C57Bl/KaLwRij mice, we measured the levels of circulating IgG2b and of the cancer testis antigen, SP17 by ELISA, Western blot and RT-PCR. 5TGM1 cells growth was monitored by viability and chemotaxis assays. Results: Our results show that Gal3M increased the therapeutic efficacy of Carfilzomib in vitroin the C57Bl/KaLwRij model carrying 5TGM1 cells by causing 85% decline in cell growth. Gal3M was able to counter the toxic effects of Carfizomib on heart and kidney by decreasing the fibrotic tissue deposition in active caspase 3 positive cells. On the other hand, Carfilzomib was able to prevent the increase in osteoclastogenic potential of MM caused by Gal3M. Conclusions: Our data represent the rationale for the use of a combined therapy in MM treatment not only to block the tumor growth but also to prevent organ toxicity caused by proteasome inhibitors.
Shared Decision Making Rarely Happens for Lung Cancer Screening—Reply
Authors: Daniel S. Reuland, Teri L. Malo, Alison T. Brenner
Journal: JAMA Internal Medicine (2019)

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Characteristics, treatments, and survival outcome of mantle cell lymphoma in women: A single center analysis.
Authors: Samantha Reiter Shams, Loretta J. Nastoupil, Christopher Flowers
Journal: Journal of Clinical Oncology (2014)

e19559 Background: Mantle cell lymphoma (MCL) is a rare non-Hodgkin lymphoma that predominately occurs in middle-age to elderly Caucasian males with a male to female ratio of 3:1. With this male predominance, limited data exist on females with MCL. We evaluated the characteristics, treatments and outcomes of females with MCL in a single-center experience. Methods: After IRB approval, a retrospective review of MCL patients (pts) diagnosed at Emory University Winship Cancer Institute, between 1984-2011 was performed. Data was collected on baseline characteristics, treatment strategies and survival. Results: Among MCL patients with complete clinical data, a total of 40 females with MCL were identified. Median age at diagnosis was 61 years old (range 32-77). An earlier median age of onset of 52 years was identified in African-Americans, as compared with age 60 in Caucasians. The majority of patients, 82%, presented stage III/IV. 3 pts (8%) had a family history of lymphoma. First-line treatments included the following: 32% received CHOP/R-CHOP, 25% received HCVAD/R-HCVAD and 10% underwent watchful-waiting approach. 3 pts (8%) received another form of initial treatment, and initial treatment was unknown for 13%. 25% underwent upfront consolidation with autologous stem cell transplantation (ASCT). With a median follow-up of 2.7 years, 35% of evaluable pts have progressed and 28% have died, with a 58% 2-year survival. Among pts who received ASCT, 55% were alive at 3 years. Conclusions: This represents one of the largest series of female MCL pts with data on treatment and outcomes. In this series, female pts had similar presentation patterns as males, commonly presenting with stage III/IV disease. Despite heterogeneity in initial therapies, women had favorable outcomes and ASCT was associated with high overall survival with available follow-up. Larger retrospective and prospective studies are needed to confirm these treatment patterns and outcomes.