tbuckley/cabot-search huggingface dataset:
Association of pro-inflammatory biomarkers and post-chemotherapy cognitive changes in Asian breast cancer patients: A prospective cohort study.
Authors: Yin Ting Cheung, Maung Shwe Ham Guo, Yuan Chuan Kee, Wai Keung Chui, Han Kiat Ho, Gilbert Fan, Wei Sean Yong, Preetha Madhukumar, Wei Seong Ooi, Wen Yee Chay, Rebecca Alexandra Dent, Soo Fan Ang, Soo Kien Lo, Yoon Sim Yap, Raymond C.H. Ng, Alexandre Chan
Journal: Journal of Clinical Oncology (2013)

9506 Background: Although existing evidence suggests that cytokines play an intermediary role in the development of post-chemotherapy cognitive changes, specific cytokines associated with this neurotoxic sequela of chemotherapy are still unknown. This study was designed to identify pro-inflammatory biomarkers that are associated with memory and attention impairment in Asian patients receiving chemotherapy. Methods: This is a prospective, cohort study conducted at the National Cancer Centre Singapore. Early-stage Asian breast cancer patients (Stage I to III), who received anthracycline and/or taxane-based chemotherapy were recruited. Computerized neuropsychological assessments (Headminder) were administered to evaluate patients’ memory and attention performances and a panel of pro-inflammatory plasma cytokines (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, GM-CSF, IFN-γ and TNF-α) was evaluated using multiplex immunoassay at three time points: prior to chemotherapy (T1), at midpoint (T2), and end of chemotherapy (T3). Memory and attention impairment were defined as a &gt;2.5 reduction of the Zscore from baseline, as calculated by the reliable change index for repeated cognitive measurements. Results: Thirty-six patients were included (mean age 49.7±9.0 years; 80.6% Chinese). Comparing to T1, 50.0% and 36.1% of the patients suffered memory and attention impairment at T3, respectively. Comparing patients with intact memory to those who suffered impairment from T2 to T3, they had higher levels of circulating IL-1β [median (IQR): 0.44 (0.1-0.5) vs 0.56 (0.4-0.7) pg/ml, p=0.069], IL-4 [0.41 (0.0-0.8) vs 0.85 (0.2-1.5) pg/ml, p=0.067) and TNF-α [1.78 (1.3-2.2) vs 3.01 (1.3-3.5) pg/ml, p=0.069]. At T3, reduction of attention scores were associated with higher levels of IL-1β (r s = -0.37, p=0.023) and IL-6 (r s = -0.33, p=0.045). No significant associations were identified with IL-2, IL-8, IL-10, GM-CSF and IFN-γ. Conclusions: These findings suggest that an increase in the post-chemotherapy levels of TNF-α, IL-1β, IL-4 and IL-6 may have an association with the manifestations of memory and attention impairment in Asian breast cancer patients.
Multiple copies of MLL as a commonly detected cytogenetic abnormality in newly diagnosed symptomatic multiple myeloma.
Authors: Chrystal Ann Landry, Dory Londono, Sean Devlin, Suresh Jhanwar, Sergio Giralt, Heather Jolie Landau
Journal: Journal of Clinical Oncology (2014)

e19585 Background: Multiple myeloma (MM) is a heterogeneous disease with variable course, response to therapy, and survival. Cytogenetics and fluorescent in-situ hybridization (FISH) have identified several recurrent chromosomal aberrations in MM that play an important role in risk stratification. We sought to define the incidence and prognostic significance of excess MLL in MM patients. Methods: We identified 122 patients with newly diagnosed symptomatic MM who had cytogenetics and FISH performed on initial, pre-treatment bone marrow specimens at Memorial Sloan-Kettering Cancer Center between 1/2009-12/2012 and were followed. Standard karyotype and FISH were performed as previously described (Gerritsen et al. Blood 1992). Poor risk was defined as p53 loss, del13q, excess 1q, or t(4,14). Favorable risk was defined as hyperdiploid karyotype, and standard risk was defined as neither hyperdiploid nor unfavorable genetics. Overall survival (OS) was calculated from diagnosis until death, progression-free survival (PFS) from treatment start to disease progression based on IMWG criteria, and both were estimated by Kaplan-Meier methods. Survival was compared using a logrank test. Results: Cytogenetic abnormalities were detected by karyotype in 24% and FISH in 61% of patients. Hyperdiploidy was identified in 10% of patients, while loss of p53, del 13q, t(4;14), and excess 1q were seen in 11%, 23%, 6% and 20% of patients, respectively; 36% had extra copies of MLL. While having excess MLL had no impact on the OS of patients without unfavorable cytogenetics (N=62) (P=0.42), a trend toward better OS (P=0.08) was evident in patients with poor-risk cytogenetics (N=60) and excess MLL. Having extra copies of MLL had no impact on PFS (P=0.12). Conclusions: Excess MLL is the most frequent cytogenetic abnormality in a large cohort of newly diagnosed patients with symptomatic MM. In patients with MM and unfavorable cytogenetics, the presence of excess MLL may ameliorate the adverse impact of these abnormalities with respect to patient’s survival. Understanding the functional significance of excess MLL may provide insight into disease pathogenesis and help identify drug targets.
Association of AREG exon 1 polymorphism with worse prognosis in Japanese and U.S. patients with gastric cancer.
Authors: Takeru Wakatsuki, Wu Zhang, Dongyun Yang, Mizutomo Azuma, Yan Ning, Nico Benjamin Volz, Sebastian Stintzing, Rita Elie El-Khoueiry, Joseph Ethan Li, Peter M. D. Wilson, Melissa Janae Labonte, Martin K. H. Maus, Yu Sunakawa, Wasaburo Koizumi, Masahiko Watanabe, Syma Iqbal, Afsaneh Barzi, Anthony B. El-Khoueiry, Manish A. Shah, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2013)

e15022 Background: Recent data suggest that Amphiregulin (AREG) and Epiregulin (EREG), ligand of EGFR pathway, is possibly a prognostic and predictive marker in gastrointestinal cancer. Previous data have shown that higher AREG and EREG gene expression levels are associated with better survival in metastatic colorectal cancer as well as gastric cancer (GC). Since polymorphisms in AREG and EREG may affect their gene expression levels or change their functions, we tested the hypothesis whether these polymorphisms could predict outcome in two ethnically and epidemiologically different GC cohorts from Japan and the US. Methods: One-hundred and sixty-nine Japanese (n=169), as a training set, and one-hundred and thirty-seven (n=137) the US patients, as a validation set, with histopathologically-confirmed localized (stage Ib to IV; AJCC-6 th ) GC were enrolled between 2002 and 2010. Four functional SNPs in AREG and five SNPs in EREG were selected. Genomic DNA was extracted from blood or tissue, and all samples were analyzed by PCR-based direct DNA-sequencing. Results: The median follow-up periods were 4.0 years in the Japanese cohort and 3.3 years in the US cohort, respectively. The median DFS and OS in the Japanese cohort were 4.8 and 5.8 years, whereas the median TTR and OS in the US cohort were 2.8 and 4.7 years, respectively. Only exon 1 polymorphism rs1615111 G/A was associated with outcome in Japanese cohort. Patients heterozygous G/A (n=23) showed a median OS of 2.7 years vs. 20.1 years for patients homozygous G/G (n=146) (HR: 1.83 [95%CI: 1.02-3.30], p=0.039). This result was successfully validated in the US cohort. Patients harboring at least one-A allele (n=14) showed a median OS of 2.8 years vs. 5.4 years for patients homozygous G/G (n=111) (HR: 2.54 [95%CI: 1.09-5.89], p=0.018). In the pooled multivariate analysis, these results were still conserved (HR=2.24 [95%CI: 1.36- 3.67], p=0.0015). Conclusions: AREG exon 1 polymorphism rs161511 may be negative prognostic factor in GC regardless ethnicity and regional differences in gastric cancer. Further clinical validation of SNPs in EGFR ligands are warranted.
Safety of bevacizumab (B) and erlotinib (E) therapy in patients (pts) with treated brain metastases (mets) in the phase III, placebo (P)-controlled, randomized BeTa trial for pts with advanced non-small cell lung cancer (NSCLC) after failure of standard first-line chemotherapy
Authors: G. A. Otterson, P. G. O’Connor, M. Lin, R. S. Herbst
Journal: Journal of Clinical Oncology (2009)

e19025 Background: Bevacizumab (B) + carboplatin/paclitaxel received FDA approval in 10/06 for improving survival in first-line treatment of advanced NSCLC patients (pts). In the past, pts with brain mets had been excluded from trials of B due to concerns about the possibility of CNS hemorrhage. We report on the safety of B therapy in combination with E in a subset of pts with treated brain mets who enrolled in the BETA lung study for NSCLC. Methods: Pts in the subset had recurrent advanced stage NSCLC. Their disease at enrollment included brain mets previously treated with whole brain radiation therapy. Neurosurgery and stereotactic radiosurgery were permissible in addition to WBRT. Patients with an ongoing requirement for dexamethasone treatment and those who had previously been treated with anti-angiogenesis or epidermal growth factor receptor-targeted therapy were not eligible. Pts were treated with E+B or E+P. E dosing was at 150 mg daily; B/P dosing was 15mg/kg intravenous every (q) 3 weeks. Responses were evaluated q 6 wks until wk 24 and every 12 wks thereafter. Treatment continued until disease progression. Results: 68 pts with brain metastases were enrolled between June 2005 and April 2008. 37 pts received E+B and 31, E +P, with median treatment durations of 2.6 and 2.7 months respectively. No CNS hemorrhages or Gr 3+ bleeding events were reported among these pts. 3 Gr 3–4 nervous system adverse events (AE) were reported in each arm. One convulsion, one case of memory impairment and one case of toxic encephalopathy was reported in the E+P arm and a case of ataxia, headache, and cerebral ischemia were reported in the E+B arm. Conclusions: 37 pts with previously treated brain mets were treated with E+B in the BETA study. No CNS hemorrhages were reported in this subset and no new safety signals identified. The treatment duration for subjects with metastasis was equivalent in the E+B and E+ P arms. These data suggest an acceptable safety profile for the subset of patients with brain mets treated with B in the BETA lung study. [Table: see text]
Clinical impact of sarcopenia on prognosis in pancreatic ductal adenocarcinoma.
Authors: Go Ninomiya, Tsutomu Fujii, Suguru Yamada, Tomonari Asano, Nao Takano, Hideki Takami, Naoki Iwata, Mitsuro Kanda, Yukiko Niwa, Masamichi Hayashi, Daisuke Kobayashi, Chie Tanaka, Goro Nakayama, Hiroyuki Sugimoto, Michitaka Fujiwara, Masahiko Koike, Yasuhiro Kodera
Journal: Journal of Clinical Oncology (2017)

259 Background: In the past, various prognostic factors in pancreatic ductal carcinoma (PDAC) have been identified, and there found to be not only tumor-specific clinicopathological factors but also individual patient characteristics. In particular, weight loss, muscle wasting and cachexia are hallmarks of PDAC that may be associated with depletion of both skeletal muscle and adipose tissue. Most notably, sarcopenia is defined to be degenerative loss of skeletal muscle mass that is quantifiable using cross sectional imaging computed tomography (CT) by measurement of psoas area and the muscle’s density. Furthermore, visceral adipose tissue loss also has been reported to associate with a poor survival among patients with PDAC. Methods: A total of 265 patients who underwent curative surgery for PDAC were examined in this study. The total skeletal muscle and fat tissue areas were evaluated in a single image obtained at the third lumber vertebra during a preoperative computed tomography (CT) scan. The patients were assigned to either the sarcopenia or non-sarcopenia group based on their skeletal muscle index (SMI) and classified into high visceral fat area (H-VFA) or low VFA (L-VFA) groups. The association of clinicopathological features and prognosis with the body composition were statistically analyzed. Results: There were 170 patients (64.2%) with sarcopenia. The median survival time (MST) was 23.7 months for sarcopenia patients and 25.8 months for patients without sarcopenia. The MST was 24.4 months for H-VFA patients and 25.8 months for L-VFA patients. However, sarcopenia patients with BMI ≥ 22 exhibited significantly poorer survival than patients without sarcopenia (MST: 19.2 vs. 35.4 months, P = 0.025). There was a significant difference between patients with and without sarcopenia who did not receive chemotherapy (5-year survival rate: 0% vs. 68.3%, P = 0.003). The multivariate analysis revealed that tumor size, positive dissected peripancreatic tissue margin, and sarcopenia were independent prognostic factors. Conclusions: Sarcopenia is an independent prognostic factor in PDAC patients with a BMI ≥ 22. Therefore, evaluating skeletal muscle mass may be a simple and useful approach for predicting patient prognosis.
Association of cfDNA androgen receptor amplifications with BRAF alterations in mCRPC.
Authors: Elisa M. Ledet, Joshua Schiff, Patrick Cotogno, Charlotte Manogue, Emma M. Ernst, Brian E. Lewis, Oliver Sartor
Journal: Journal of Clinical Oncology (2017)

234 Background: Cell free DNA (cfDNA) present in plasma of cancer pts can reflect tumoral alterations. Genomic alterations in cfDNA alter prognosis and abiraterone/enzalutamide resistance in mCRPC. The goal of this evaluation was to characterize AR amplifications (Amps) and various somatic point mutations (Muts) detected in mCRPC cfDNA and to relate those changes to other common alterations in the cfDNA landscape. Methods: A heterogenous group of 46 mCRPC patients (pts) with evidence of clinical progression from Tulane Cancer Center underwent cfDNA analysis using Guardant360 test (Guardant Health, Redwood City, CA). This evaluation included full exonic coverage of 70 genes and amplifications in 18 genes. Mutations reported herein include both known pathogenic mutations as well as mutations uncharacterized for functional importance. Results: 69.5% (n = 32) of the mCRPC pts evaluated had an AR alteration. Of the pts with AR alterations, 46.8% (n = 16) had AR Amps, 43.7% (n = 14) had AR Muts, and only 6.25% (n = 2) had both. In this cohort, AR alterations were the most commonly observed aberration. In addition to amplifications, 12 different AR Muts were detected. AR Muts included: T878A (n = 9), H875Y (n = 5), W742C (n = 4), AR L702H (n = 3), and others. To better understand the relationship between AR alteration and other commonly detected cfDNA aberrations, association between BRAF (35.5%), TP53 (46.7%), and MYC (22.2%) alterations and AR were assessed. Among these genes, TP53 alterations were all Muts and MYC alterations were all Amps. BRAF alterations were predominantly Amps (N = 15) though Muts were also detected (N = 6). Neither TP53 Muts or MYC Amps were significantly associated with AR alterations. On the other hand, BRAF alterations were significantly associated with AR Amps (p = 0.041); 60% (9/15) pts with AR Amps also had BRAF alteration (Odds ratio = 7.71, 95% CI 1.284- 46.366). Conclusions: AR alterations in cfDNA impact both disease progression and response to therapy. Co-segregation of AR and BRAF alterations may have significant prognostic and therapeutic implications. Further research and larger sample size is needed to further elucidate associations between the common somatic alterations detected in mCRPC.
Survival and prognostic factors after complete response to first-line cisplatin-based chemotherapy in patients with advanced testicular seminoma: The Instituto Nacional de Enfermedades Neoplásicas experience.
Authors: Silvia P. Neciosup, David Callacondo, Oliver Rua, Jose Ernesto Rojas, Jose Quesada, Luis Jesus Schwarz, Ivan Carlos Aguilar Marin, Luís Más, Henry Gomez, Carlos S. Vallejos
Journal: Journal of Clinical Oncology (2012)

e15036 Background: The IGCCCG classification, used to guide the management of metastatic seminomas may underestimate the predictive value of other prognostic factors. We aimed to identify prognostic factors for long term survival in patients with advanced testicular seminoma who achieved a complete response to first line cisplatin based chemotherapy. Methods: A retrospective analysis was carried out on 101 patients with advanced testicular seminoma who received induction cisplatin based chemotherapy between 1990 and 2010.Data regarding clinical and laboratory parameters that may influence the overall survival (OS) or progression free survival (PFS) were collected from clinical records. Univariate analysis was performed using the Kaplan-Meier method, while Cox regression modeling was used for multivariate analysis. Results: The mean follow up time was 8.4 years. 9 (9%) patients died and 16 (16%) developed relapse. The 10 year OS and PFS rates were 91% and 84%. In univariate analysis, a testicular tumor ≥5.5cm and a retroperitoneal metastases ≥16 cm were associated with poor OS and PFS. The prechemotherapy LDH levels ≥2.4xUNL and age ≤36 years showed a trend to shorter PFS. Multivariate analysis showed that only the retroperitoneal metastases ≥16 cm was significant independent prognostic factor for OS (p=0.04, HR 3.86; 95% CI, 1.03-14.41) and PFS (p=0.05, HR 3.17; 95% CI, 0.99-10.15). Age ≤36 years (p=0.03, HR 4.29; 95% CI, 1.12-16.34) was also an independent prognostic factor for PFS. Conclusions: The presence of a retroperitoneal metastases ≥16 cm, a testicular tumor ≥5.5cm and age ≤36 years are associated with decreased OS and/or PFS in patients who achieved a complete response to first line cisplatin based chemotherapy. The use of these factors may assist the elaboration and implementation of new prognostic models that can guide the follow-up and management of patients with advanced testicular seminomas.
Phase I/II trial of PD-1 antibody nivolumab with peptide vaccine in patients naive to or that failed ipilimumab.
Authors: Jeffrey S. Weber, Ragini Reiney Kudchadkar, Geoffrey Thomas Gibney, Ronald C. De Conti, Bin Yu, Wenshi Wang, Amod Sarnaik, Alberto J Martinez, Jodi Kroeger, Cabell Eysmans, Donna Gallenstein, Xiuhua Zhao, Ann Chen
Journal: Journal of Clinical Oncology (2013)

9011 Background: Nivolumab, an IgG4 fully human monoclonal antibody against checkpoint protein PD-1, is active in metastatic melanoma, renal cell and non-small cell lung cancer. It was administered with a multi-peptide vaccine to patients (pts) with unresectable melanoma who failed at least one regimen for metastatic disease and were ipilimumab naïve, or failed ipilimumab, to assess the toxicity and tolerability of the combination and perform correlative immune assays. Methods: Three cohorts of 10 HLA A0201 positive ipilimumab-naïve pts received nivolumab at 1, 3 or 10 mg/kg, then three additional cohorts of pts who had failed prior ipilimumab received nivolumab at 3 mg/kg: two cohorts of 10 pts each who were A0201 positive and had either grade 2 or less ipilimumab toxicity, or grade 3 dose limiting ipilimumab toxicity; finally 40 pts were treated with antibody who had grade 2 or less ipilimumab toxicity and were not HLA restricted. Pre-treatment archived tumor tissue as well as pre- and post-treatment peripheral blood cells were collected. Results: Median age for all pts was 59;76% were M1c. Response rates by RECIST were 28% in 34 pts naïve to, and 32% for 46 pts who failed prior ipilimumab. Nivolumab did not induce the same irAEs in pts with prior ipilimumab induced toxicity. No cohort had more than one dose limiting toxicity. 2 pts had grade 3 pneumonitis. Three of ten pts who failed nivolumb had stable disease or a partial response to subsequent ipilimumab. Biomarker studies showed that elevated NY-ESO 1 and MART-1 specific CD8 T cells pre-treatment were associated with non-response (p&lt;0.005 and &lt;0.001), and that CTLA-4 positive CD4 T cells and T regulatory cells were elevated after treatment in non-responders (p&lt;0.01). Immunohistochemical analysis of pre-treatment tumors indicated that PD-L1 staining was associated with response, but responses were also observed in pts whose tumors did not stain. Conclusions: Objective responses to nivolumab were observed after failing ipilimumab, and to ipilimumab after failing nivolumab. Elevation of CTLA-4 after nivolumab in non-responders suggest that sequential therapy with the combination should be tested. Tumor PD-L1 was associated with but not predictive of response. Clinical trial information: NCT01176461.
Accuracy of FDG-PET to diagnose lung cancer in the ACOSOG Z4031 trial.
Authors: Eric L. Grogan, Stephen A Deppen, Karla V. Ballman, Gabriela Maria Andrade, Francys C Verdail, Melinda C Aldrich, Heidi Chen, Paul A. Decker, David Harpole, Robert Cerfolio, Robert Keenan, David R Jones, Thomas A. D'Amico, Joseph B Shrager, Bryan F Meyers, Joe B. Putnam
Journal: Journal of Clinical Oncology (2012)

7008 Background: Fluoro-deoxyglucose positron emission tomography (FDG-PET) is recommended for diagnosis and staging of known or suspected NSCLC. Meta-analyses examining the accuracy of FDG-PET to diagnose lung cancer demonstrated high sensitivity 94% and specificity 83% but were performed in select centers. The purpose of this study is to evaluate the accuracy of FDG-PET to diagnose NSCLC and examine enrolling site differences in the national prospective ACOSOG Z4031 trial. Methods: 1,074 patients with clinical stage I (cT1-2N0M0) known or suspected NSCLC were enrolled between 2004 and 2006 in the Z4031 study and underwent surgical resection. The final diagnosis was determined by pathological examination. FDG-PET results were abstracted from radiology interpretations included in the case report forms. FDG-PET avidity was categorized based on either radiologist description or reported maximum standard uptake value (SUV). The four categories were: not avid and not cancerous (SUV=0), low avidity and likely not cancerous (SUV&gt;0 and &lt;2.5), avid and probably cancerous (SUV&gt;2.5 and &lt;5) and highly avid and likely cancerous (SUV&gt;5). Sensitivity analysis of FDG-PET diagnostic accuracy was performed for varying levels of avidity and by preoperative lesion size. Differences in accuracy by enrolling site were examined. Results: There were 51 enrolling sites in 39 cities with 969 eligible participants. Preoperative FDG-PET results were available for 682 participants. Lung cancer prevalence was 83%. FDG-PET sensitivity was 82% (95% CI: 79-85), and specificity was 31% (95% CI: 23-40). Positive and negative predictive values were 85% and 26%, respectively and accuracy improved with lesion size. There were 80 false positive scans and 69% were granulomas. False negative scans occurred in 101 patients (11were ≤10mm) with adenocarcinoma, squamous, bronchoalveolar cell and neuroendocrine tumors responsible for 64%, 12%, 10% and 8% of false negative results, respectively. Specificity did not differ between the 8 sites with &gt;25 patients (p=0.74). Conclusions: In a national surgical population with clinical stage I NSCLC, FDG-PET to diagnose lung cancer performed poorly compared to published studies. Reasons for poor test performance should be explored.