tbuckley/cabot-search huggingface dataset:
Genotypic and Phenotypic Characteristics of CRB1 -Associated Retinal Dystrophies
Authors: Mays Talib, Mary J. van Schooneveld, Maria M. van Genderen, Jan Wijnholds, Ralph J. Florijn, Jacoline B. ten Brink, Nicoline E. Schalij-Delfos, Gislin Dagnelie, Frans P.M. Cremers, Ron Wolterbeek, Marta Fiocco, Alberta A. Thiadens, Carel B. Hoyng, Caroline C. Klaver, Arthur A. Bergen, Camiel J.F. Boon
Journal: Ophthalmology (2017)
Multivariate assessment of SPARC expression in resected pancreatic ductal adenocarcinoma to identify subgroups that are sensitive to adjuvant gemcitabine.
Authors: Steve Kalloger, Joanna Karasinska, Hui-li Wong, Daniel John Renouf, David F. Schaeffer
Journal: Journal of Clinical Oncology (2017)

297 Background: Secreted Protein, Acid, Cysteine-Rich (SPARC) has recently been postulated as a therapeutic target in pancreatic ductal adenocarcinoma (PDAC). The clinical trial findings investigating SPARC expression and nab-paclitaxel sensitivity have been discordant. This study aims to develop an integrated component based approach to the quantification of SPARC in PDAC to identify discrete predictive subgroups in a cohort of resected patients treated with an gemcitabine (GEM) or subjected to post-surgical observation. Methods: Immunohistochemical quantification of SPARC was performed on the epithelial and stromal compartments of resected PDAC on 219 patient samples on a tissue-microarray. The staining was assessed by the generation of H-Scores. The resultant scores were subjected to unsupervised hierarchical clustering. The maximum number of clusters was determined through an a priori decision that no cluster could be composed of less than 15% of the cohort. Univariable disease specific survival (DSS) analysis was performed with the Kaplan-Meier method to examine the cluster specific survival profiles with regard to gemcitabine sensitivity. Results: Mean age was 67 [38-88] with 56% being male. Most of the cohort had advanced disease with pT3 = 95% and pN1 = 72%. Lymphovascular and perinueural invasion were found in 58% and 93% of the cohort respectively. Clusters ranging in size from 35 to 76 cases were derived and represented the four-biomarker combinations of Low/Low, Low/High, High/High, and High/Low for the epithelial and stromal components respectively. None of the clinico-pathologic variables were significantly enriched in the clusters. Assessment of the predictive ability of the 4 clusters demonstrated that only one cluster (High/High) representing 76 (35%) patients in this cohort was sensitive to adjuvant GEM (p = 0.0067). Conclusions: This study shows that there is enhanced value in a combinatorial approach to the examination of SPARC in the stromal and epithelial components of PDAC where we have discovered that co-expression in both the epithelial and stromal components is significantly associated with sensitivity to adjuvant GEM.
Characterization of antibody response in neuroinvasive infection caused by Toscana virus
Authors: A. Pierro, S. Ficarelli, N. Ayhan, S. Morini, L. Raumer, M. Bartoletti, A. Mastroianni, F. Prati, S. Schivazappa, P. Cenni, C. Vocale, G. Rossini, P. Gaibani, V. Sambri, M.P. Landini, R.E. Lewis, R.N. Charrel, S. Varani
Journal: Clinical Microbiology and Infection (2017)
Clinical characteristics of patients with non-<i>V600 BRAF</i> mutant melanomas.
Authors: Dae Won Kim, Sasan Nowroozi, Kunhwa Kim, Michael A. Davies, Mark Routbort, Alexander J. F. Lazar, Silva Frankian, Alan Siroy, Agop Y. Bedikian, Nicholas E. Papadopoulos, Wen-Jen Hwu, Patrick Hwu, Scott Woodman, Sapna Pradyuman Patel, Kevin Kim
Journal: Journal of Clinical Oncology (2014)

9100 Background: V600E and V600K mutations are the most common BRAF mutations in melanoma. We previously showed that non-V600 BRAF mutations account for 12% of all BRAF mutations in melanoma. Limited clinical data are available for non-V600 BRAF mutant melanomas. To better understand non-V600 BRAF mutations in melanoma, characteristics of tumor and clinical outcomes were investigated. Methods: Clinical and pathologic data were collected retrospectively in patients (pts) with melanoma who had multi-gene mutation analysis (next-gene sequencing) at MD Anderson Cancer Center. Fisher's exact test was used for all comparisons. Results: We found 52 pts with non-V600 BRAF mutations, among whom 8 had NRAS/non-V600 co-mutations. Common non-V600 mutations were K601E (17.3%), G469E (15.4%), G469R (7.7%), D594G (5.8%), L597S (5.8%), and S467L (5.8%). Compared with V600E mutations as a control (n=82) , the presence of a non-V600 mutations was significantly associated with older age (median, 58 years vs 50; P=0.001), less superficial spreading type (13.6% vs 32.9%; P=0.02), more lentigo maligna type (20% vs 1.2%; P=0.001), more mucosal subtype (9.1% vs 1.2%; P=0.03), more head/neck primary tumor location (36.4% vs 15.9%; P=0.03), less lower extremity primary tumor location (4.5% vs 24.4%; P=0.003), more co-mutations with NRAS (15.4% vs 2.4%, p=0.005) and stage IV disease at initial diagnosis (31.8% vs 7.3%; P=0.0003). Among the 33 pts with non-V600 mutant metastatic melanoma, 7 received selective BRAF inhibitor (BRAFi). Of the 5 evaluable patients (2 could not tolerate treatment), all had disease progression within 2 months. Conclusions: Non-V600 BRAF mutant melanomas have more aggressive clinical characteristics, more likely to have co-mutations with NRAS, and not responsive to selective BRAFi than V600E mutations. A larger cohort and a longer follow-up will better define the prognostic indication of non-V600 mutated melanoma.
SMAD4 loss in colorectal cancer: Correlation with recurrence, chemoresistance, and immune infiltrate.
Authors: Isaac Wasserman, Lik Hang Lee, Jinru Shia, Chao Wu, Xi Chen, Jose G. Guillem, Philip Paty, Martin R. Weiser, Garrett Michael Nash, Larissa K. F. Temple, Leonard Saltz, Rona D. Yaeger, Afsar Barlas, Katia O Manova-Todorova, Efsevia Vakiani, Arthur E Elghouayel, Nancy E. Kemeny, Julio Garcia-Aguilar, Charles L. Sawyers, Jesse Joshua Smith
Journal: Journal of Clinical Oncology (2017)

587 Background: Few markers reliably identify colorectal cancer (CRC) patients at risk of recurrence and death. SMAD4 loss occurs in 10-20% of cases and has shown promise in identifying high-risk stage II/III patients. We examined SMAD4 status and association with clinical/pathologic features in 446 stage I-IV CRC patients at Memorial Sloan Kettering (MSK). Methods: Patients undergoing curative resection were included (1981-2010). Familial polyposis syndrome patients and those with inadequate tissue were excluded. Tissue microarrays were constructed (n=364). Immunohistochemistry for SMAD4 and mismatch repair (MMR) proteins was completed. SMAD4 nuclear stain intensity was scored (scale=0-3; 0=loss). On whole sections, MMR proteins (present or absent), tumor-infiltrating lymphocytes (TILs) and peritumoral lymphocyte aggregates (PLAs) were scored (scale=0-3). Associations between clinical/pathologic features and SMAD4 loss vs. retention were analyzed. Kaplan-Meier estimates and log-rank test were used for recurrence-free and overall survival analyses (RFS and OS). Results: SMAD4 loss was noted in 13%. Median age at diagnosis was 53 years, and 51% were male. The cohort consisted of 61% hindgut tumors and 62% stage II/III patients. With up to 33 years of follow-up, the mean was 6 years. SMAD4 loss correlated with higher tumor and nodal stage, adjuvant therapy use, and lower TIL and PLA scores (p&lt;0.04 for all). Unlike prior studies, no significant differences in OS based on SMAD4 status across the entire cohort were noted; however, older patients (&gt;median) were noted to have worse OS with SMAD4 loss (p&lt;0.01). SMAD4 loss did correlate with worse RFS (p=0.02), persisting even when excluding MMR-deficient patients. Additionally, SMAD4 loss was associated with worse RFS in both the adjuvant chemotherapy group (median RFS=3.8 vs. 13 years; p=0.06) and the resection-only group (median RFS=4.2 years vs. not yet reached; p&lt; 0.01). Conclusions: SMAD4 loss correlates with worse RFS and resistance to adjuvant therapy. SMAD4 loss also correlates with lower TIL and PLA scores. Future work will address chemoresistance mechanisms, relevance to adjuvant therapy use, and loss of immune infiltrate in SMAD4-null tumors.
Turning free speech into commercial speech: Philip Morris' use of journalists to discredit the EPA report on secondhand smoke
Authors: R. D. Hurt, M. E. Muggli, L. B. Becker
Journal: Journal of Clinical Oncology (2004)

6151 Background: Tobacco company documents show that it launched a multifaceted effort to influence journalists in the scientific debate about the harmful effects of secondhand smoke in order to derail the risk assessment on environmental tobacco smoke. Methods: Searches of previously secret internal tobacco industry documents were conducted on-line and at the Minnesota Tobacco Document Depository. Lexis-Nexis was used to locate news stories written by the journalists cited in this paper. Results: To address a potential backlash in public opinion from the 1992 EPA risk assessment, Philip Morris used its public relations firm Burson Marsteller to "build considerable reasonable doubt… particularly among consumers" about the "scientific weaknesses" of the report. Media and political consultant Richard Hines was a key player in carrying out "EPA bashing" for Philip Morris. Steve Parrish, vice president at Philip Morris wrote, "Richard is responsible for a number of articles that have appeared in…major news publications regarding EPA and ETS." Philip Morris expanded its journalist network by creating a school of journalism through the National Journalism Center (NJC) and planned to "design innovative strategies to communicate our position on ETS through education programs targeting policy makers and the media." NJC was to "train budding journalists in free market political and economic principles" and was financially supported by Philip Morris. Conclusions: This is the first report to show the extent to which the tobacco industry has gone to influence the print media on the health effects of secondhand smoke. Journalists can fall victim to well orchestrated public relations efforts regardless of their scientific validity. More scrutiny is warranted by professional media organizations that oversee the ethical conduct of their members. Supported by R01 CA90791 "Tobacco Industry Documents on ETS -The Next Front" No significant financial relationships to disclose.
The role of cytoreductive radical prostatectomy (cRP) in men with hormone-sensitive, metastatic prostate cancer (mPCA).
Authors: Axel Heidenreich, Nicola Fossati, Nazareno Suardi, Francesco Montorsi, Jeffrey Karnes, Shahrokh F. Shariat, Giorgio Gandaglia, Alberto Briganti
Journal: Journal of Clinical Oncology (2017)

241 Background: Androgen deprivation represents the standard treatment for PCA with osseous metastases. We explored the role of cRP in the largest cohort of contemporary patients with mPCA treated in 4 tertiary referral centres. Methods: A total of 114 patients with mPCA, lymph node, osseous or visceral metastases underwent cRP. Surgery related complications (Clavien-Dindo classification) and functional outcome were analysed. Oncologic outcome parameters such as cancer specific &amp; overall survival as well as biochemical and clinical-free survival were evaluated using descriptive statistical analysis. Results: Mean patient age was 61 (42-69) years. Mean and median follow-up was 39.7 months (7-75) and 47 months (28-96), resp. 93 (81.6%) and 21 (18.4%) patients had low volume and high volume mets, resp.,. 80(70.2%) pts underwent neoadjuvant ADT with LHRH analogues. Surgical approach was open retropubic RP in 104 (92%) pts and 2 (1.8%), 10 (8.8%) and 101 (89.4%) pts underwent no, limited or extended pelvic LAD, resp. Adjuvant therapy was delivered in 99 (86.8%) pts. Pathohistology revealed significant vital PCA in 100% of cases: n = 16 (14.0%) exhibited pT4a, n = 21 (18.4%) had pT2 and the remainder had pT3a/b PCA. Positive lymph nodes or positive surgical margins were identified in 61.6% and 36.8%, resp.. 110 (96.5%) are alive and 66.7% are relapse-free. 74 (64.9%) pts did not experience any surgery related complications; 15 (13.1%) pts experienced Clavien Dindo grade IIIb/IV complications and underwent reintervention. Low versus high volume (32.2% vs 50%, p = 0.03), PSA at cRP &lt; 1ng/ml vs PSA &gt; 4 ng/ml, (18.9% vs 45.6%, p = 0.02) were associated with relapse. Low vs high volume disease (7.1% vs 32.1%), PSA &lt; 4ng/ml vs PSA &gt; 4 ng/ml (6.1% vs 47.8%) and neoadjuvant vs no neoadjuvant therapy (8.75% vs 24.2%) were associated with Clavien-Dindo IIIB complications (p &lt; 0.05). Conclusions: cRP is feasible in men with mPCA independent on the extent of disease with a low rate of significant complications and good functional outcome. About two thirds of the patients remain relapse-free after a median follow-up of close to 4 years. cRP might be an individualized treatment option in the multimodality management of mPCA.
Utility of the Edmonton Frail Scale (EFS) in identifying frail elderly patients during treatment of colorectal cancer (CRC).
Authors: Brandon M Meyers, Radhika Yelamanchili, Sara Rask, Humaid Obaid Al-Shamsi, Callista Maria Phillips, Alexandra Papaioannou, Kevin M. Zbuk, Chu Shu Gu, Neera Jeyabalan, Sukhbinder K. Dhesy-Thind
Journal: Journal of Clinical Oncology (2012)

e14001 Background: CRC is the second leading cause of cancer-related death, and 40-50% of patients are older than 70 years. Frailty is a concept that has been proposed by geriatricians as an indicator of functional age. The EFS is a 15 point incremental scale; it is quick (&lt;5 min), and simple to administer. We conducted a pilot study to establish if the EFS would add utility beyond clinician’s expertise. The primary objective was to determine if there was an association between the EFS and receipt of chemotherapy. Methods: The EFS was administered to stage II-IV CRC patients ≥70 years, referred to a Medical Oncologist at a tertiary care centre. The EFS was completed by one of the investigators, with the treating oncology team blinded to results and a follow up 14 month chart review. Results: Forty-six patients were enrolled with the following characteristics: average age 76, 48% male, 78% performance status (PS) 0-1, and 21 (46%) started chemotherapy. The EFS was reproducible between visits (r = 0.81 [CI 0.64-0.9, p&lt;0.0001]). There was no correlation between the EFS and receipt of chemotherapy for the study population as a whole. As none of the 16 stage II patients had high-risk features requiring chemotherapy, the analysis was repeated excluding these patients. There was a reduced likelihood of receiving chemotherapy for stage III/IV patients with higher EFS scores (Odds ratio 0.56 [CI 0.37-0.85, p&lt;0.01] per unit increment). A similar effect was observed after multivariable analysis (adjusting for PS, age, stage and gender, Odds ratio 0.41 [CI 0.18-0.96, p&lt;0.05] per unit increment). No correlation existed between EFS and upfront dose reductions, choice of less toxic regimens, or hospitalization secondary to grade 3/4 toxicities. Conclusions: This pilot study suggests the EFS can identify patients that Oncologists may have thought were too frail for chemotherapy, independent of PS. Therefore, the EFS has the potential to add a reproducible, and quantifiable measure of frailty to the clinician’s decision making armamentarium. The next study phase will employ the EFS real-time, and determine if using the EFS can minimize complications and unplanned health care utilization in elderly cancer patients.
The association between severe treatment-related lymphopenia and progression-free survival in patients with newly diagnosed squamous cell head and neck cancer.
Authors: Jian Li Campian, Guneet Sarai, Xiaobu Ye, Shanthi Marur, Stuart A. Grossman
Journal: Journal of Clinical Oncology (2013)

6068 Background: Severe treatment-related lymphopenia (TRL) occurs in 50% of glioblastoma and pancreatic cancer patients and is associated with early death from tumor progression. We sought to determine if similar findings were seen in head and neck squamous cell carcinoma (HNSCC). Methods: Eligible patients for this retrospective study had: 1) HNSCC cancer diagnosed in 2007-2009, 2) good performance status, 3) platinum-based chemoradiation, and 4) follow-up at Johns Hopkins. Serial total lymphocyte counts (TLC), overall survival (OS) and progression-free survival (PFS) were analyzed accounting for known prognostic factors. Results: Fifty-six adults met eligibility criteria: median age: 57 years, female: 21%, HPV+: 61%, surgery prior to chemoradiation: 16%, stage IVA-IVB: 77%, T stage 3-4: 40% and N stage 2b-3: 56%. Changes in TLC are shown below (Table). 14/56 patients (25%) had tumor recurrence and 9 (16%) died of their tumor. HPV+ patients had longer PFS (p=0.01) and OS (p=0.006) than HPV- patients. 10/22 HPV- patients had disease progression and 7 died. HPV- patients who developed grade III-IV TRL two months after beginning chemoradiation had a strikingly higher hazard rate for disease progression than those whose TLC remained higher (multivariate analysis HR 6.2, 95%CI: 1.1-35.2; p=0.039). Too few events occurred in the HPV+ cohort for analysis. Conclusions: TLCs were normal before chemoradiation. However, two months after chemoradiation ~60% of patients had severe TLC regardless of HPV status. HPV- patients with severe TRL were much more likely to have disease progression than those without TRL. Prospective studies are needed to confirm these findings which are similar to those reported in other cancers. Preservation of the immune system during chemoradiation may be important to improving PFS and OS. [Table: see text]
Prophylactic doxycycline (doxy) lessens rash from dacomitinib (D) an EGFR inhibitor with no rash or diarrhea improvement from corticosteroids or probiotics.
Authors: Mario E. Lacouture, Dorothy Mary Kate Keefe, Stephen T. Sonis, Nagdeep Giri, Tao Wang, Arlene Reisman, Eric Sbar, Diana R. Gernhardt, Aminah Jatoi
Journal: Journal of Clinical Oncology (2015)

e19049 Background: ARCHER 1042 (NCT01465802) was a randomized patient (pt) blinded trial that explored prophylactic interventions to minimize select dermatologic adverse events of interest (SDAEI) and diarrhea toxicities associated with D, an irreversible small molecule PanHER. Methods: In Cohorts I (CI) and II (CII) pts with advanced NSCLC, ≥ 1 prior chemo, ECOG 0–2, were randomized (pt blinded) in CI to (a) D 45 mg daily (QD) plus placebo (pbo) (D+pbo) or (b) D 45 mg QD plus doxy 100 mg twice daily x 4 wks (D+doxy) and in CII assigned to D 45 mg QD plus probiotic (prob) and topical alclometasone (alclo) (D+prob+alclo). Primary endpoints in first 8 wks included: all grade (G) and G ≥ 2 SDAEI and PRO (Skindex-16) (CI, CII) and CII G and G ≥ 2 diarrhea and PRO (modified Mucositis Daily Questionnaire). Results: As of August 25, 2014,112 pts randomized to Cohort I D + pbo versus D + doxy (median age 66 years, 53% male) and 59 pts to CII D+prob+alclo (median age 66 years, 66% male) were evaluable (> 6 wks treatment). PRO Skindex scores improved with prophylactic doxy, but not alclo; prophylactic probiotic was not associated with improved CTCAE or PRO. D exposure was not altered by doxy. Conclusions: These preliminary data suggest prophylactic doxy improves Select Dermatologic AEs. In contrast, prophylactic topical corticosteroids had minimal effect on rash; probiotic did not impact diarrhea. Clinical trial information: NCT01465802.All cause all G and G ≥ 2 SDAEI incidence, diarrhea burden index and adverse events discontinuations (evaluable, data first 8 weeks). SDAEI ≥ G2 %, 95% CI G SDAEI %, 95% CI Diarrhea Burden Indexb mean D related Discontinuations for AE% Placebo N = 56 48.2 34.7,62.0 82.1 69.6,91.1 2.4 8.9 Doxy N = 56 25.0 14.4,38.4 vs. Pbo P = 0.019a 76.8 63.6,87.0 vs. Pbo P = 0.640 1.8 vs. Pbo P = 134 5.4 Alclometasone+probiotic N = 59 35.6 23.6,49.1 vs. Pbo P = 0.237 vs. Doxy P = 0.302 79.7 67.2,89.0 vs. Pbo P = 0.920 vs. Doxy P = 0.883 2.4 vs. Pbo P = 0.943 vs. Doxy P = 0.140 3.4 a All P-values based on risk difference. ≥ G2 SDAEI for Doxy statistically significantly lower than Pbo; b Diarrhea burden index factors both duration and grade for all episodes in first 8 weeks.
Correlation of specific genetic aberrations and signaling pathways with T-cell inflamed phenotype (TCIP) in head and neck cancer and as novel candidate biomarkers for checkpoint blockade therapy.
Authors: Zhixiang Zuo, Vassiliki Saloura, Holbrook Edwin Kohrt, Michaela K. Keck, Arun Khattri, Mark W. Lingen, Justin Paul Kline, Thomas Gajewski, Everett E. Vokes, Tanguy Y. Seiwert
Journal: Journal of Clinical Oncology (2015)

6079 Background: Anti-PD-1/PD-L1 blockade is active in patients (pts) with head and neck squamous cell carcinoma (HNSCC) (Seiwert ASCO 2014). The T-cell inflamed phenotype (TCIP)/INF-g driven gene expression delineates a group of HNSCC that are likely to benefit from anti-PD-1 therapy (Seiwert ASCO 2015). We examined the genetically annotated TCGA cohort to determine genetic aberrations and signaling pathways associated with TCIP HNSCC, and validated findings in vitro, in order to identify novel candidate genetic biomarkers for immunotherapy and possible combination strategies. Methods: 416 HNSCC tumors from the TCGA cohort were used to calculate T-cell inflamed phenotype (TCIP) (Saloura ASCO 2014). Mutation/copy number data, expression intrinsic subtypes (Keck CCR 2015), and KEGG pathways were evaluated for correlation with TCIP in a hypothesis-forming analysis. In-vitro validation was performed in cell lines with similar genetic background. Results: Aberrations in the histone-methyl-transferase NSD1, altered in 41% of HNSCC via mutation/deletion. Considering HPV(-) tumors only, both NSD1 mutation and NSD1 deletion were strongly correlated with non-TCIP (p = 0.0035 and p = 6.60e-09, respectively). NSD1 mutation distribution suggested loss of function. Secondly, EGFR amplification occurred in non-TCIP tumors (p = 3.88e-11) and overlapped with active EGFR signaling in the Basal (BA) intrinsic subtype. BA cell lines treated with an EGFR inhibitor (gefitinib) consistently showed an increase in PD-L1 expression by immunoblotting. Pathway analysis identified WNT signaling as significantly associated with non-TCIP. CD274 (PD-L1)/JAK2 co-amplified in 101 out of 416 HNSCC tumors, which was significantly enriched in TCIP (p = 5.93e-13). Conclusions: NSD1 aberration,EGFR amplification, basal subtype, and WNT signaling are biomarkers of non-TCIP tumors, CD274/JAK2 amplification of TCIP tumors. These newly identified candidate biomarkers for immunotherapy require additional clinical and functional validation. Combination therapy with anti-EGFR and anti-PD-1/PD-L1 should be further explored.