tbuckley/cabot-search huggingface dataset:
Targeted next-generation sequencing (NGS) of advanced prostate cancer (PCA) using formalin-fixed tissue.
Authors: Himisha Beltran, Roman Yelensky, Garrett Frampton, Kyung Park, Sean Downing, Theresa Macdonald, Doron Lipson, Scott T. Tagawa, David M. Nanus, Philip Stephens, Juan Miguel Mosquera, Maureen T. Cronin, Mark A. Rubin
Journal: Journal of Clinical Oncology (2012)

4649 Background: The genomic landscape of advanced PCA is not well characterized, partly due to limited availability of frozen metastatic tissue. This has created a gap in our knowledge of treatment related and potentially targetable genomic alterations. The purpose of this study was to demonstrate feasibility of performing NGS to molecularly characterize advanced PCA using formalin-fixed paraffin embedded (FFPE) tissue. Methods: 25 metastatic CRPC, 4 metastatic hormone naïve PCA, 3 primary localized PCA, and 18 benign matched prostates were evaluated (40mm FFPE tissue per case). High-density foci were captured and sequenced for 3230 exons of 182 cancer-related genes and 37 introns of 14 genes often rearranged in cancer to an average depth of &gt;800x in a CLIA lab (Foundation Medicine). Recurrent mutations, copy number alterations, and fusions were validated using PCR and FISH. Results: In &gt;90% of samples, there was sufficient DNA (≥50 ng) for analysis. Recurrent high confidence cancer alterations in CRPC included: TMPRSS2-ERG fusion (44%), PTEN loss (44%), TP53 mutation (40%), AR mutation (24%), AR gain (24%), RB mutation (28%), MYC gain (12%), and BRCA2 loss (12%). Overall 48% of CRPC harbored AR gene alterations. Additionally, there were mutations in CTNNB1 (12%), ATM (8%) and PIK3CA (4%). Copy number alterations not previously described in PCA included CCND1, CDK4/6 gains and CDKN2A/CDKN2B deletions. Hormone naïve metastatic and high risk localized PCA demonstrated similar frequency of TMPRSS2-ERG gene fusion, BRCA2 deletion, and TP53 mutations as CRPC, but AR alterations and MYC gain were not seen. Conclusions: This study demonstrates feasibility of in-depth, NGS based DNA analysis using FFPE tissue, even biopsy material. Frequent AR alterations in CRPC, mutations associated with disease progression, and potential drug targets were identified. Focused NGS has clinical potential to identify actionable genomic alterations in advanced PCA that can impact patient participation in trials as well as treatment and outcome. Treatment options include PARP inhibitors for patients with BRCA2 and ATM alterations (20% of cases) and PI3K/AKT inhibitors for PIK3CA mutations.
DE-NOVO ANTIVIRAL THERAPY WITH NUCLEOS(T)IDE ANALOGUES IN 'REAL-LIFE' PATIENTS WITH CHRONIC HEPATITIS B INFECTION: COMPARISON OF VIROLOGICAL RESPONSES BETWEEN LAMIVUDINE plus ADEFOVIR VS. ENTECAVIR VS. TENOFOVIR THERAPY
Authors: Ivana Carey, Huyen-Ly Nguyen, Dorothy Joe, Mohammad Al-Freah, Sarah Knighton, Abid Suddle, Phillip Harrison, Kosh Agarwal
Journal: Hepatology (2011)
Phase II trial of erlotinib maintenance therapy after platinun-based chemotherapy in advanced non-small cell lung cancer (NSCLC)
Authors: M. Cobo, J. Martinez, A. Montesa, S. Gil-Calle, E. Villar-Chamorro, I. Ales, V. Gutierrez, G. Durán, F. Carabantes- Ocón, M. Benavides
Journal: Journal of Clinical Oncology (2009)

e19013 Background: phase II trial-efficacy &amp; toxicity of sequential erlotinib in advanced NSCLC after platinum-based CT Methods: Pts with adv NSCLC, PS 0/1, adequate renal, hepatic and bone marrow function, no PD after CT. Treatment: erlotinib 150 mg/day starting 3–4 weeks after CT until progression. Safety was evaluated monthly and tumor evaluation bimonthly. Results: 47 pts enrrolled:42(89%)stageIV &amp; 5(11%)wet IIIB, all valid for response &amp; toxicity. Median age 62 y(r:39 -77): 39(83%) males and 8(17%) females. Histology: adenocarcinoma 8(61.7%), bronquioloalveolar 3(6.4%), large cell 3(6.4%), squamous12(25.5%). PS 0: 23(49%), PS 1:24(51%). 38(81.9%) completed 6 cycles of CT. Response: CR: 1(2.1%), PR: 2(51.1%), EE: 22 (46%). Sequential erlotinib improved RR in 6 (12.8%), 23 (48.9) prolonged stabilization, 18 (38.3%) had progression. Median TTP and OS were 9.4 m (95% CI, 4.96–13–84), and 19.23 m (95% CI, 8.82–29.64). No significant differences in TTP according to age, sex, PS, histology or previous response to CT, but yes depending on RR to erlotinib: PR: 31.5 m (95% CI 15.37–47.63), EE: 12.8 m (95% CI, 10.58–15.03), PD: 6.3 m (95% CI, 5.36–7.3), p &lt; 0.001; and moreover depending on smoking status: Never: 21.67 m(95% CI, 5.39–37.94), previous smoker &gt; 5 years: 14.03 m(95% CI, 10.77–17.30), previous smoker 1 year: 7.77 m(95% CI, 7.62–7.91), current smoker: 5.9 m(95% CI, 5.12–6.34), p &lt;0.001. In Cox-regression model, smoking status ( p&lt; 0.001), and response to erlotinib (p=0.002) were associated with a significant difference in TTP. Similar results in OS, although in Cox-regression model only never smoker or &gt; 5 years previous smoker pts had a significant better survival. Toxicity: The most frequent was skin rash, grade (g) 1 in 11(23.4%), g 2: 16(34%) and g 3: 3(6.4%). Only 1 p had diarrea g 3, and no other side effects were observed. We found a significant benefit in p with g 2–3 skin toxicity respect g 0–1, in both TTP( p= 0.0003) and OS (p= 0.0014). Conclusions: Erlotinib-maintenance therapy after platinum-based CT had promising results. Pts with the best benefit were those with response to erlotinib, in never or past (&gt; 5 years) smokers and with g 2–3 skin toxicity. No significant financial relationships to disclose.
Erratum: A Novel Folate Transport Activity in Human Mesothelioma Cell Lines with High Affinity and Specificity for the New-Generation Antifolate Pemetrexed (Cancer Research (November 15, 2002) (6434-6437))
Authors: Yanhua Wang, Rongbao Zhao, S. Chattopadhyay, I. David Goldman
Journal: Cancer Research (2003)
Prognosis disclosure to terminally ill cancer patients: A qualitative study among Japanese physicians.
Authors: Masanori Mori, Miho Ogawa, Mashiho Nishimura, Hirohide Yamada, Tatsuya Morita
Journal: Journal of Clinical Oncology (2013)

e20717 Background: Prognosis disclosure could facilitate end-of-life discussions and advance care planning in advanced cancer patients. However, many Japanese and Japanese American patients do not wish to know of their own prognosis, and physicians infrequently disclose terminal prognosis in Japan. We aimed to investigate Japanese physicians’ practice and emotion regarding prognosis disclosure. Methods: We adopted a qualitative design based on semi-structured interviews and content analysis. Attending physicians in a local cancer center were eligible if they had disclosed terminal prognosis to their cancer patients and/or families more than three times in the past year. The sample size was justified by recruiting participants through consistent comparison analysis until data saturation occurred. Results: We conducted 11 face-to-face interviews and detected the following categories; [practice in disclosure], [reasons for/against disclosure], and [emotion regarding disclosure]. [Practice] indicated that some physicians have almost always disclosed prognosis to their patients, while others have almost never done so. It included various skills such as “having families/nurses attend the meeting,” “asking families how much prognostic information physicians should provide to patients,” “asking patients why they want to know,” and “answering with a range of estimation.” [Reasons for disclosure] included “to help patients deal with unfinished business” and “to support realistic hope.” [Reasons against disclosure] included “uncertain prognosis,” “physicians’ concern about hurting patients,” “lack of time and staff support for physicians,” and “insufficient training in communication skills.” Lastly, many physicians felt “sad,” “nervous,” and “difficult,” while few felt “fulfilled” when disclosing prognosis. Conclusions: Practice patterns, reasons and emotional experiences vary widely in prognosis disclosure among Japanese physicians. Team approach, physician training in communication skills, and understanding of families’ as well as patients’ preferences may contribute to better-quality individualized cancer care based on patients’ goals, not on physicians’ personal preferences.
Clinical outcomes based on multigene profiling in metastatic breast cancer patients.
Authors: Reva Kakkar Basho, Debora De Melo Gagliato, Naoto T. Ueno, Ricardo H. Alvarez, Chetna Wathoo, Huiqin Chen, Caimiao Wei, Aysegul A. Sahin, Sinchita Roy-Chowdhuri, Stacy L. Moulder, Mariana Chavez-Mac Gregor, Jennifer Keating Litton, Vicente Valero, Rajyalakshmi Luthra, Kenna Rael Shaw, John Mendelsohn, Gordon B. Mills, Debu Tripathy, Funda Meric-Bernstam
Journal: Journal of Clinical Oncology (2015)

1524 Background: Identifying the clinical impact of mutations in cancer-related genes can help define their role in cancer. Here, we aim to classify frequent hotspot mutations in metastatic breast cancer (MBC) patients and determine how they may affect clinical outcomes. Methods: Hotspot mutation testing was conducted in 500 MBC patients using an 11 gene Sequenom (N = 126) and/or 46 or 50 gene Ion AmpliSeq Panel (N = 391). Patients were stratified by hormone receptor (HR) and HER2 status, type of therapy (chemo, endocrine or targeted therapy) and line of therapy. Clinical outcomes including recurrence-free survival from diagnosis (RFS) and time to treatment failure due to progression (TTP) were retrospectively collected, and comparative analysis between patients who did and did not harbor mutations in certain genes was conducted. Results: The most frequent genes with hotspot mutations were TP53 (30%), PIK3CA (26%) and AKT1 (4%). Triple-negative breast cancer patients had the highest incidence of TP53 (58%) and the lowest incidence of PIK3CA (8%) mutations. TP53 mutation was associated with significantly shorter RFS (median 19 vs 41 months; P < 0.001), TTP with first-line (median 6 vs 12 months; P < 0.001) and second-line (median 4 vs 7 months; P = 0.006) therapy and TTP with chemotherapy (median 6 vs 8 months; P = 0.005) and targeted therapy (median 4 vs 14 months; P = 0.009) in the first-line setting. Conversely, presence of PIK3CA mutation did not significantly affect RFS or TTP with first-line therapy. In HR-positive patients, TP53 mutation was associated with significantly shorter RFS (median 24 vs 46 months; P < 0.001), distant RFS (median 30 vs 46 months; P = 0.002) and local-regional RFS (median 51 vs 131 months; P < 0.001). However, there was no significant association between TTP and mutation status of TP53, PIK3CA, or AKT1 in HR-positive patients treated with endocrine therapy in the first- or second-line setting. Conclusions: Correlating clinical outcomes with the presence of hotspot mutations in cancer-related genes can help define the clinical significance of these mutations. In this cohort of MBC patients, TP53, the most frequent hotspot mutation, was associated with worse clinical outcomes, both overall and in HR-positive patients. Clinical trial information: NCT01772771.
Inflammatory markers and symptom burden in patients with multiple myeloma undergoing autologous stem cell transplantation.
Authors: Loretta A. Williams, Xin Shelley Wang, Valen E. Johnson, Ping Liu, Nina Shah, Tito R. Mendoza, James M. Reuben, Evan N. Cohen, Katherine R. Gilmore, Venus M Ilagan, Charles S. Cleeland
Journal: Journal of Clinical Oncology (2012)

9081 Background: We explored the association between activation of inflammatory networks and development of severe symptoms during mobilization and the acute phase of autologous hematopoietic stem cell transplantation (ASCT) for multiple myeloma (MM). Methods: From mobilization through the first 3 months after ASCT, multiple symptoms were measured repeatedly via the myeloma module of the M. D. Anderson Symptom Inventory (MDASI-MM). Serum levels of interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-a, soluble TNF receptors 1 and 2 (sTNF-R1, sTNF-R2), IL-1 receptor antagonist (IL-1RA), vascular endothelial growth factor (VEGF), macrophage inflammatory protein-1 (MIP-1a), monocyte chemoattractant protein (MCP)-1 and C-reactive protein (CRP) were collected up to 11 times per patient and assayed by Luminex. Ordinal regression modeling was used to analyze repeated-measures data. Results: Among50 MM patients, the most severe symptoms reported by werefatigue, pain, muscle weakness, disturbed sleep, drowsiness, numbness, poor appetite, and bone aches. Symptoms worsened rapidly from conditioning therapy and peaked at WBC nadir. Over time, controlling for age, sex, and MM stage, increased serum IL-6 (P=.0007) and MCP-1 (P=.0005) were significantly associated with worsening of the most severe symptoms; MIP-1a (P=.005) and VEGF (P=.002) were inversely associated with these symptoms. Increased CRP was significantly associated with worsening pain (P=.01), fatigue (P=.007), and bone aches (P=.006). Conclusions: This longitudinal study indicates a strong association between dynamic changes in circulating inflammatory molecules and the most severe symptoms in MM patients during the acute phase of ASCT. This observation, similar to IL-6-related multisymptom development around WBC nadir of allogeneic SCT (Wang et al, 2008), provides evidence of potential inflammation-induced behavioral changes in humans. Testing of anti-inflammatory interventions is warranted to further confirm the role of inflammation in the development of symptoms and identify effective mechanism-driven symptom management during ASCT.
Expression of FLI-1 and the proliferation and survival of small cell lung cancer cells.
Authors: Wei Song, Jiuwei Cui, Wei Li, Guanjun Wang, Yan Li
Journal: Journal of Clinical Oncology (2013)

e18550 Background: Small cell lung cancer (SCLC) exhibits aggressive behavior, rapid growth, early spread to distant sites. Over the last few decades, prognosis for patients with SCLC has changed little and there remains an critical need for evaluating novel agents. Here, we report that Fli-1 (Friend leukemia virus integration 1), a transcription factor and member of the Ets family, has an essential role in SCLC progression and may be a promising target for therapy. Methods: Immunohistochemical staining was used to investigate the expression level of Fli-1 in 25 patients with SCLC, including 12 patients in limited stage and 13 patients in extensive stage. The growth, apoptosis assay and molecular mechanism of Fli-1 in SCLC cell line (NCI-H446) was studied by down-regulating Fli-1 expression through RNA interference. Results: It was shown that expression level of Fli-1 was significantly up-regulated in SCLC tissues compared with adjacent tissues (p=0.0002). Its staining was found specifically in the nuclei of cancer cells. Expression level of Fli-1 was higher in extensive stage disease than that in limited stage disease (p=0.0045). Down-regulation of Fli-1 expression by RNA interference in NCI-H446 was found to strongly decrease cell growth, promote cell apoptosis and reduce metastasis. Importantly, when Fli-1 was down-regulated in NCI-H446, epidermal growth factor (EGF)-induced Akt activation was dramatically decreased. It was implied that Fli-1 was involved in the Akt regulation passway. It was also confirmed that the apoptosis induced by decrease of Fli-1 expression via down-regulation of its target regulation gene, bcl-2. Conclusions: The novel mechanistic insight into a critical role of Fli-1 in SCLC progression was shown in this study. Fli-1 overexpression promotes SCLC aggression partly via activating Akt phosphorylation. We propose that Fli-1 is a new powerful predictor for SCLC progression, and is also a new potential target for SCLC treatment.
Trends in the use of cytoreductive nephrectomy for metastatic renal cell carcinoma in the VEGFR tyrosine kinase inhibitor era.
Authors: Che-Kai Tsao, Alexander C. Small, Max Kates, Benjamin Adam Gartrell, Juan P. Wisnivesky, Guru Sonpavde, Michael Palese, Simon Hall, William K. Oh, Matt D. Galsky
Journal: Journal of Clinical Oncology (2012)

4623 Background: Two large randomized trials (SWOG, EORTC) published in 2001 established the role of cytoreductive nephrectomy (CyNx) for the treatment of metastatic renal cell carcinoma (mRCC) in the cytokine era. A paradigm shift occurred in 2005 with the approval of VEGFR tyrosine kinase inhibitors (TKIs). We hypothesized that uncertainty regarding the role of CyNx in the VEGFR TKI era has resulted in a change in practice patterns. Methods: Using the Surveillance, Epidemiology and End Results (SEER) registry, we identified 2780 patients with histologically-confirmed mRCC between 2000 and 2008 who underwent CyNx or no surgery. Patients were separated into pre- or VEGFR TKI-eras (2000-2005 vs. 2006-2008). Differences in baseline characteristics between these patient groups were assessed and controlled for in a logistic regression analysis to determine the likelihood of undergoing CyNx. Results: Overall, 1202 of 2780 patients (43%) underwent CyNx. CyNx increased from 41% in 2000 to 49% in 2005, and decreased to 35% in 2008, with a 20% decreased likelihood of undergoing CyNx in the VEGFR TKI era compared to the pre-VEGFR TKI era. Logistic regression analysis showed that tumor size, age, race, marital status and pre- versus post-2005 periods were independent predictors of CyNx (Table). Patients who were non-Caucasian, single, with primary tumor &lt;3cm, or older were less likely to undergo CyNx. Conclusions: Use of CyNx increased after supporting level I evidence was published in 2001, and decreased after regulatory approval of VEGFR TKIs in 2005. Racial and demographic differences exist in the utilization of CyNx. The results of pending randomized trials evaluating the role of CyNx in the TKI-era are awaited to optimize use of this modality and address potential disparities. [Table: see text]
Oxaliplatin, UFT and oral leucovorin combination chemotherapy in 5-fluorouracil refractory colorectal carcinoma: A phase II study
Authors: H.-M. Ryoo, S. H. Bae, H. I. Lee, J. L. Lee, K. H. Lee, M. Hyun, K. U. Park
Journal: Journal of Clinical Oncology (2004)

3774 Background: This phase II study evaluated the efficacy and safety of a combination of oxaliplatin and UFT/oral leucovorin in Korean Patients with advanced colorectal cancer (ACC) previously treated with a fluorouracil-based regimen. Methods: From December 1998 to December 2001, 28 patients [male : female 12:16, median age 61 (range 37–71)] with measurable disease and Easter Cooperative Oncolgy Group performance status of 0–2 were treated with a combination of oxaliplatin (130 mg/m2 i.v. for 2 hours) on day 1, UFT (300 mg/m2 p.o.) and 5-FU (20mg/m2 p.o.) on day 1–21, every 3 weeks. Results: 10 out of 28 evaluable patients achieved complete (n=3) or partial (n=7) response, leading to an overall response rate of 35.7%. The estimated median time to progression and survival were 5.5 months and 8.5 months respectively. From the 129 cycles analyzed, sensory neuropathy was the most common toxicity (73%), grade 3,4 hematologic toxicities included neutropenia 1.5%, and thrombocytopenia 1.5%, other toxicities were mild. Conclusions: This combination of oxaliplatin and UFT/oral leucovorin is active and feasible in patients with advanced colorectal cancer previously treated with a fluorouracil-based regimen No significant financial relationships to disclose.
A gene expression signature of eventual brain metastases in patients with breast cancer
Authors: Y. Tham, C. Creighton, C. Gutierrez, C. K. Osborne, P. Brown, J. C. Chang
Journal: Journal of Clinical Oncology (2007)

1019 Background: The incidence of brain metastases (BM) from breast cancer may be increasing, in part due to more effective systemic therapy. A metastatic signature of bone or lung metastases has been identified in mice but not for BM in human. We hypothesized that gene expression patterns of primary breast cancers may provide a specific metastatic signature for eventual BM. Methods: Core biopsies from primary breast cancers of 11 patients with BM and 12 patients who have other non-brain metastases were identified. Double- stranded cDNA was synthesized using an oligo-dT primer containing a T7 RNA polymerase promoter, followed by in vitro transcription with biotinylated ribonucleotides. The labeled cRNA was hybridized to Affymetrix U133-A chips. Results: Of the patients with BM, 55% were ER negative/HER-2 positive while 36% were ER positive/HER-2 negative. Of the patients with non brain metastases, 42% were ER negative/HER-2 positive and 50% were ER positive/HER-2 negative, with. A differential pattern of gene expression was seen in primary tumors of patients with BM when compared with those who had non-brain metastases. Many more genes were found elevated in patients with BM over what would be expected by chance (after correcting for multiple testing). Tumors that developed BM had expression of genes related to the neurological development pathways such as fetal Alzheimer antigen, MAD, neuropilin 1, and others. Several kinase pathways were involved such as protein kinase C and casein kinase substrate in neurons 2, and A kinase (PRKA) anchor protein 13. These genes will be validated in an independent set of patients with BM and non-brain metastases using real time PCR. Conclusions: The identification of genes that may predict for future development of brain metastases has many implications in terms of screening or prophylactic treatment. This would also help identify potential targets for the treatment of brain metastases. No significant financial relationships to disclose.
The clinical value and prognostic role of preoperative thin-section computed tomography findings in small-sized adenocarcinomas of the lung (10 mm or less in diameter).
Authors: Fumi Karino, Shuji Murakami, Tetsuro Kondo, Haruhiro Saito, Fumihiro Oshita, Teppei Nishii, Hiroyuki Ito, Haruhiko Nakayama, Tomoyuki Yokose, Kouzo Yamada
Journal: Journal of Clinical Oncology (2014)

e18514 Background: Thin-section computed tomography (TS-CT) findings of lung cancer were reported to reflect the histopathological findings with some accuracy. However, we do not fully understand the small-sized carcinomas of the lung. The purpose of this study was to examine the correlations between tumor shadow disappearance rate (TDR) on TS-CT, pathological and clinical findings of the small-sized adenocarcinomas of the lung. Methods: We retrospectively analyzed 111 peripheral non-mucinous adenocarcinomas resected between 1997 and 2013. Tumor diameters measured 10mm or less in size. TDR was defined as the ratio of the maximum tumor diameter on the mediastinal window to that on the lung window of TS-CT. We examined the relationship between the TDR, pathological and clinical findings. The histologic subtypes were analyzed according to the 2011 IASLC/ATS/ERS International Multidisciplinary Classification of Lung Adenocarcinoma. Results: The median age of the patients was 64 (range, 23-83) years, and 66 patients (59.5%) were female. Sixty-four patients (57.7%) were never-smokers. The average tumor size was 8.7 mm (range, 5-10 mm). Seventy cases were adenocarcinoma in situ (AIS) or minimally invasive adenocarcinoma (MIA), 19 were acinar predominant (AP), 13 were papillary predominant (PP) and seven were solid predominant (SP). Two cases could not be determined. All 70 cases diagnosed AIS or MIA were stage IA and did not relapse during the follow-up. The TDR of AIS and MIA cases were all more than 50%. Six of 39 invasive adenocarcinoma cases relapsed after surgery; three cases of AP, two of PP and one of a SP tumor. All six cases relapsed after surgery showed 40% or less in TDR. Four cases diagnosed with lymph node metastasis showed 22% or less in TDR. Twelve cases with pleural invasion or vascular invasion or lymphatic invasion in the pathological factors of the resected lesions showed 28% or less in TDR. There were no relapse cases in 42% or more in TDR. Conclusions: There is a correlation between the TDR, pathological and clinical findings in small-sized adenocarcinomas of the lung. The TDR may contribute to the determination of the optimal therapeutic strategy.