tbuckley/cabot-search huggingface dataset:
A finalized phase II report of pemetrexed (P) plus gemcitabine (G) as front-line chemotherapy for patients with peritoneal mesothelioma (PM)
Authors: G. R. Simon, P. A. Janne, C. Langer, V. Clarie, A. Dowlati, S. M. Gadgeel, K. Kelly, Z. Ye, C. K. Obasaju, K. E. Hood, H. L. Kindler
Journal: Journal of Clinical Oncology (2006)

2050 Background: P in combination with cisplatin is approved for the treatment of malignant pleural mesothelioma. In an expanded access program, P ± cisplatin was shown to have activity in PM. P plus G are synergistic in preclinical models, but the activity of this combination in PM is unknown. The primary objective of this study was to determine time to disease progression in pts with PM receiving P plus G. Methods: Twenty pts were accrued. Treatment consisted of G 1250 mg/m 2 /30 minutes on D 1 and 8, and P 500mg/m 2 /10 minutes on D 8, immediately before G. Treatment was repeated every 21 days for a total of 6 cycles or until progressive disease. All received folic acid, vitamin B12 and steroid prophylaxis. Results: Median age was 67.5 years (range: 46–79). Histology was epithelial:other = 14:6, M:F = 15:5, and ECOG PS 0:1:2 = 9:6:4. A total of 93 cycles (median 6) were administered. Patient-specific Grade 3/4 hematologic toxicity included neutropenia (60.0%), febrile neutopenia (10%; including one toxic death), anemia (5%), and thrombocytopenia (0%). Grade 3/4 nonhematologic events were fatigue (20.0%), constipation (10.0%), diarrhea (5.0%), peripheral neuropathy (5.0%), and dyspnea (5.0%). Median relative dose intensity was 94.5% for P and 82.9% for G respectively. Investigator-reported response rate was 15% (95% CI: 3.2–37.9%) with 1CR, 2PR, 7SD, 7PD, and 3 Unknown. Median time to progressive disease (MTTPD) and median survival (MS) were and 16.5 months (95% C: 6.6-TBD) and 19.1 months (95% CI: 6.6-TBD) respectively. Conclusions: P plus G is well tolerated in patients with PM. The clinical benefit rate (PR + SD) of 50%, MTTP and MS suggest that this non-platinum doublet can be a reasonable alternative to a platinum doublet in this disease. [Table: see text]
Outcome of Patients with Peripheral T-Cell Lymphoma Undergoing Allogeneic Stem Cell in British Columbia
Authors: Musa Alzahrani, Kerry J Savage, Cynthia L. Toze, Laurie H Sehn, Raewyn Broady, Yasser Abou Mourad, Michael J Barnett, Donna L. Forrest, Alina S Gerrie, Donna E. Hogge, Stephen H. Nantel, Sujaatha Narayanan, Thomas J. Nevill, Maryse M Power, David Sanford, David W. Scott, Heather J. Sutherland, Diego Villa, Hilary O'Leary, Joseph M. Connors, Kevin W. Song
Journal: Blood (2016)
The prevalence of cachexia among patients with solid and hematologic malignancies at a National Cancer Institute (NCI)-designated cancer center in the 12 months prior to death.
Authors: Egidio Del Fabbro, Nevena Skoro, Brian Cassel
Journal: Journal of Clinical Oncology (2014)

e20642 Background: An international consensus definition characterizes cancer cachexia as a multifactorial syndrome with loss of lean body mass and progressive functional impairment. The core criterion for diagnosis is weight loss >5%; or a Body Mass Index (BMI) <20 with weight loss >2%. Because of high prevalence of obesity in the general population, few patients are underweight at diagnosis and cancer cachexia may be under-recognized. Anti-cachexia therapy may be less effective when initiated towards the end of life. Our goal was to determine the prevalence of cachexia among solid (SC) and hematological cancer (HC) decedents using weight loss and BMI criteria, at a NCI designated cancer center. Methods: Social Security Death Index data were linked to our health system's electronic medical records. A retrospective review was performed of all 2471 adult cancer decedents seen at our institution in the 12 months before death, between July 2009 and June 2012. 1891 patients had ≥2 weight measures and were included in the analysis. Patients' height, weight, body mass index and albumin were analyzed relative to date of death from both outpatient clinic and inpatient records. Descriptive statistics and odds ratios were calculated. Results: 8 months prior to death, 52% n=289 of patients were overweight or obese by BMI. 41% n=42 of patients with HC had >5% weight loss compared to 27% n=114 with SC (OR= 1.93, 95% CI 1.23-3.02).A higher proportion of hypoalbuminemia was found in HC than SC (42% vs 29%). At 6 months, 36% n=192 with SC met the criterion for cachexia, and 40% n=46 with HC. At 3 months, almost half the patients in each group (48 %, n=65 and 45%, n=322) had weight loss consistent with cachexia. In the final month of life, patients with HC were less likely to have experienced weight loss (OR 0.65, CI 0.48-0.89) than those with SC, and more SC patients had an underweight BMI (17%, n=142 vs 6%,n=12, OR 3.23, CI 1.76-5.95). Conclusions: There is a high prevalence of weight loss consistent with cachexia in both SC and HC, although more than half of patients are overweight/obese at baseline. Depending on the interval to death, cachexia prevalence varies between HC and SC patients.
Detecting characteristics of nodal invasion in advanced squamocellular oral cavity cancer through a gene expression profile on primary tumor.
Authors: Loris De Cecco, Federica Perrone, Barbara Cortelazzi, Salvatore Alfieri, Laura Pala, Laura D. Locati, Marco Giannoccaro, Silvana Pilotti, Silvana Canevari, Lisa F. Licitra, Paolo Bossi
Journal: Journal of Clinical Oncology (2015)

e17069 Background: In oral cavity squamocellular cancer (OCSCC), the nodal/extranodal extension of disease is not easily discovered by clinical and radiological exams. We evaluated if a gene-expression (GE) signature from specimens obtained on primary tumor (T) could predict for nodal status. Methods: A series of archival specimens from patients with stage III-IV OCSCC treated with surgery at T and N level as first treatment from 1989 to 2008 was collected. The histological samples were randomly chosen to have an adequate number of cases with pathological negative nodes (pN0), positive nodes with (pN+ECS+) or without (pN+ECS-) extracapsular extension. The histological specimens of primary disease (T) were microdissected to obtain one sample from the central area of the tumor (pTcent) and one from the peripheral area (pTperiph). The samples of primary tumors were profiled for GE on DASLwg Illumina BeadChips. Pathway analysis was performed through GSEA v2.0.14. Results: We included 87 patients in the analysis (pN0 = 34; pN+ECS- = 24; pN+ECS+ = 29). GE profile resulted in a data matrix containing 17,138 detected genes. Imposing a significance threshold of false discovery rate (FDR) < 10%, we found patterns of differentially expressed genes comparing pN0 with pN+ and pN+ECS- with pN+ECS+. Interestingly, the differences in GE were much greater in pTperiph compared to pTcent. To gain further insight into the biologic pathways involved in pTperiph samples, GSEA analysis was performed between pN+ECS+ and pN+ECS-. We then applied an enrichment map tool allowing the visualization of coherent clusters of enriched gene sets. The analysis revealed that 206 and 40 gene sets are enriched at q-val < 0.25 in pN+ECS+ and pN+ECS-, respectively. The most significant pathways enriched in ECS+ include immune response, positive regulation of cell proliferation and cell cycle, negative regulation of apoptosis, while ECS- cases show enrichment in pathways linked to cell signaling. Conclusions: Different GE patterns on pTperiph samples of primary tumor are useful to predict nodal status in OCSCC. *Acknowledgment: Italian Ministry of Health call “Ricerca Finalizzata” (Project code: GR -2009 -1492184)
Evaluation of <i>CYP3A5, VEGF-a</i>, and <i>VEGFR2</i> polymorphisms as markers of sunitinib toxicity.
Authors: Cristina Rodriguez de Antona, Enrique Grande Pulido, Lj Leandro-Garcia, Jorge Barriuso, Jaume Capdevila, Paula Jimenez, Beatriz Castelo, Daniel E. Castellano, Federico Longo, Jesus Garcia-Donas
Journal: Journal of Clinical Oncology (2012)

10546 Background: Sunitinib (Sun) is a multitargeted tyrosine-kinase inhibitor approved for the treatment of renal cell carcinoma (RCC), GIST and pancreatic neuroendocrine tumors (pNETs). It is known that a polymorphism in Sun metabolizing gene CYP3A5, was associated with an increased risk of dose reductions due to toxicity (tox). Additionally, polymorphisms in VEGF-A and VEGFR2 were suggested to increase the risk of hypertension (HT) during treatment (García-Donas, et al. Lancet Oncol 2011). These data have not been validated so far. We aim to assess the value of these polymorphisms as markers of tox using a wide range of solid tumors treated with Sun. Methods: In this non-interventional and retrospective study, DNA was collected from 28 patients with different pathologies (16 pNETs, 5 medullary thyroid carcinomas, 2 NETs of the lung, 2 undifferentiated follicular carcinomas, 1 undifferentiated papillar carcinoma, 1 GIST, and 1 carcinoid of the rectum) treated with Sun in a daily practice setting. Genotyping for CYP3A5*1 allele (rs776746), VEGF-A -2578C&gt;A (rs699947) and VEGFR2 Q472H (rs1870377) was performed. Associations between the genotypes and Sun dose reductions and HT were performed using univariable analyses. Results: In agreement with previous reports, we found that VEGF-A rs699947 conferred a statistically significant increased risk of developing HT during treatment (HR=9.8, 95%CI=1.2-82.0, P=0.034). CYP3A5*1 high metabolizing allele showed a trend towards the increase in the risk of Sun dose reductions due to tox (HR=2.4, 95%CI=0.8-6.8, P=0.11) with a median time to dose reduction of 7.0 months for wild type homozgygous patients and 4.6 months for heterozygous patients. A trend was also found on the relation between VEGF-A rs699947 A/A patients (HR=3.8, 95%CI=0.8-16.8, P=0.080) and dose reduction risk. No significant associations were found for VEGFR2 rs1870377. Conclusions: The present study suggests that VEGF-A rs699947 is a risk factor for Sun HT and has a role in other tox leading to dose reductions. Similarly, CYP3A5*1 shows a trend towards an increased risk of Sun dose reductions. If confirmed, these markers could be used to identify a subset of patients with an increased risk of Sun toxicity.
A unique gene expression signature in tumor positive or negative sentinel lymph nodes in patients with melanoma.
Authors: Ahmad A. Tarhini, Yan Lin, Hui-Min Lin, William A LaFramboise, Uma N. M. Rao, Hussein Abdul-Hassan Tawbi, Madeeha Ashraf, James F. Pingpank, Matthew Peter Holtzman, Christin Sciulli, Cindy Sander, John M. Kirkwood
Journal: Journal of Clinical Oncology (2014)

9087 Background: Molecular characterization through gene expression (exp) profiling of node positive and node negative sentinel lymph nodes (SLNs) in patients with clinical stage I-II melanoma may improve the understanding of mechanisms of metastasis and identify gene signatures for SLN+/SLN- that correlate with clinical outcome. Methods: Gene exp profiling was performed on SLN biopsies of 48 (24 SLN+, 24 SLN-) patients (T3a/b, T4a/b) who underwent SLN for staging using transcriptome profiling analysis on 5μ sections of fresh LN. U133A 2.0 Affymetrix gene chips were used. SAMR used to test the association between gene exp level and SLN status. Genes with fold change>1.5 and q value <0.05 were considered differentially expressed. Pathway analysis was performed using Ingenuity Pathway Analysis. Benjamini and Hochberg method was used to adjust for multiple testing in pathway analysis. Results: We identified 45 significantly increased transcripts (1.5-27 fold). Upon pathway analysis, 25 genes were commonly significantly expressed among the most significant and biologically relevant canonical pathways. Top pathways and associated genes were notably related to melanoma microenvironment and signaling pathways implicated in immunosuppression and development of cancer. Conclusions: Gene exp profiling identified pathways enriched with genes significantly differentially expressed in SLN+ vs SLN-. These findings warrant investigation in relation to diagnosis and prediction of outcome. Select top pathways and associated genes. Pathway Adjusted P value Mitotic roles of polo-like kinase 0.0000 DNA damage-induced 14-3-3 sigma signaling 0.0001 G2/M DNA damage checkpoint regulation 0.0001 Cyclins and cell cycle regulation 0.0012 Eumelanin biosynthesis 0.0023 Melanocyte development signaling 0.0096 Role of CHK in cell cycle checkpoint control 0.0199 Antiproliferative role of TOB in T cell signaling 0.0401 p53 signaling 0.062 Genes: BIRC5, CCL20, CCNA2, CCNB1, CCNB2, CCNE2, CDC20, CDC6, CDK1, CHEK1, DCT, KIF11, KIF23, MCM4, PRC1, RFC3, RRM2, SERPINE2, SGK1, SOX10, TOP2A, TTK, TYMS, TYR, TYRP1
Prognostic Value of Complex Karyotype and Monosomal Karyotype in Patients with Adult Acute Lymphoblastic Leukemia Treated with Risk-Adapted Protocols
Authors: Cristina Motlló, Josep-Maria Ribera, Mireia Morgades, Isabel Granada, Javier Grau, Pau Montesinos, José González-Campos, Pascual Fernández-Abellán, Mar Tormo, Concha Bethencourt, Salut Brunet, Jesús M Hernández-Rivas, MJ Moreno, Jose Sarra, Eloy Del Potro, Pere Barba, Teresa Bernal, Maria-Luz Amigo, Carlos Grande, Arancha Bermudez, Ramon Guardia, Andrés Llorente, Maria Jesús Peñarrubia, Jesús Arias, Miguel Angel Sanz, Evarist Feliu
Journal: Blood (2012)
Clinical Outcomes of Patients with Newly Diagnosed Multiple Myeloma Receiving Triplet Therapy in the Connect MM® Disease Registry
Authors: Jatin J. Shah, Rafat Abonour, Mohit Narang, Jayesh Mehta, Howard R. Terebelo, Cristina J Gasparetto, Kathleen Toomey, James W Hardin, Shankar Srinivasan, Gail Larkins, Yasir Nagarwala, Robert M. Rifkin
Journal: Blood (2015)
Association of clinical and nutritional factors with treatment related toxicity of “fixed standard dose” of afatinib in patients with advanced NSCLC.
Authors: Oscar Arrieta, Martha de la Torre, Dana Pérez, Jenny Turcott, Eva Juárez, Karla Sanchez-Lara, Diego López
Journal: Journal of Clinical Oncology (2013)

e19068 Background: Afatinib, an irreversible tyrosine kinase inhibitor of ErbB-family, has shown clinical benefits and prolonged progression free survival in EGFR mutated patients. Adverse effects related to afatinib such as diarrhea, stomatitis and rash can negatively impact on QoL and survival by interrupting treatment. Dose of TKI´s of EGFR are fixed regardless of weight or body surface (BS), which could affect the severity of treatment related toxicity. Methods: We prospectively studied patients with advanced NSCLC treated with afatinib in order to determine if malnutrition and clinical factors are associated to higher incidence of severe toxicity. Prior treatments with afatinib 40mg, 78 patients were assessed. Nutritional status was assessed by Subjective Global Assessment (SGA), and toxicity was obtained during 2 cycles by CTCAE 4.0, severe toxicity is defined as grades 3 and 4. Results: Mean age was 59.2 years, 71.8% were women, 89.7% had adenocarcinoma, 76.9% had a good performance status (ECOG 0-1), and median weight and BS were 59.9kg and 1.58m 2 . Sixty percent of patients had some grade of malnutrition (SGA B+C). Factors associated to severe diarrhea, mucositis and other gastrointestinal toxicity are shown in Table 1, no factors were found to be associated with the development of severe rash. Conclusions: The performance status, malnutrition and body surface are independent factors related to severe gastrointestinal toxicity to Afatinib. This study suggests that for the initial dose selection of TKI´s of the EGFR these factors should be considered in order to reduce the risk of severe toxicity.
Antitumor Activity of Human CD34+ Cells Expressing Membrane-Bound Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (mTRAIL).
Authors: Carmelo Carlo-Stella, Cristiana Lavazza, Massimo Di Nicola, Loredana Cleris, Paolo Longoni, Marco Milanesi, Michele Magni, Daniele Morelli, Annunziata Gloghini, Antonino Carbone, Alessandro M. Gianni
Journal: Blood (2006)
Compassionate use of bedaquiline in highly drug-resistant tuberculosis patients in Mumbai, India
Authors: Zarir F. Udwadia, Shashank Ganatra, Jai B. Mullerpattan
Journal: European Respiratory Journal (2017)

Bedaquiline, a mycobacterial ATP synthase inhibitor [1], is the first new tuberculosis (TB) drug in almost 50 years. So far, over 800 patients have received the drug globally through compassionate use (CU) programmes. Drug-resistant TB has emerged as global public health priority [2] and TB strains are being reported with increasing levels of resistance, such as those that are multidrug resistant (MDR), extensively drug resistant (XDR) and beyond [2–4]. India bears the burden of the largest number of MDR cases in the world [2] and alarming patterns of resistance are frequently encountered in urban hot-spots like Mumbai, including the first Indian cases resistant to all first-line drugs and second-line drugs (SLDs) [5]. Several studies around the world have shown increased treatment efficacy after addition of bedaquiline to optimised background regimens (OBRs) [6–8]. In such settings, newer drugs like bedaquiline are urgently needed; however, accessing them has proven to be challenging in India. Of the 76 applications received from India, no more than 52 Indian patients throughout the country have received bedaquiline under the CU programme (personal communication: Janssen Pharmaceuticals, India, August 2, 2016). At the P.D. Hinduja hospital, a large private hospital in Mumbai, we have been treating patients with MDR-TB for the last two decades [9]. Between January 2013 and September 2015, 27 patients with drug-resistant TB strains were considered for bedaquiline. Applications for all 27 patients were made to the Janssen pharmaceuticals CU programme and, of these, 20 were approved and bedaquiline was administered. The resulting cohort is the largest in India to have received bedaquiline (20 patients from a countrywide total of 52). Bedaquiline was considered for patients based on the clinical judgement of the treating physician and there was no consultation with any panel of experts or TB consilium at this stage. Bedaquiline is a promising new drug treatment for drug-resistant TB. Urgent access is required in selected centres http://ow.ly/o1l73074ugh
Protein S-100β serum levels predicts clinical outcome of high-risk melanoma patients treated with high-dose adjuvant interferon alfa2b
Authors: X. Garcia-Albeniz, J. Domingo-Domenech, J. Auge, R. Molina, S. Puig, J. Malvehy, M. Mármol, P. Gascón, B. Mellado, T. Castel
Journal: Journal of Clinical Oncology (2007)

8543 Background: S-100β serum levels have been shown to be useful to monitor response to therapy in metastatic melanoma patients. We have recently reported that S-100β levels could also be useful in the adjuvant context. In this study we analyze the clinical relevance of S-100β serum levels in an homogeneuos stage IIB-III group of patients treated with high-dose interferon. Methods: Patients with melanoma diagnosis were prospectively tested for serum S-100β protein by luminoimmunometric assay (LIA) before starting interferon (baseline) and every 3 months thereafter (on.therapy), until treatment was completed. Median time to progression and overall survival were assessed. Multivariate analysis using the Cox proportional hazards model with covariable dependent on time was perfomed since S-100β under therapy changes during time. Results: Ninety-seven patients were included. Median follow-up was 62.9 months (range 32.7–87.4). Median baseline S-100β levels were 0.06μg/l (range 0.06–0.53). S-100 was considered high (=0.15 μg/l) in 20.6% of the patients. High baseline S-100β levels were associated with positive lymph-node status (p=0.02). High S-100β levels (while on therapy) showed relation with positive lymph-node status (p=0.014), number of positive lymph-nodes (p=0.01), macroscopic lymph-node involvement (p=0.002) and second melanoma diagnosis at study entry (p=0.001). By univariate analysis, high baseline S-100β levels were associated with disease free survival (DFS) (p=0.004) and overall survival (OS) (p=0.0007). Similarly, high on therapy S-100β levels were associated with DFS (p&lt;0.0001) and OS (p&lt;0.0001). In the multivariate analysis, high on therapy S-100β levels (HR 1.029, CI95% 1.015–1.042; p&lt;0.0001) was an independent prognostic factor for DFS. High on therapy S-100β levels (HR 1.017, CI 95% 1.10–1.026; p&lt;0.0001) and high baseline S-100β levels (HR 3.31, CI 95% 1.10–9.89; p=0.032) were independent prognostic factors for OS. Conclusions: These results provide novel evidence of the clinical usefulness of serum S-100β levels determination for monitoring the clinical outcome of high-risk melanoma patients treated with adjuvant therapy. No significant financial relationships to disclose.
Results of a randomized phase II trial of an anti-notch 2/3, tarextumab (OMP-59R5, TRXT, anti-Notch2/3), in combination with nab-paclitaxel and gemcitabine (Nab-P+Gem) in patients (pts) with untreated metastatic pancreatic cancer (mPC).
Authors: Eileen Mary O'Reilly, Vaibhav Sahai, Johanna C. Bendell, Andrea J. Bullock, Noelle K. LoConte, Hassan Hatoum, Paul S. Ritch, Hugo Hool, Joseph W. Leach, James Sanchez, Davendra Sohal, John H. Strickler, Ravindranath Patel, Andrea Wang-Gillam, Irfan Firdaus, Ann M. Kapoun, Eric Holmgren, Lei Zhou, Jakob Dupont, Vincent J. Picozzi
Journal: Journal of Clinical Oncology (2017)

279 Background: Tarextumab (TRXT), fully human IgG2 antibody inhibits signaling of Notch2/ 3 receptors. Tumor regression seen in Notch3 (N3) expressing pt-derived pancreatic cancer xenografts when TRXT combined with Nab-P+Gem. Phase 2, randomized, placebo-controlled trial conducted to evaluate efficacy, safety of combination in mPC. Methods: Pts randomized 1:1 to TRXT or placebo (PL). TRXT given IV at 15 mg/kg q 2wks (D 1, 15), nab-P 125 mg/m 2, GEM 1000mg/m 2 on D1, 8, 15 q 28 days. Tissue for N3 gene expression determination was required. Primary endpoints: overall survival (OS) in all and in 3 subgroups determined by Notch 3 gene expression. Secondary: safety, progression-free survival (PFS) and overall response rate (ORR). Results: N = 177 pts randomized. Performance status (0 or 1), CA19-9 stratum (0 – ULN, &gt; ULN – 59ULN, ≥ 59ULN) balanced. Clinical trial information: NCT01647828. . Conclusions: Addition of TRXT to Nab-P+Gem did not improve OS in 1st line mPC. A potential detrimental effect on PFS and ORR was seen in subjects with N3 &lt; 25%ile.[Table: see text]