tbuckley/cabot-search huggingface dataset:
Somatic copy number abnormalities (SCNAs) and mutations in PI3K/AKT pathway and prognostic significance for overall survival (OS) in platinum-treated locally advanced or metastatic urothelial cancer (UC).
Authors: Joaquim Bellmunt, Lillian Werner, Markus Riester, Paul Van Hummelen, Jonathan E. Rosenberg
Journal: Journal of Clinical Oncology (2014)

358 Background: An integrative analysis was conducted to identify genomic alterations and mutational status on the gene pathway level that could predict OS in patients (pt) with UC treated with platinum chemotherapy. Methods: DNA was extracted from 94 FFPE samples from invasive UC and screened for mutations and CNAs. Of those, complete clinical data was available from 85 cases. Mutations in the cancer genome were analyzed by a mass-spectrometry based genotyping platform (Oncomap version 3) and genomic imbalances were detected by comparative genomic hybridization (CGH) analysis. Regions with threshold of log2 ratio ≥0.4, or ≤ -0.6 were defined as either having copy number gain or loss and significantly recurrent CNAs across the set of samples was determined using a GISTIC analysis. To better define the co-occurrence pattern of mutations and CNAs, we grouped genes into 3 core signal transduction pathways: (1) TP53 pathway; (2) Abnormalities of in the RTK-RAS-RAF pathway including either ERBB2, FGFR3, MET, FGFR1, KRAS BRAF, RAF1 and NF1; (3) abnormalities on PI3K/AKT pathway including PTEN, PIK3CA, AKT1, TSC1, and MTOR. OS was measured from treatment to time of death or censored. Cox regression was used to assess pathways abnormalities and mutations with outcome. Results: Thirty five samples (41%) harbored mutations on at least one gene, mainly TP53 (16%), PIK3CA (9%), FGFR3 (2%), HRAS/KRAS (5%), and CTNNB1 (1%). Sixty-six per cent of patients had some sort of copy number variation. PI3K/AKT was the most affected pathway and was associated with shorter overall survival (hazard ratio (HR) =2.3 with 95% CI: 1.3 to 4.2). There was no significant association between mutational status and OS. Combined analysis of SNCA and mutations in the same pathway will be presented. Conclusions: Patients with advanced urothelial cancer receiving platinum chemotherapy have a significantly poor survival which correlated with copy number abnormalities in the PI3K/AKT pathway. This can help to identify patients that can benefit from targeted pathway specific agents.
The relationship between common EGFR, b-raf, k-ras mutations, and prognosis in advanced-stage NSCLC with response to the treatment.
Authors: M. Dogan, A. Demirkazik, A. Tukun, H. Akbulut, S. Dizbay Sak, K. Ceyhan, B. Yalcin, F. Icli
Journal: Journal of Clinical Oncology (2011)

e18075 Background: Epidermal growth factor receptor (EGFR) mutations are common in NSCLC and they are predictive in EGFR tyrosine kinase inhibitor treatment. K-ras mutation is associated with poor prognosis in NSCLC, however role of b-raf mutation is not so clear. The aim of the study was to evaluate EGFR (exon 19 deletion, exon 21 L858R point mutation), k-ras and braf mutation rates besides their relationship with survival and response to the treatment. Methods: We evaluated 513 NSCLC patients followed-up between January 2004 and November 2009 according to our registration data, retrospectively. Only 42 advanced stage NSCLC patients had enough tumor tissue material in paraffin blocks for all mutation analysis. These 42 advanced stage NSCLC patients were enrolled to the study. They were evaluated for clinicopathological features, EGFR, k-ras and b-raf mutations, erlotinib treatment, time to progression (TTP) and overall survival (OS). Results: Mutation rates were as 7.14% for EGFR exon 19 deletion; 4.76% for k-ras codon 61 deletion and 2.38% for b-raf V600E mutation. Median folow-up was 26 months (5-83) for all patients. It was 43 months (23-83) for the patients who had erlotinib and 23 months (5-61) for those who did not. Ten (23.8%) patents had erlotinib. Two patients had EGFR exon 19 deletion and one patient had k-ras mutation among these patients. They had neither EGFR exon 21 point mutation nor different mutations together. There was significant survival difference between the patients taking erlotinib and the others (28 + 3 months versus 15 + 4 months, p=0.05). TTP and OS were longer in the patients who had mutations, however the difference was not significant (p=0.119 and p=0.06). Conclusions: This is the first study evaluating EGFR, k-ras and braf mutations in advanced stage NSCLC in our country. Survival of the patients who had erlotinib was longer.
Impact of imatinib plus best supportive care in imatinib- and sunitinib-exposed patients with refractory advanced gastrointestinal stromal tumor.
Authors: A. Sawaki, T. Kanda, Y. Komatsu, T. Nishida
Journal: Journal of Clinical Oncology (2010)

10064 Background: This retrospective non-randomized study investigated the effect on survival of imatinib (IM) plus best supportive care (BSC) after IM and sunitinib (SU) treatment for pts with locally advanced or metastatic gastrointestinal stromal tumor. Methods: 39 pts who had previously been exposed to both IM and SU and who were refractory to or intolerant of their latest therapy regimen were enrolled in this retrospective study. 13 pts were excluded due to participating in clinical trials. 26 pts were included in this study. Treatment regimen was BSC either with or without IM (400mg/day or less) according to pts selection. The primary endpoint was survival, and secondary endpoints were response rate assessed by CHOI and safety. Results: 14 pts were treated with IM and 12 were only BSC. Performance status (PS) at the termination of their latest therapy regimen was similar in both groups. Median dose of IM was 400 mg/day, and median duration of IM was 6 M. Median survival was greatly improved for IM pts although the overall difference in survival was marginally non-significant. (22M for IM and 4M for only BSC, p=0-059). Three pts (21%) were assessed as stable disease in IM group with no pts in the BSC group having a response of SD or better. IM was well tolerated, as in previous studies, and had little influence on PS. Conclusions: Treatment with IM may be associated with improvement in survival without deteriorating PS. Prospective study should be considered to confirm the efficacy of IM for pts with third-line or more treatment. No significant financial relationships to disclose.
Genomics of Multiple Myeloma
Authors: Sebastien Robiou du Pont, Alice Cleynen, Charlotte Fontan, Michel Attal, Nikhil Munshi, Jill Corre, Hervé Avet-Loiseau
Journal: Journal of Clinical Oncology (2017)

Multiple myeloma (MM) is characterized by wide variability in the chromosomal/genetic changes present in tumor plasma cells. Genetically, MM can be divided into two groups according to ploidy and hyperdiploidy versus nonhyperdiploidy. Several studies in gene expression profiling attempted to identify subentities in MM without convincing results. These studies mostly confirmed the cytogenetic data and subclassified patients according to 14q32 translocations and ploidy. More-recent data that are based on whole-exome sequencing have confirmed this heterogeneity and show many gene mutations but without a unifying mutation. These newer studies have shown the frequent alteration of the mitogen-activated protein kinase pathway. The most interesting data have demonstrated subclonality in all patients with MM, including subclonal mutations of supposed driver genes KRAS, NRAS, and BRAF.
Gemcitabine (G) fixed-dose-rate infusion (FDR) plus erlotinib (E) in patients with advanced pancreatic cancer (APC).
Authors: A. Munoz Llarena, J. Mane, G. Lopez-Vivanco, A. Ruiz de Lobera, A. Sancho, E. Iruarrizaga, M. Arruti, I. Marrodan, N. Fuente, D. Ballesteros
Journal: Journal of Clinical Oncology (2011)

304 Background: G (30-minute infusion) plus E improves survival in patients with APC compared with G alone. In a recent phase III trial, G-FDR showed a trend to better OS compared with standard G (6.2 vs. 4.9 months, HR 0.83, p=0.04), although the study was underpowered to detect great difference in OS. Based on our previous experience with G-FDR, we decided to evaluate the combination of G-FDR plus E, after E approval for APC. Methods: Patients with previously untreated pathologically confirmed APC, locally advanced (LAPC) or metastatic (MPC), and ECOG PS 0-2 were included. G 1500 mg/m 2 was given by 150-min infusion (10 mg/m 2 /min) on days 1, 8, and 15 every 28 days combined with E 100 mg/day orally. Treatment modifications for G-FDR were planned according with previously Tempero's phase II trial, and as described in prescribing information for E. Results: 62 pts were included (36M/26F), with a median age of 63 y-o (range 37-78). ECOG PS 0/1/2: 19/40/3. LAPC/MPC: 16/46. All except one had measurable disease. ORR was 13% (8 PR), 95% CI: 4.7-21.3, and there were 34 (55%) SD. Mean relative dose intensity for G was 0.76 and 0.90 for E. Main hematologic toxicities 3/4 per pt: anaemia 12/0, thrombocytopenia 7/4, neutropenia 18/7. Acneiform rash 1/2/3 occurred in 16/16/3 pts. Other relevant adverse events were (grade 2/3/4): diarrhoea 18/3/0, mucositis 5/1/0, infection 9/8/1, thrombosis 1/4/1 and vomiting 6/4/0. There were three treatment-related deaths (septic shock, cholangitis, and bilateral pulmonary embolism). Ten pts (all LAPC) received RT after ≤ 6 cycles, all with concomitant capecitabine 825 mg/m 2 bid. In 4 pts salvage surgery were performed: 2 R0, 1 R1 and 1 R2. Median PFS was 4.9 months (95% CI: 3-6.7), 7.9 m for LAPC and 2.5 m for MPC (p = 0.004). Median OS was 10 months (95% CI: 7.1-12.9), 17.5 m for LAPC and 7 m for MPC (p = 0.019). OS was significantly shorter in males (p = 0.01) and in pts taking major opioids (p = 0.027). There was a trend to better OS in pts who developed skin rash grade ≥ 2 (p = 0.078). Conclusions: In this noncomparative study, G-FDR plus E is a feasible regimen in APC with an acceptable toxicity and notable activity. G-FDR seems to increase hematologic toxicity compared with standard infusion. No significant financial relationships to disclose.
Coronary Artery Bypass Grafting With and Without Manipulation of the Ascending Aorta
Authors: Dong Fang Zhao, J. James Edelman, Michael Seco, Paul G. Bannon, Michael K. Wilson, Michael J. Byrom, Vinod Thourani, Andre Lamy, David P. Taggart, John D. Puskas, Michael P. Vallely
Journal: Journal of the American College of Cardiology (2017)
Late toxicity rates following definitive radiotherapy for prostate cancer: A meta-analysis revealing interactions between dose and technique.
Authors: N. Ohri, W. Shi, A. Dicker, T. N. Showalter
Journal: Journal of Clinical Oncology (2011)

4608 Background: Most patients survive many years following external beam radiotherapy (RT) for nonmetastatic prostate cancer and are therefore at risk for late treatment sequelae. The relationships between RT dose, treatment technique, and late toxicity rates are poorly understood. Here we perform a meta-analysis to characterize those effects. Methods: We performed a review of published series that report late gastrointestinal (GI) and genitourinary (GU) toxicity rates following definitive RT for prostate cancer using the RTOG Late Radiation Morbidity Scoring Schema. Univariate and multivariate analyses were performed to test RT technique, RT dose, pelvic irradiation, and androgen deprivation therapy (ADT) as predictors of moderate (grade ≥ 2) and severe (grade ≥ 3) GI and GU toxicity. Results: Seventeen published reports detailing the treatment techniques and toxicity outcomes of 32 patient series including a total of 11,567 patients were included in this analysis. Two-dimensional (2-D) RT was used in nine series, three-dimensional (3-D) RT was used in 17 series, and intensity-modulated radiotherapy (IMRT) or proton beam radiotherapy (PBRT) was used in six series. Median rates of moderate late toxicity were 16% (GI) and 18% (GU). For severe effects, these values were 2% (GI) and 3% (GU). Multivariate analysis revealed that, compared to series using IMRT/PBRT, the use of 3-D RT was associated with dose-dependent increases in severe GI and GU effects. Utilization of 2-D RT was also associated with increased severe GU toxicity. At a dose of 80 Gy, we estimate severe late toxicity rates of 9% with 3-D RT and 4% with IMRT/PBRT. Conclusions: Severe late toxicity is uncommon following definitive RT for prostate cancer. However, this analysis demonstrates that the use of advanced techniques such as IMRT or PBRT significantly reduces the incidence of severe late effects following dose-escalated RT for prostate cancer. Toxicity estimates with 80 Gy. Toxicity Grade 3D IMRT/PBRT GI ≥2 17% 17% GI ≥3 4% 2% GU ≥2 18% 18% GU ≥3 5% 2%
Uptake of recommendations for adequate nodal removal in colorectal cancer resection.
Authors: Daniel Jacob Becker, Mina Samir Erian Hanna, Eileen Carter, Joy Henderson, Michael L. Grossbard
Journal: Journal of Clinical Oncology (2013)

557 Background: The number of lymph nodes removed during colorectal cancer (CRC) resection is associated with overall survival. The National Cancer Institute published recommendations to remove at least 12 lymph nodes in 2001. Previous analyses noted that as of 2001 the majority of patients in the US had inadequate lymph node resection (&lt;12); geographic location is strongly associated with adequacy of lymph node resection. In this study, we examined the association between the year of cancer diagnosis and the number of lymph nodes removed between 2000 and 2008. Methods: We used the Surveillance Epidemiology and End Results (SEER) New Jersey cancer registry to identify patients diagnosed with stage I- III colon cancer from 2000 to 2008 who underwent resection and had lymph nodes removed. We used multiple linear regression to test for the independent association of year of diagnosis and the number of lymph nodes resected. We controlled for age at diagnosis, gender, race, tumor grade, tumor stage, and tumor location. Results: Our inclusion and exclusion criteria yielded 25,407 cases. The patients were 51% male, and 49% female; 48% had right–sided colon cancer, 29% had left–sided colon cancer and 23% had rectal cancer. The majority of the patients were white (87%); 25% had stage 1 CRC, 28% had stage 2 CRC, and 37% had stage 3 CRC. The mean number of lymph nodes removed was suboptimal in the year 2000 (11.4) but gradually rose to the recommended cut-off of 12 in 2002 and was 15.6 in 2008 (p&lt;0.0001 for comparison of 2000 and 2008). The regression confirmed the independent association of year of diagnosis and number of lymph nodes removed. For every 1 year increase in the year of diagnosis, keeping all covariates constant, there is an increase of 0.55 lymph nodes removed (p &lt; 0.0001). Higher grade, higher stage, female gender, and right colon tumors were also associated with increased lymph node removal. Conclusions: Between 2000 and 2008 in the New Jersey, there was a steady increase in the number of lymph nodes removed with CRC resection, reflecting an increased adherence to evidence-based guidelines and an improvement of cancer care.
The potential of shape-based treatment plan optimization for pancreatic IMRT treatments to spare organs at risk and allow for dose escalation to the tumor PTV.
Authors: S. F. Petit, B. Wu, M. Kazhdan, A. Dekker, P. Simari, R. Kumar, R. H. Taylor, J. M. Herman, T. McNutt
Journal: Journal of Clinical Oncology (2011)

316 Background: Due to the low dose tolerance of the organs at risk (OARs) in the abdomen the tumor dose for pancreatic cancer patient is restricted to 50-60 Gy in 1.8-2.0 Gy fractions when combined with chemotherapy. The goal of this study was to develop a system that can determine the minimal radiation dose to the OARs of each individual patient that is achievable while maintaining adequate tumor coverage. This could guide treatment planners to spare the OARs to the fullest extent. When the minimal doses to the OAR are achieved, the total plan can be upscaled until the normal tissue dose constraints are met, allowing for an increase in tumor dose without increased normal tissue toxicity. Methods: The minimal achievable dose to the OARs depends on its proximity to the planning target volume (PTV). The overlap volume histogram (OVH) was used to describe the spatial relation of each OAR to the PTV. A database of 33 patients, treated with IMRT, was queried to find the lowest achieved dose to an organ for any of the prior patients with less favorable PTV-OAR configurations than the current patient. This minimal dose must also be achievable for the OAR of the new patient. For 25 randomly chosen patients the lowest achievable dose to the liver and kidneys was predicted this way. Then the patients were replanned to verify if this dose could be achieved. The new plans were compared to the original clinical plans. Results: After replanning the predicted achievable dose to the liver was realized within 1 and 2 Gy for more than 86% and 96% of the patients respectively. For the kidneys these numbers were 83% and 96%. The average improvement in terms of mean dose was 1.4 Gy (range 0 – 4.6 Gy) for the liver and 1.7 Gy (range 0 – 6.3 Gy) for the kidneys. This would have allowed an increase in PTV dose of on average 5 Gy (range 0-13 Gy) based on the liver and 8.5 Gy (range 0-38 Gy) based on the kidneys compared to the original plan, without an increase in dose to the bowel, cord, and stomach. Conclusions: The lowest achievable dose to the OARs could accurately be predicted for pancreatic cancer patients within seconds. This can guide dosimetrists to spare the OARs or increase the PTV dose by 5 Gy without increased toxicity. [Table: see text]
Role of XPA, ERCC1, mtTFA on the survival of patients with metastatic germ cell tumors of testis treated with cisplatin
Authors: C. H. Hernandez
Journal: Journal of Clinical Oncology (2008)

5090 Background: Advanced Testis Germ Cell Tumors (TGCT) are treated with platinum based chemotherapy. It has been proposed that DNA repair proteins play a role in the TGCT response to cisplatin. DNA repair deficiencies have been related with better treatment response; such deficiencies could be the result of polymorphisms on DNA repair genes or of the presence of High Mobility Group Proteins B (HMGB). Thus we have investigated whether the presence of XPA, ERCC1 and HMGB (mtTFA), as well as the polymorphism C8092A of the ERCC1 gene may influence the survival of TGCT patients treated with cisplatin. Methods: ERCC1, XPA and mtTFA were detected by immunohystochemistry using tissue microarrays in 58 samples from normal and neoplastic tissue. ERCC1 C8092A polymorphism was determined on DNA isolated from blood and paraffin-embedded tumor samples by PCR/RFLP´S. The results were associated with survival and response. Results: Only 58 full filled the inclusion criteria. The age-media was 23 years. According to the Royal Marsden stratification, stages IB, II, III and IV showed a frequency of 6.8, 46.5, 8.7 and 38% respectively. The lung (89.7%), mediastine (34.5%) and lymphatic nodes (10.3%) were the most frequent sites for metastases. Prognosis was approached by evaluating three groups: good (25.9%), medium (36.2%) and poor (37.9%). Global survival median was 60 months. Patients presenting samples XPA-negative had a four-years survival of 62% compared to 23% observed in patients (p=0.04). The presence of the A allele of ERCC1 C8092A polymorphism was related with an increased survival (p=0.07). Eighty percent of patients carrying at least one allele A responded to treatment, compared to those individuals with genotype CC, which only 20% of them responded (p=0.023). Conclusion: This is the first study that evaluates XPA, ERCC1 y mt-TFA in TGCT patients treated with cisplatin. XPA absence was related with a better response to cisplatin-based chemotherapy and an increased survival, suggesting an important role of this protein in the nucleotide excision repair pathway. Carrying the ERCC1 C8092A polymorphic allele promotes resistance to cisplatin treatment in TGCT patients. No significant financial relationships to disclose.
Survival of upper tract urothelial carcinoma: A population-based analysis.
Authors: Sima P. Porten, Vancheswaran Gopalakrishnan, Graciela M. Nogueras-Gonzalez, Ashish M. Kamat, Arlene O. Siefker-Radtke, Colin P.N. Dinney, Surena F. Matin
Journal: Journal of Clinical Oncology (2013)

257 Background: Urothelial carcinoma involving the upper tract (UTUC) accounts for only 5% of urothelial malignancies; thus the majority of data are from single institution series or highly selected patient populations. We sought to examine contemporary trends in overall (OS) and disease-specific survival (DSS) for UTUC using a large, population based dataset. Methods: Patients within the Surveillance, Epidemiology, and End Results (SEER) database with de novo UTUC from 1973-2008 were included and analyzed in 5 year increments to evaluate disease trends. Univariate and multivariate for OS and DSS competing risks analysis were performed adjusting for age, gender, and race for renal pelvis and ureteral tumors. Results: A total of 14,237 patients met inclusion criteria. For renal pelvis tumors (n=9,318), overall survival was 54.4% at 3 years. On multivariate analysis factors that were significant predictors of OS were: age (HR 1.03, p&lt;0.001), and year of diagnosis (HR 1.32, p&lt;0.001). Competing risks regression estimated DSS of 60.5% at 5 years, with male gender, black race, and year of diagnosis remaining significant after adjusting for covariates (p&lt;0.05). For ureteral tumors (n=4,919), overall survival was 56.1% at 3 years. On multivariate analysis, age was a significant predictor of OS (2.73, 95%CI 2.52-2.93, p&lt;0.001). Competing risks regression estimated DSS of 61.9% at 5 years, with female race, and year of diagnosis remaining significant after adjusting for covariates (p&lt;0.05). For both renal pelvis and ureteral tumors, the more contemporary era (1997-2002, 2003-2008) showed worse survival than prior eras (p&lt;0.05). Conclusions: Disease-specific survival for patients with renal pelvis and ureteral UTUC appears to be worse in the contemporary era. While sociodemographic factors (age, gender, and race) appear to impact prognosis, it is unclear what factors may be contributing to this decline. This data adds to the growing literature supporting a paradigm change in the treatment of this disease.
Both Functions of Antigen Uptake/Presentation and Anti-Tumor Cytotoxicity Are Possessed by Human Blood γδ T Cells.
Authors: Norihiro Watanabe, Miwako Narita, Ayumi Yokoyama, Asuka Sekiguchi, Anri Saito, Nozomi Tochiki, Jun Takizawa, Tatsuo Furukawa, Ken Toba, Yoshifusa Aizawa, Masuhiro Takahashi
Journal: Blood (2005)