tbuckley/cabot-search huggingface dataset:
Tumor mutation burden to predict progression in high-risk non-muscle invasive bladder cancer.
Authors: Joshua Meeks, Benedito A. Carneiro, Sachin Gopalkrishn Pai, Daniel Oberlin, Alfred Rademaker, Kyle Fedorchak, Sohail Balasubramanian, Julia Andrea Elvin, Nike Beaubier, Francis J. Giles
Journal: Journal of Clinical Oncology (2017)

397 Background: The genetic mechanisms associated with progression of high-risk non-muscle-invasive bladder cancer (HR-NMIBC) have not been described. We conducted next-generation sequencing (NGS) of HR-NMIBC and compared the genomic profiles of cancers that responded to intravesical therapy and those that progressed to muscle-invasive or advanced disease. Methods: DNA was extracted from formalin-fixed paraffin-embedded sections of tumor from 25 patients with HR-NMIBC (23 with T1HG; 3 with TaHG and carcinoma in situ). Ten patients with HR-NMIBC developed progression (pT2+ or N+) (“progressors”). Fifteen patients had no progression (“non-progressors”). Tissue from 11 patients with metastatic bladder cancer (BC) were analyzed for comparison. Results: We identified no difference in the frequency of mutations of TP53, PIK3CA, or KMT2D between the primary tumors of progressors compared to non-progressors and metastatic tumors. An increased frequency of mutations and deletions causing loss of function of CDKN2A and CDKN2B was identified in tumors at progression (37%) compared to non-progressors (6%) (p=0.10). We found a significant decrease in total mutational burden (TMB) comparing non-progressors, progressors and metastatic tumors at 15, 10.1 and 5.1 mutations/MB respectively (p=0.02). This association suggests more advanced tumors have decreased neoantigen burden and may potentially explain the mechanism of BCG response in non-progressors. Conclusions: TMB was significantly greater in non-progressors compared to progressors. We found no novel genetic drivers in tumors that progressed and HR-NMIBC had many genetic features similar to metastatic BC. The loss of CDKN2A appears to occur late in the process of invasion of BC and may represent an important step in progression. Further research is necessary to evaluate loss of CDKN2A as a biomarker for progression of NMIBC.
Role of prostaglandin pathways in radiotherapy-induced mucositis.
Authors: Steven M. Grunberg, Madhuri V. Vithala, Margaret Vizzard, Nathan Bradley Adams, Havaleh Marie Gagne, William Brundage, Takamaru Ashikaga
Journal: Journal of Clinical Oncology (2013)

e20509 Background: Pathways associated with proinflammatory molecules are upregulated in oral mucositis. Lalla (Support Care Cancer 18:95, 2010) found an association between mucositis pain scores, tissue COX-1, and salivary prostaglandins in 4 patients receiving dose-dense chemotherapy. We investigated whether similar changes would be seen with radiotherapy (XRT)-induced mucositis. Methods: Patients receiving XRT including the oropharynx were evaluated at 4 time points, before XRT, midway through XRT, end of XRT, and 1 month after XRT. Subjective report of pain and objective mucositis scores were recorded. Patients also provided a 5-minute stimulated saliva specimen at each time point collected on ice with a protease inhibitor cocktail. Proteins were estimated using a Bradford assay. Prostaglandins were measured using ELISA assays. Results: 8 evaluable patients entered the study, including 7 male/1 female, median age 60 (range 48-66), primary site (oropharynx 1, unknown primary 1, base of tongue 3, tonsil 1, tongue 1, supraglottis 1), median XRT 7000 rads (range 6000-7200 rads), concomitant chemotherapy (cisplatin 7, none 1), histology (squamous 7, mucoepidermoid 1). Pain and mucositis scores increased during XRT and improved at 1 month after XRT. No increase in COX-2 levels was seen. Salivary PGD2, PGE2, and PGF2 increased from baseline with the greatest increase 1 month after XRT. There was a significant time effect for PGF2 (p=0.028) and marginal time effects for PGD2 (p=0.107) and PGE2 (p=0.069). Conclusions: Increased salivary prostaglandins are seen during and after XRT-induced oral mucositis, suggesting a role for proinflammatory mediators and providing a possible therapeutic target. Clinical trial information: NCT01252498. [Table: see text]
Adjuvant chemotherapy of cisplatin, 5-fluorouracil (5-FU) plus leucovorin (LV) for esophageal cancer: A case-matched cohort study in east china
Authors: J. Zhang, J. Xiang, Y. Zhang, X. Zhou
Journal: Journal of Clinical Oncology (2007)

15135 Background: There are very few prospective randomized clinical trials regarding the adjuvant chemotherapy of esophageal cancer. This study is to compare the survival between the patients who received adjuvant chemotherapy of cisplatin, 5-Fluorouracil (5-FU) plus leucovorin (LV) and those who did not. Methods: Between 1998 and 2004, 90 esophageal cancer patients with adjuvant chemotherapy, and clinic-pathologically well- matched 180 patients without chemotherapy, were included in this study. Results: There was no significant difference for disease-free-survival and overall-survival in stage I (P=0.59&amp;p=0.59), stage II (P=0.2778&amp;P=0.2778) and stage III patients (P=0.695 &amp;P=0.8667) between observation group and chemotherapy group. Chemotherapy was most effective for the patients who had metastasis in cervical and /or celiac lymph node (IVa subgroup) by both univariate analysis and multivariate COX regression model. 1 and 3-year DFS and OS are significantly better than those who did not receive the chemotherapy(P= 0.038,and 0.01, respectively). Among the factors evaluated by immunohistochemical staining, Bcl-2 expression in the primary tumor was a worse prognostic factor, and was more predictive in adjuvant chemotherapy group than no chemotherapy group. Conclusions: Adjuvant chemotherapy significantly improved the treatment result of stage IVa patients. Bcl-2 could be potentially used to analyze the prognosis and guild the adjuvant treatment in esophageal cancer. No significant financial relationships to disclose.
Phase II trial of sorafenib (S) and vinorelbine (V) in metastatic breast cancer (mBC) with pharmacokinetics (PK) analysis.
Authors: Cristiano Ferrario, Wilson H. Miller, Helen Charamis, Adrian Langleben, Gerald Batist, Emanuela Scarpi, Oriana Nanni, Lawrence C. Panasci
Journal: Journal of Clinical Oncology (2012)

1099 Background: S inhibits pathways involved in cancer resistance to treatments (Raf, VEGFR, PDGFR). This phase 2 trial aimed to define tolerability and efficacy of full doses of S and V in mBC. Toxicity data were previously reported: frequent dose reductions were noted, for which we investigated a possible PK interaction. Indeed, the metabolism of both S and V depends on hepatic CYP3A isoenzymes. Methods: Patients with measurable (RECIST), HER2 negative mBC received first-line therapy with V (30 mg/m 2 days 1, 8 every 21) + S (400 mg bid). After 8 cycles patients could be switched to S alone. For PK analysis 6 patients started S on day 4 of cycle 1, to compare plasma levels of V, S and M2 (N-oxide active metabolite of S) when V and S were administered apart from each other versus concomitantly. Plasma samples were collected at time 0 (oral intake of S or right before V infusion), at completion of V infusion and after 0.5, 1, 2.5, 5, 7, 24, 48 and 72 hours from time 0 (cycle 1 day 1 for V and day 21 for S+M2; cycle 2 day 1 for both). Samples were analyzed using validated LC-MS/MS assays. Results: 27 patients (median age 57, 35-71) received a median of 8 cycles (1-28), with one patient still on treatment. With repeated cycles 48% of patients required at least 1 dose reduction and 3 patients discontinued therapy for toxicity. 30% of patients had a partial response, 85% had clinical benefit (including stable disease ≥ 4 cycles). Median progression-free survival was 5.7 months (95% CI 4.4-7.6). Plasma levels of V were influenced by S, with a mean Cmax right after the infusion of 1301 ng/mL for V administered alone (cycle 1 day 1) versus 2039 ng/mL with concomitant S (cycle 2 day 1; paired t-test, p=0.004). Plasma levels of S and M2 showed a greater degree of interpatient variability, with no significant difference observed in the presence or absence of concomitant V. Conclusions: Combining S with V at full doses is feasible, but not devoid of toxicity. A PK interaction may contribute to the frequent dose reductions. A reasonable option in clinical practice is to start therapy at lower doses of both agents, with a gradual dose increase if well tolerated. Promising efficacy of this combination is documented, with a very high rate of disease control.
Phase II trial of preoperative radiation with concurrent capecitabine, oxaliplatin, and bevacizumab followed by surgery and postoperative 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX), and bevacizumab in patients with locally advanced rectal cancer: 5-year clinical outcomes of a trial of the ECOG-ACRIN Cancer Research Group (E3204).
Authors: Jerome Carl Landry, Yang Feng, Roshan Sudhir Prabhu, Steven J. Cohen, Charles A. Staley, Richard M. Whittington, Elin R. Sigurdson, Halla Sayed Nimeiri, Udit N. Verma, Al Bowen Benson
Journal: Journal of Clinical Oncology (2015)

3592 Background: As previously reported, the regimen of preoperative capecitabine, oxaliplatin, and bevacizumab with radiation therapy (RT) followed by surgery and postoperative 5-FU, leucovorin, oxaliplatin (FOLFOX) andbevacizumabfor locally advanced rectal cancer did not improve pathologic complete response (path CR) rates. However, the effect of an intensified adjuvant regimen is not reflected in path CR. The purpose of this report is to describe the 5-year oncologic outcomes of this regimen. Methods: Fifty-seven patients (pts) with resectable T3/T4 rectal adenocarcinoma were enrolled. Preoperative treatment: capecitabine (825 mg/m² bid M-F), oxaliplatin (50 mg/m² weekly), bevacizumab (5 mg/kg D1,15,29), and RT (50.4 Gy). Surgery was performed by 8 weeks after neoadjuvant therapy. Beginning 8 – 12 weeks after surgery, patients received FOLFOX plus bevacizumab (5 mg/kg) Q2 weeks for 12 cycles. Results: Fifty-three of 57 enrolled pts were eligible and included in the analysis. Most patients were clinical (c)T3 (92%) and cN positive (64%). Of the 48 patients who underwent curative surgery, 26 (54%) began adjuvant chemotherapy. After a median follow-up period of 41 months, the 5-year overall survival (OS) rate for all patients was 80% (90% confidence interval (CI) [67%, 92%]). Only 2 patients experienced cancer recurrence, 1 distant and 1 loco-regional, respectively. The 5-year recurrence free survival rate (RFS) was 81% (90% CI [68%, 94%]). Conclusions: Despite the path CR primary endpoint of this trial not being reached, the 5-year OS and RFS rates were excellent. However, as previously reported, the neoadjuvant and surgical toxicity of this regimen was significant and was the primary reason for the low compliance with adjuvant systemic therapy. Due to the lack of an improvement in the path CR rate, the substantial associated toxicity, and negative phase III trials of adjuvant bevacizumab in colon cancer, this regimen cannot be recommended for further study. Clinical trial information: NCT00321685.
Particulate air pollution and mortality in 38 of China’s largest cities: time series analysis
Authors: Peng Yin, Guojun He, Maoyong Fan, Kowk Yan Chiu, Maorong Fan, Chang Liu, An Xue, Tong Liu, Yuhang Pan, Quan Mu, Maigeng Zhou
Journal: BMJ (2017)

Objectives To estimate the short term effect of particulate air pollution (particle diameter <10 μm, or PM10) on mortality and explore the heterogeneity of particulate air pollution effects in major cities in China.Design Generalised linear models with different lag structures using time series data.Setting 38 of the largest cities in 27 provinces of China (combined population >200 million).Participants 350 638 deaths (200 912 in males, 149 726 in females) recorded in 38 city districts by the Disease Surveillance Point System of the Chinese Center for Disease Control and Prevention from 1 January 2010 to 29 June 2013.Main outcome measure Daily numbers of deaths from all causes, cardiorespiratory diseases, and non-cardiorespiratory diseases and among different demographic groups were used to estimate the associations between particulate air pollution and mortality.Results A 10 µg/m3 change in concurrent day PM10 concentrations was associated with a 0.44% (95% confidence interval 0.30% to 0.58%) increase in daily number of deaths. Previous day and two day lagged PM10 levels decreased in magnitude by one third and two thirds but remained statistically significantly associated with increased mortality. The estimate for the effect of PM10 on deaths from cardiorespiratory diseases was 0.62% (0.43% to 0.81%) per 10 µg/m3 compared with 0.26% (0.09% to 0.42%) for other cause mortality. Exposure to PM10 had a greater impact on females than on males. Adults aged 60 and over were more vulnerable to particulate air pollution at high levels than those aged less than 60. The PM10 effect varied across different cities and marginally decreased in cities with higher PM10 concentrations.Conclusion Particulate air pollution has a greater impact on deaths from cardiorespiratory diseases than it does on other cause mortality. People aged 60 or more have a higher risk of death from particulate air pollution than people aged less than 60. The estimates of the effect varied across cities and covered a wide range of domain.
Tumor-size-based endpoints as surrogates for overall survival in the ARCAD Advanced Colorectal Cancer Database.
Authors: Tomasz Burzykowski, Elisabeth Coart, Everardo D. Saad, Dan Sargent, John Raymond Zalcberg, Qian Shi, Dirkje Willemien Sommeijer, Marc E. Buyse
Journal: Journal of Clinical Oncology (2017)

766 Background: Tumor-size-based endpoints such as depth of response have recently become a focus of investigations related to search for early on-treatment predictive markers for patients with colorectal cancer (Piessevaux et al. 2013; Cremolini et al., 2015; Heinemann et al., 2015). We evaluate the use of time-to-nadir (TTN) and depth-of-nadir (DoN) as potential surrogates for overall survival (OS). Methods: We have used the data from trials included in the ARCAD Advanced Colorectal Cancer Database. We have considered three sets of treatment comparisons: comparisons involving only chemotherapy agents (CT); involving anti-angiogenesic agents (ANG); and involving anti-EGFR agents (EGFR). For each of the sets separately, we applied a two-stage modelling approach (Renard et al. 2002) to jointly analyze the relative change of tumor size versus baseline (RCTS) and OS. In particular, in the first stage, a joint model for the repeated measurements of RCTS and OS was fitted to the data. Based on the model, treatment effects on OS and RCTS were estimated. Treatment effects on OS were expressed as log-hazard-ratios, while the effects on RCTS were expressed in terms of differences in the time-to-nadir (TTN) and in the depth of nadir (DoN). In the second stage, a linear regression was fitted through the estimated treatment effects on TTN/DoN and OS. The coefficient of determination (R 2 ), computed by using the comparison-specific sample-size as weights, was used to quantify the strength of association between the treatment effects on TTN/DoN and OS. In particular, values of R 2 larger than 0.75 were considered as indicating a good surrogate. Results: The CT set included 18 comparisons with 5726 pts. in total. For the treatment effects on TTN and OS, the value of R 2 was estimated to be equal to 0.31, while for DoN and OS, it was equal to 0.01. For the ANG set (11 comparisons, 3964 pts.) the values of R 2 were equal to 0.26 and 0.21, respectively, while for the EGFR set (16 comparisons, 4687 pts.) they were equal to 0.10 and 0.45, respectively. Conclusions: These preliminary results suggest that TTN and DoN are not good surrogates for OS in advanced colorectal cancer. More detailed analyses are ongoing and will be presented at the meeting.
Phase I study of the safety and pharmacokinetics of epitinib, an oral EGFR tyrosine kinase inhibitor, in patients with advanced solid tumors.
Authors: Qing Zhou, Yi Long Wu, Xiyong Yu, Jinji Yang, Limin Wen, Yang Sai, Hua MU
Journal: Journal of Clinical Oncology (2013)

e19042 Background: Epitinib is an oral small molecule compound selectively inhibits epidermal growth factor receptor (EGFR). It has demonstrated potent inhibitory effects on multiple human tumor xenografts with a large safety window and broad tissue distribution including high drug contribution in brain. This first-in-human study is being conducted to assess the safety and tolerability, pharmacokinetics (PK), and preliminary anti-tumor activity of Epitinib. Methods: This phase I study uses a 3+3 design for dose-escalation of Epitinib given once daily (QD) in 28-day treatment cycles in patients with solid tumors who failed or have no access to standard therapies. Safety and tumor response are assessed according to NCI CTCAE 4.0 and RECIST 1.1, respectively. Results: By Dec 31 , 2012, 19 pts aged 40-66 yr old (ECOG PS 1) with NSCLC (n=16) or breast cancer (n=3) were enrolled in 5 dose cohorts of 20-160 mg. Six NSCLC pts had EGFR mutations (3 with T790M). All pts had ≥2 lines of prior systemic treatments (7 pts with gefitinib or elotinib). Most AEs were mild (Gr1). Treatment-related AEs included skin rash (36.8%), abnormal liver function tests (42.1%), diarrhea (10.5%), vomiting (5.3%), paronychia (5.3%), decreased neutrophil count (5.3%) and increased creatinine (5.3%). Three SAEs were reported as possibly unrelated to the study drug. No DLT was observed and MTD has not been reached yet. PK analysis showed that the mean elimination half-life of Epitinib was approximately 40 hours and T max was around 2 h. Both C max and AUC exhibited good dose proportionality over the studied dose range with low inter-patient variability following single and multiple doses. Among 15 evaluable pts, 1 EGFR mutation+ NSCLC pt achieved confirmed partial response (66.7% tumor reduction) for more than 6 months and the treatment is ongoing; 8 pts had stable disease, including 1 with T790M for 6 months and 1 with brain metastasis for 12 months who is still on treatment. Conclusions: Epitinib was well tolerated at doses up to 160mg QD to date with manageable adverse events and excellent pharmacokinetic properties. Encouraging clinical activity was observed, including durable SD in NSCLC patients with T790M or brain mets.
Radiation-induced sarcoma: A single center experience with 36 cases
Authors: F. Mayer, H. G. Kopp, J. Classen, T. Kluba, A. Koenigsrainer, M. Horger, M. Bamberg, J. T. Hartmann
Journal: Journal of Clinical Oncology (2007)

20525 Background: Radiation-induced sarcoma (RIS) is a rare complication of radiation therapy for any cause. With increasing numbers of patients receiving radiotherapy, data concerning the incidence and treatment outcome of RIS are urgently needed. Methods: We screened our local sarcoma registry for patients with RIS. 36 cases of RIS that had developed after radiation for malignant disease were identified and analyzed retrospectively over a 12 year period (1994–2006). Results: All patients had received radiation therapy between 1968 and 2002. The most frequent primary tumors were breast cancer (n = 19) and lymphoma (including Hodgkin`s and non-Hodgkin`s lymphoma, n = 9). The remainder received radiation therapy for tumors of the female reproductive organs (n = 2), head and neck cancer (n = 4), neuroblastoma (n = 1), and seminoma (n = 1).The median of delivered total radiation dose per patient was 50 Gy (35 to 72 Gray). Sources of irradiation were photons (n = 9), cobalt (n = 6), electrons (n = 2), and unknown in 19 cases. The median time interval from the start of irradiation the detection of the sarcoma was 11 years (1 - 35 years). The tumors arose within the radiation field in 29 cases, on the border of the field in 6 cases, and out of field in 1 case. The histology of RIS was angiosarcoma in most cases (n = 12), followed by pleomorphic sarcomas (n = 11), leiomyosarcoma (n = 4), fibrosarcoma (n = 2), osteosarcoma (n = 2), and others (n =5). Most cases were detected in a localized stage of disease (n = 33), and therefore, complete surgical removal was achieved in almost 50% (n = 17). However, this did not translate into long term survival within the overall study population. Only 11 patients remain free of disease during a mean follow-up period of 29 months (range, 0 - 51). Conclusions: Angiosarcomas within or on the border of the radiation field are the most common histological subentity of RIS. Therefore, follow-up of previously irradiated patients should include examination of irradiated regions with a high level of suspicion if cutaneous atypical vascular lesions are found. However, the clinician should be aware of the fact that RIS also occurs out of field and can be of non-angiogenic subtype as well. As far as treatment is concerned, RIS is treated the same as non-radiation induced sarcoma. No significant financial relationships to disclose.
Effect of antiangiogenic therapy on tumor-associated macrophages in recurrent glioblastoma.
Authors: Christine Lu-Emerson, Matija Snuderl, Christian Davidson, Nathaniel D. Kirkpatrick, Yuhui Huang, Dan G. Duda, Marek Ancukiewicz, Anat Stemmer-Rachamimov, Tracy Batchelor, Rakesh K. Jain
Journal: Journal of Clinical Oncology (2012)

2010 Background: Antiangiogenic therapy is associated with increased radiographic responses in glioblastoma (GBM), but tumors invariably recur. Tumor associated macrophages (TAMs) have been proposed as a mechanism of resistance to anti-angiogenic therapy in preclinical models. To examine the role of TAMs in recurrent GBM, we analyzed autopsy specimens from patients with or without history of antiangiogenic therapy. Methods: We compared autopsy brain specimens from 17 recurrent GBM patients who received anti-angiogenic treatment and chemoradiation (AAT+) to 7 patients who received chemotherapy and/or radiotherapy without anti-angiogenic therapy, or no treatment (AAT-). TAMs were morphologically and phenotypically identified with flow cytometry and immunohistochemistry (IHC) with CD68, CD11b, CD14, and CD163 markers. All specimens were obtained from the Department of Pathology at Massachusetts General Hospital and clinical information gained through review of the patients’ records. Results: Using flow cytometry, we observed an increase in CD11b+CD14+ cells in the AAT+ patients compared to AAT- patients. Using IHC analysis, we observed a significant increase in CD68+ macrophages in the tumor bulk (p&lt;0.01) and infiltrative areas (p&lt;0.05) in AAT+ versus AAT- patients. We also observed a significant increase in CD11b+ myeloid cells in the tumor bulk (p&lt;0.01) and a significant increase in CD163+ cells in the infiltrative areas (p&lt;0.05) in the AAT+ group. Finally, we noted a trend toward an increase in CD163+ cells in the tumor bulk (p=0.087) in the AAT+ versus the AAT- patients. Conclusions: Patients with recurrent GBM after antiangiogenic therapy showed a significant increase in CD68+ TAMs and in CD11b+ cells in the tumor bulk. Additionally, antiangiogenic treatment induced an increase in CD68+ and CD163+ TAMs in the infiltrative region. These data indicate that TAMs may participate in escape from antiangiogenic therapy and may represent a future therapeutic target in recurrent GBM.