tbuckley/cabot-search huggingface dataset:
Impact of cachexia at diagnosis on radiotherapy utilization and survival in non-small cell lung cancer.
Authors: Steven Lau, Fantine Giap, Bhavani S. Gannavarapu, Puneeth Iyengar
Journal: Journal of Clinical Oncology (2016)

133 Background: The presence of cachexia at the time of cancer diagnosis and its influence on disease management and treatment outcomes for patients receiving radiotherapy are poorly described. Here, we assess the role of baseline cachexia in patients with NSCLC on first-line treatment modality and clinical outcomes. Methods: Retrospective review of medical records identified 1,334 patients with NSCLC consecutively treated at a tertiary care health system between 1/1/06 and 12/31/13. Cachexia was defined using the well-accepted and validated international consensus definition. The delivery of radiotherapy and its treatment intent were abstracted. Results: The cohort included a representative group of patients with a median age at diagnosis of 64 years, 47% females, and 32% patients of non-White race. Stage at diagnosis was I, II, III, and IV in 291, 105, 356, and 578 (43.3%) patients, respectively. Cachexia was present at the time of diagnosis in 403 (30.2%) patients including 18%, 14%, 32%, and 39% of stage I, II, III, and IV patients, respectively. Palliative intent radiotherapy was received by significantly more stage IV patients with cachexia (74%) than without cachexia (63%) (X 2 , P = .01). In contrast, baseline cachexia was not associated with curative intent radiotherapy in stage I-III disease. At a median follow-up of 24 months, 857 deaths have been observed. Cachexia at the time of diagnosis was prognostic for worse survival by stage. For patients with stage IV NSCLC, median survival was 11 months for patients without cachexia but 6 months for patients with cachexia at diagnosis (P &lt; .001). Cachexia remained significant in stage I NSCLC, with median survival of 45 and 67 months with or without cachexia at diagnosis, respectively (P = .03). Conclusions: Cancer cachexia at the time of diagnosis is common in patients with NSCLC even with early stage disease. The presence of cachexia at diagnosis is associated with utilization of radiotherapy as a palliative treatment. However, cachexia at diagnosis of NSCLC, even with early stage disease, is prognostic of worse outcomes despite curative intent radiotherapy.
Interferon (IFN)-based chemoradiation (CRT) as initial therapy (RX) for locally advanced pancreatic cancer (LAPC): A single-center experience.
Authors: V. J. Picozzi, N. K. Boone-Hill, G. Song
Journal: Journal of Clinical Oncology (2011)

e14648 Background: LAPC has poor survival with median (med)/2-yr overall survival (OS) of 9-12 mo/10-15%. Multiple studies (e.g. Picozzi et.al. Proc ASCO 2003, Picozzi et.al. Proc ASCO 2008, Marten et.al. Proc ASCO 2010) showed benefit for IFN-based CRT as PC adjuvant rx. We thus examined its safety/efficacy as LAPC initial rx. Methods: From 1/2002-12/2010, 54 pts received IFN-based CRT as initial rx for LAPC at our center. 87% (47/54) pts were surgically staged; all were nondownstageable/inoperable. Pt characteristics were med age 62 (range 34-78) yrs, ECOG PS 0/1/2 26%/72%/2% (14/39/1 pt) , med tumor size 3.3 (range 1.4-7.0) cm. CRT included 5040 cGy XRT (180 cGy/28 fxs/38d); cisplatin 30 mg/m2 IV d 1,8,15,22,29,36; 5-FU 175-200 mg/m2IVCI d 1-38; IFN 3x106U q M,W,F(17 doses). 96% (52/54) pts received chemotherapy (C) post CRT. Results: 100% (54/54 pts) received full XRT dose. 32/54 pts (59%) needed CRT break (1-2 wks) and C dose reduction due to (#pts) mucositis (MUC) 7, N/V 7 , neutropenia (N) 6 , biliary obstruction (bil obs) 3, diarrhea (D) 3, C.diff colitis (CD) 2, thrombocytopenia (T) 2, fever 2, GOO 1. 65% (35/54) pts had grade 3 toxicity (≥ 10% incidence MUC 22%, N/V 13%, N 11%, D 10%, T 10%). No grade 4/5 toxicity occurred. 33% (18/54) pts were hospitalized during CRT- (6 N/V, 5 bil obs, 2 CD,1 each D, drug rxn, GOO, MUC, neutropenic fever). Response rate (RR) was 90% by CA 19.9 (36/40 pts, 14 non-expressed, med decline 78%, 10 normalized), but 10% by CT RECIST (5/54 pts, 44/54 (80%) pts SD , 5/54 pts (10%) progression). 69% (37/54 pts) disease progression (med TTP 13, range 2-87+ mo). Initial recurrence sites were 16 local, 16 systemic, 4 both, 1 unknown; systemic sites were 11 liver, 5 omentum, 2 lung , 2 node). Med OS is 17 mo; 1/2/3 yr OS is 70%/ 29%/13%. 4 pts are alive/ NED at 38+, 51+, 80+, 87+ mo. Conclusions: 1) IFN-based CRT was safely and reliably given as inital rx for LAPC. 2) Toxicity is similar as in PC adjuvant rx. 3) RR by CA19.9 and CT RECIST differ significantly. 4) Initial recurrences are equally local/ systemic . 5) OS was excellent by literature standards; long-term OS w/o surgery was seen. 6) Further study of this rx in LAPC is needed, particularly for downstaging of borderline resectable PC.
The Role of FGFR in the Progression of Waldenstrom's Macroglubulinemia and the Effect of Its Inhibition by TKI-258.
Authors: Feda Azab, Abdel Kareem Azab, Aldo M. Roccaro, Antonio Sacco, Phong Quang, Hai T Ngo, Molly R Melhem, Judith M. Runnels, Patricia Maiso, Irene M Ghobrial
Journal: Blood (2009)
Multicenter prospective phase II trial of neoadjuvant (neo) dose dense gemcitabine and cisplatin (DD-GC) in patients (pts) with muscle-invasive bladder cancer (MIBC).
Authors: Arjun Vasant Balar, Gopa Iyer, Matthew I. Milowsky, William C. Huang, Michael Woods, S. Machele Donat, Harry W. Herr, Guido Dalbagni, Bernard H. Bochner, Irina Ostrovnaya, Hikmat Al-Ahmadie, Tracy Lynn Rose, Jamie Cathleen Riches, Brooke Elizabeth Kania, Ashley Marie Regazzi, Asia S. McCoy, Daniela Delbeau, Jonathan E. Rosenberg, Dean F. Bajorin
Journal: Journal of Clinical Oncology (2016)

436 Background: Cisplatin-based chemotherapy before radical cystectomy (RC) improves survival in pts with MIBC. DD-GC therapy is active in the metastatic setting [6 cycles (cy), 18 months median survival; Bamias et al, 2012)] and as neo therapy (3 cy, 44% ≤ pT1 rate; Plimack et al, 2014), but the optimal dose and number of cy of neo therapy has not been defined. We prospectively evaluated the activity and safety of 6 cy of neo DD-GC over 12 weeks in MIBC. Methods: Pts with T2-4aN0 disease received six 14-day cy of DD-GC as follows: G 2500 mg/m2 day 1, C 35 mg/m2 days 1 and 2, pegfilgrastim day 3. RC with bilateral pelvic lymph node dissection was planned within 8 weeks of DD-GC completion, regardless of clinical response. The primary endpoint was pathologic response ( ≤ pT1) rate ≥ 55% (exact Binomial one-sided test). Pts not undergoing RC were deemed non-responders regardless of clinical stage after DD-GC. Pts receiving &lt; 3 cy were inevaluable and replaced. All pts were evaluable for toxicity. Results: 49 pts (40 male) were enrolled. Median age was 64 (range: 37-78). Clinical stage was T2N0 (32 pts), T3N0 (12 pts), and T4aN0 (5 pts). Toxicities resulting in cy delay and/or dose modifications included thrombocytopenia (9 pts), renal insufficiency (5 pts), vascular access complication (2 pts), ototoxicity (1 pt), significant urinary symptoms (1 pt), and transient ischemic attack (1 pt). Three pts are inevaluable for the primary endpoint ( &lt; 3 cy). As of 9/7/15, 2 pts are pending RC. Of the 44 pts evaluable for response to date, 31 completed 6 cy of DD-GC, 6 pts completed 5, 3 pts completed 4, and 4 pts completed 3 (median: 6 cy). The median time to RC was 46 days. Four of 44 pts did not undergo RC (consent withdrawal, pt refusal, disease progression prior to RC, death from other causes). Trial accrual has closed with completion of clinical and pathologic data expected by 11/1/15. Of 40 pts with RC pathology available to date, 24 (60%) were ≤ pT1 and 7 (18%) were pT0. Conclusions: Six cy of DD-GC is an active well-tolerated neo chemotherapy regimen in pts with MIBC. The pathologic response rate is encouraging. Thrombocytopenia was the most common toxicity resulting in cy delays/dose modifications. Clinical trial information: NCT01589094.
Duodenal and ampullary carcinoid tumors: Using size to predict necessity for lymphadenectomy.
Authors: Epameinondas Dogeas, Ioannis Hatzaras, John L. Cameron, Christopher Lee Wolfgang, Kenzo Hirose, Ralph H. Hruban, Martin Makary, Timothy M. Pawlik, Michael A. Choti
Journal: Journal of Clinical Oncology (2013)

316 Background: The metastatic potential and choice of therapy of duodenal and ampullary carcinoid tumors are poorly understood. We evaluated the local management and outcomes in patients with these uncommon tumors and determined factors predicting risk of nodal involvement. Methods: 117 patients were identified with duodenal or ampullary carcinoid tumors between 1996 and 2012, who were treated in a single high-volume center. Clinicopathologic data and overall survival by local treatment modality were analyzed. Results: Among all patients, 64 (55%) were treated surgically, including 34 (29%) who underwent pancreaticoduodenectomy (PD), 14 (12%) who underwent local resection (partial duodenectomy), and 16 (13.6%) where a carcinoid tumor was found incidentally after PD for another indication. The remaining 53 patients (45%) underwent endoscopic excision. The average tumor size was 1.8 cm (0.1-8.5) and the majority were of duodenal origin (n=93, 80%). Surgical management was more commonly performed for ampullary tumors compared to tumors of duodenal origin (83% vs. 47%, p=0.002), and endoscopic excision was more common with smaller tumors (p=0.001). Most carcinoids were well-differentiated (94%) and 55% were T1/T2. Yet, among the 55 patients in whom lymph nodes were histologically assessed (PD or lymph node sampling), 51% had positive nodes (N+). In addition, on multivariate analysis nodal involvement was strongly associated with tumor size (OR: 9.9, p=0.001). Specifically, tumors larger than 1-cm had positive nodes in more than 70% of cases whereas those ≤1cm had a 5% risk of nodal involvement (1 of 21 patients) (Table). Similar rates of N+ were observed for both duodenal and ampullary carcinoids. With long-term follow-up, only one recurrence was observed (1%). The overall survival was similar among all treatment groups (median=139 months). Conclusions: Lymph node involvement is common in patients with duodenal and ampullary carcinoid tumor, particularly among tumors &gt;1 cm in size. When possible, surgical resection with lymphadenectomy is recommended for such tumors. [Table: see text]
Non-invasive monitoring of patient-derived orthotopic xenograft: An optimal system for rapid in vivotesting.
Authors: Mayrim V. Rios Perez, Michael Pratt, Ya'an Kang, Jason B. Fleming
Journal: Journal of Clinical Oncology (2016)

235 Background: Heterotopic patient-derived xenografts (PDX) have been used to assess response to therapy however they underrepresent the role of tumor microenvironment and rarely develop metastasis, both of which are overcome by orthotopic models. Fluorescent orthotopic mouse models require invasive measures to determine tumor bioluminescence. Ultrasonography (US) is a cost-effective, non-invasive imaging technique that has been used in genetically engineered mouse models of pancreatic cancer for a three-dimensional (3D) acquisition of tumor volume, which allows rapid and safe in vivo drug testing. We intend to demonstrate that this technique allows real time monitoring of in vivo response to therapy using patient-derived orthotopic xenograft (PDOX) of pancreatic ductal adenocarcinoma (PDAC). Methods: A non-survival study using PDOX was designed with control (n = 5) and treatment (n = 5) groups. Weekly 3D US images were obtained pre and post-treatment over 4 weeks. Tumor growth curves were generated to monitor progression of disease. Metastatic burden was determined during necropsy. Results: One mouse was excluded from control and treatment groups due to baseline tumor size exceeding 300mm 3 and drug toxicity, respectively. Pre-treatment average tumor volumes for control and treatment groups were (36±12)mm 3 and (34±12)mm 3 , respectively. No difference was found in average tumor growth over time between groups (p = 0.9120). A 20% tumor regression was observed per group. Both groups exhibited gross metastasis to spleen, peritoneum, and omentum. Liver, periportal metastasis and local extension to the gastrointestinal and genitourinary system were present on the treatment group. Conclusions: This study describes a rapid technique for in vivo drug response by using 3D US to monitor PDOX; failure of response to therapy correlated with metastatic burden observed. PDOX regression could be explained by tumor heterogeneity. PDOX models, as challenging as they could be, remain to be necessary in vivo models to show therapeutic response to human PDAC, which could be easily monitored using 3D US imaging.
Proapoptotic effect of the aryl-hydrocarbone receptor ligand aminoflavone in human kidney cancer.
Authors: B. Itkin, M. Callero, B. Nguyen, A. Loaiza Perez
Journal: Journal of Clinical Oncology (2011)

e21094 Background: In our previous work we demonstrated that the antiproliferative effect of aminoflavone (NSC686288, AF) in human kidney cancer is mediated by aryl-hydrocarbon receptor (AhR) activation leading to an increase in a drug metabolizing cytochrome CYP1A1 transcription.TK10, SN12-c and A498 cell lines growth was inhibited, but not ACHN, by treatment with AF (100nM-1μM). Methods: The aim of this work was to assess if the AF anti-proliferative and pro-apoptotic activity in human clear cell and papillary renal carcinoma cell lines was mediated by AhR. Results: We demostrated that in human clear cell renal carcinoma CAKI-1, treatment with AF reduced cells viability by 35 +/-14%, p<0.05 compared with controls, as assesed by MTS assay; preincubation with AhR inhibitor alpha-naftoflavone (alpha-NF) 1μM partially reverted the AF effect (viability reduction of 25 +/-8% compared with controls, p<0.01). Also AF induced the AhR nuclear translocation evaluated by Western Blot analysis. We also demonstrated that the patient derived papillary carcinoma cell strain called “112”, was extremely sensitive to AF (84% viability reduction compared with controls). The drug also induced AhR nuclear translocation and apoptotic bodies formation. All these effects were reverted by pre-treatment with the AhR inhibitor alpha-NF. On the other hand, we have studied if AhR mediates the apoptosis triggered by AF in TK10 cells. Apoptotic bodies formation was evaluated by acridine orange/ ethidium bromide assay. Pre-treatment with alpha-NF before treatment with AF 1μM reduced the number of apoptotic bodies formed.These results are in agreement with the finding of an increase in phosphorilated P53 and P21 between 3 and 6 hours of treatment with AF1μM, (assessed by Western Blot) indicating that the drug would induce apoptosis and cell cycle arrest in this cell line. Conclusions: We concluded that in human kidney cancer cells (clear cell and papilary histology) the anti-tumoral/pro-apoptotic effect of AF is mediated by AhR. The activation of this pathway could be a new therapeutic target, different from those currently in use.
Evaluating PSA nadir drift in high-risk and metastatic prostate cancer.
Authors: Eric Tyler Miller, Lorna Kwan, Sandy Liu, Isla Garraway
Journal: Journal of Clinical Oncology (2016)

310 Background: Prostate cancer (PC) is a heterogeneous, clinically disparate, and often unpredictable disease whereby nearly 3% of patients present with bone metastatic PC (BMPC). Virtually all patients diagnosed with stage M1 disease fail to achieve complete remission and rapidly progress to castration-resistant PC (CRPC) and death (28% 5-year survival). Androgen deprivation therapy (ADT), the current standard of care for M1 disease, does not induce durable remissions. Improved understanding of tumor biology associated with lethal progression is desperately needed to guide clinical trials. Methods: We assembled a diverse, clinically annotated biorepository with diagnostic biopsy tissue from 428 patients with high-risk M0 and M1 disease. Retrospective analysis was performed on M0 (n = 157) and M1 (n = 112) patients stratified by treatment sequence. Clinical and pathological variables analyzed included age at diagnosis, race, primary Gleason sum, tumor burden, initial treatment received, PSA at time of biopsy, PSA velocity and length of follow-up. Primary endpoints included PSA nadir per treatment round, time from biopsy to CRPC, and death. Results: Compared to M0 cases, M1 patients were older, displayed significantly higher PSAs at the time of biopsy, and were more likely to display primary Gleason pattern 5. Patients with stage M1 disease had significantly worse survival, shorter time to CRPC, and median PSA nadir following each treatment round never fell below 2ng/ml. Median PSA nadirs associated with each treatment round demonstrated marked upward drift in the M1 cohort when compared to the M0 cohort. Conclusions: The presence of distant metastases is a major obstacle in achieving durable remissions for very high-risk PC. Our data confirms that ADT has limited effect on controlling cancer progression in M1 patients. PSA nadir drift in M1 compared to M0 patients may indicate intrinsic tumor resistance to currently available therapies. Multimodal profiling of M1 primary tumors may reveal actionable targets for initiation of combination treatment regimens at diagnosis.
Overexpression of the ABC-Transporters BCRP and MDR1 in CML Patients with Resistance to Imatinib and in Untreated CML Patients.
Authors: Israel Bendit, Monika C. Mello, Pedro E. Dorliac-Llacer, Luciana Nardinelli, Marina Bendit, Mafalda N.Y. Novaes, Joao E.B. Neto, Walter M. Lima, Ricardo R. Giorgi, Dalton A.F. Chamone
Journal: Blood (2006)
Comprehensive genomic analysis in metastatic pancreatic ductal adenocarcinoma (PDAC).
Authors: Hui-Li Wong, Martin Jones, Peter Eirew, Joanna Karasinska, Kasmintan A Schrader, Howard John Lim, Yaoqing Shen, Steven Jones, Stephen Yip, Janessa J. Laskin, Marco Marra, David F. Schaeffer, Daniel John Renouf
Journal: Journal of Clinical Oncology (2016)

285 Background: In the absence of defined tumor molecular subtypes and validated predictive markers, PDAC has been largely treated as a single disease. Recent studies of molecular subtyping in PDAC reveal a complex mutational landscape with data suggesting the presence of genomic and gene expression signatures that may have prognostic and therapeutic significance. These studies predominantly focused on resected PDAC and lack data on metastatic tumors. We aim to explore the clinical utility of whole genome sequencing (WGS) and transcriptome analysis from metastatic biopsy samples in patients (pts) with advanced PDAC. Methods: Pts with incurable advanced cancers undergo tumor biopsy for in-depth WGS and RNA sequencing (RNASeq) as part of an ongoing prospective study (NCT02155621). Comprehensive bioinformatics analysis is performed to identify somatic cancer aberrations, gene expression changes and cellular pathway abnormalities. Here we describe clinical and molecular data on the subset of pts with advanced PDAC. Results: Sixteen PDAC pts have been enrolled; median age 59 years, 8 males (50%), 10 with de novo metastases (63%). Full WGS and RNASeq were completed in 11 pts (1 failed biopsy, 4 had insufficient tumor). KRAS codon 12 and TP53 mutations were present in all but one pt. CDKN2A and SMAD4 were also frequently altered (7 and 4 pts respectively). Gene expression analysis for classical and basal subtypes similar to those recently described (PMID 26343385) identified 3 and 6 pts with classical and basal expression patterns respectively, and 2 pts with mixed expression. Overall survival (OS) was significantly worse for the basal subtype vs all others (median OS 7 vs. 13.9 months (ms), p = 0.017). When separated into 3 subtypes a significant difference was still noted (median OS 7 ms in basal, 19.2 ms in classical and 11.8 ms in mixed subtype, p = 0.032). Conclusions: WGS analysis demonstrated a similar mutation pattern to that described in resectable PDAC, with no novel actionable mutations identified. Gene expression analysis demonstrated the presence of distinct gene expression signatures significantly associated with outcome, despite small pt numbers. These results need to be validated prospectively in larger cohorts. Clinical trial information: NCT02155621.
Correlation of 3'-deoxy-3'-18F-fluorothymidine PET/CT uptake to DNA ploid, S phase fraction, and proliferation index in esophageal squamous cell carcinoma.
Authors: D. Han, J. M. Yu, Z. Fu, X. Wang, S. Q. Zhao
Journal: Journal of Clinical Oncology (2011)

e21035 Background: To evaluate the correlation between standardized uptake values (SUV) of 3’-Deoxy-3’-18F-Fluorothymidine (FLT) of tumor at PET/CT examination and DNA and cell cycle analysis in esophageal squamous cell carcinoma. Methods: 24 patients with esophageal squamous cell carcinoma were evaluated with FLT PET/CT examination before operation, 22 of those were evaluated with FDG PET/CT. Flow cytometry was used to measure DNA ploidy, synthesis-phase fraction (SPF) and proliferation index (PI) of the resected esophageal tissues from the patients. Results: The FLT PET/CT SUV of diploidy and aneuploidy in carcinoma tissue had significantly difference (P =0.000), whereas, FDG PET/CT SUV had not significantly difference (P=0.111). The correlation coefficients between FLT PET/CT and SPF, PI were 0.649 (P=0.001), 0.680 (P=0.000), respectively. The correlation coefficients between FDG PET/CT and SPF, PI were 0.555 (P=0.007), 0.426 (P=0.048), respectively. Conclusions: The correlation of esophageal carcinoma uptake of FLT PET/CT to SPF, PI and Ki-67 LI is more obvious than that of FDG. FLT is a promising PET tracer for reflecting cell proliferation in esophageal squamous cell carcinoma.
Significance of lymphovascular invasion and lymph node involvement: Impact on survival after adjuvant chemotherapy in locally advanced bladder cancer
Authors: C. Song, J.-H. Ahn, H. Ahn
Journal: Journal of Clinical Oncology (2005)

4774 Background: Lymphovascular invasion(LVI) and lymph node involvement(LNI) have been reported to be associated with poor prognosis in bladder cancer despite aggressive local treatment. Benefit of adjuvant chemotherapy for locally advanced bladder cancer has been debated. We evaluated the impact of LVI and LNI on survival after adjuvant chemotherapy (CTx). Methods: A retrospective analysis was conducted on 157 patients who had pT3–4(N=68) or pN+(N=89) disease after radical cystectomy and pelvic lymphadenectomy between 1991 and 2004. Adjuvant chemotherapy consisted of 3–6 cycles of MVAC (N=42) or GC (N=40). Medical records and tissues were studied for LVI and LNI. Mean follow-up was 31 months. Results: LVI was present in 59% of the patients. Thirty-seven percent of pT3–4 and 64% of pN+ patients received CTx. There were no significant differences in the distribution of T stage, number of involved lymph nodes, lymph node density or patients’ performance status between the patients who did and did not receive CTx. LNI was independently associated with survival whereas LVI, T stage or CTx had no impact. However, LVI increased the risk of recurrence (p=0.004, odds ratio 3.661). CTx significantly prolonged survival of patients with N+ disease (mean survival 62 mos. vs. 23 mos, p=0.003). Adjuvant CTx was not beneficial in patients with N- disease. Conclusions: LNI was an independent prognostic factor for survival while LVI was associated with recurrence-free survival in locally advanced bladder cancer. Adjuvant CTx prolonged survival only in those with N+ disease. No significant financial relationships to disclose.