tbuckley/cabot-search huggingface dataset:
Concomitant chemoradiation in locally advanced head and neck squamous cell carcinoma: A literature-based meta-analysis on the platinum concomitant chemotherapy.
Authors: M. G. Ghi, A. Paccagnella, I. Floriani, D. Garavaglia
Journal: Journal of Clinical Oncology (2011)

5534 Background: Concomitant platinum-based chemoradiation (CRT) is the standard treatment for locally advanced squamous cell carcinoma. As no consensus regarding the optimal concomitant platinum-based regimen exist, a literature based meta-analysis was performed. Methods: Randomized trials comparing radiation alone (RT) vs concomitant platinum-based CRT were identified by electronic search. The main endpoints were to compare the efficacy with regards to cisplatin total dose and platinum compounds (cisplatin vs carboplatin). Hazard ratios (HRs) and their 95% confidence intervals (CIs) were used to measure the relative effect of treatments on overall survival (OS). Heterogeneity among trials wastested by Chi-Square test and I2index. The incidence of Grade (G) 3-4 mucositis was also analyzed by means of a Chi-Square test. Results: Fifteen trials were identified and 2502 patients were available for the analysis. No difference in OS was observed between cisplatin high dose (300mg/sqm) (HR 0.59, 95% CI 0.46-0.74) and cisplatin dose <300mg/sqm plus 5-fluorouracil (5FU) (HR 0.59, 95% CI 0.45- 0.77) when compared to RT alone. The HR of death was 0.68 (95% CI 0.54-0.86) for cisplatin at intermediate dose (200-225mg/sqm) without 5FU, 1.04 (95% CI 0.85-1.27) for cisplatin dose <150mg/sqm without 5FU and 0.69 (95% CI 0.59-0.79) for carboplatin-based CRT. The Grade 3-4 mucositis incidence was 57% for concomitant cisplatin high dose, 46.1% for cisplatin dose <300mg/sqm plus 5FU (P=0.023), and 45.9% for carboplatin based CRT (P=0.096). Conclusions: Our meta-analysis seems to suggest that there is a dose/efficacy relation for concomitant cisplatin total dose. Concomitant cisplatin dose <300mg/sqm plus 5FU give the same survival benefit of concomitant cisplatin high dose, with a significant lower incidence of G3-4 mucositis. No advantage in OS was observed between CRT with cisplatin total dose <150mg/sqm monochemotherapy and RT alone. CRT with carboplatin and cisplatin, independently from doses and schedules, seems to give the same survival advantage over RT alone with a similar G3-4 mucositis incidence.
Signal transduction and activator of transcription 3 (STAT3), host inflammatory responses and survival of patients with colorectal cancer.
Authors: James Hugh Park, Donald C. Mcmillan, Jennifer Clark, Paul G. Horgan, Campbell S.D. Roxburgh, Joanne Edwards
Journal: Journal of Clinical Oncology (2016)

606 Background: In patients with colorectal cancer (CRC), the local and systemic inflammatory responses (LIR and SIR) are important determinants of disease progression, and may be linked by activation of the IL-6/JAK/STAT3 pathway. The present study examines the associations between STAT3 expression and activation with LIR and SIR of patients undergoing resection of CRC. Methods: Patients with stage I-III CRC who underwent curative resection in a single institution and who were included in a previously constructed tissue microarray were studied. IHC was utilised to examine cytoplasmic total STAT3 and nuclear phosphorylated STAT3 Tyr705 (pSTAT3) expression. The relationship between STAT3/pSTAT3 expression and clinicopathological characteristics, LIR (Klintrup-Makinen (KM) grade, CD3 + and CD8 + T-cell density) and SIR (modified Glasgow Prognostic Score (mGPS)) and cancer-specific survival (CSS) was examined. Results: 201 patients were included. Cytoplasmic STAT3 expression was associated with nuclear pSTAT3 expression (P= 0.019). Increased cytoplasmic STAT3 expression was associated with high density of T-cells within the intraepithelial compartment (CD3 + : low STAT3 – 49% vs. high STAT3 – 29%, P= 0.008; CD8 + : low STAT3 – 43% vs. high STAT3 – 20%, P = 0.002) and with an elevated mGPS (mGPS &gt; 1: low STAT3 – 31% vs. high STAT3 – 49%, P= 0.003) but not with any other clinicopathological features. Increased nuclear pSTAT3 expression was associated with younger age and lymph node involvement (P&lt; 0.05) but was not associated with the LIR or SIR. Combined assessment of cytoplasmic STAT3 and nuclear pSTAT3 expression stratified 5-year CSS from 78% (both low) to 50% (both high) (P= 0.006). Conclusions: Activation of the IL-6/JAK/STAT3 pathway may be an important determinant of the LIR and SIR in patients with colorectal cancer. Furthermore, assessment of host inflammatory responses may identify patients likely to benefit from therapies targeting this pathway. Taken together with the results of recent clinical trials, the results of the present study suggest that recruitment of patients into future trials of such agents should be stratified by the inflammatory status of the patient.
Characterization of the immune profile of cancer stem cells isolated from human glioblastoma
Authors: C. Maccalli, S. Mazzoleni, R. Galli, G. Parmiani
Journal: Journal of Clinical Oncology (2008)

22176 Background: Glioblastoma multiforme (GBM) represents the most aggressive brain tumors. It has been recently reported that cancer stem cells (CSCs) can be isolated from GBM and in vitro established. CSCs have been proposed as elective cellular target for immunotherapy. The main objectives of our project are represented by the identification of markers with immunological relevance expressed by CSCs and the validation of their role as target molecule to design immunotherapeutic protocols for GBM. Methods: We carried out a set of experiments using immunofluorescence and cytofluorimetric or confocal microscopy analysis aimed at the immunological characterization of CSCs in vitro cultured either in the presence or not of mitogens. Results: We found that GBM CSCs were negative or weakly positive for the expression of MHC class I or class II molecules, with only 1 out of 8 GBM CSC lines expressing high level of HLA molecules. Along this line, NKG2D ligands (MICA/B or ULBPs) were weakly or not expressed by most GBM CSCs with only one cell line being positive for all these molecules. Moreover, up-regulation of MHC class I molecules was achieved after IFN-γ treatment of GBM CSC lines, while weak or no modulation of MHC class II molecules was observed, suggesting that antigen processing machinery defects could occur in these cell lines. Heterogeneous expression of MHC molecules or NKG2D ligands was also observed in tumors generated by intracranial or subcutaneous trasplantation of GBM CSCs in immunodeficient mice. Notably, cancer-testis TAAs, such as NY-ESO or MAGE were weakly expressed only by one cell line; while survivin was efficiently detected in all GBM CSC lines (N=.8). However, the in vitro stimulation of peripheral blood-derived lymhocytes with autologous CSCs could elicit an efficient CSC-specific T cell-mediated immune response. Conclusions: Taken together, these results indicate that MHC molecules and NKG2D ligands are expressed heterogeneously by both in vitro established CSC lines and in xenogenically transplanted tumors. In addition, though the antigenic profile of GBM CSCs still needs to be defined, we found that these cells can represent an efficient source of TAAa that can be exploited to generate efficient T cell-mediated immune responses in at least some GBM patients. No significant financial relationships to disclose.
Variation in patterns of health care and survival among patients with brain metastases in the VHA health system.
Authors: Saurabh Ray, Li Wang, Marie-Josee Martel, Onur Baser
Journal: Journal of Clinical Oncology (2013)

204 Background: Brain metastases (BM) occur in approximately 15-25% of patients with advanced primary cancers and cause significant morbidity and mortality. This study examines the variation in patterns of healthcare and survival among patients with brain metastases in the US veterans’ population. Methods: A retrospective cohort design identified BM patients, divided into 5 most prevalent primary cancer cohorts using claims and enrollment data (10/1/2005 - 5/31/2012) from the Veterans Health Administration (VHA), the largest integrated health care system in US. Inclusion required ≥ 2 diagnoses of BM (ICD-9 code 198.3x) separated by ≥ 7 days with 1 primary cancer diagnosed before BM. The different BM cohorts were compared to the cohort with the highest prevalence of a primary cancer for the following outcomes: median survival (Kaplan-Meier estimates), per patient month (PPM) rate of healthcare utilization, baseline comorbidities, and use of brain-directed and supportive treatments. Results: Study sample consisted 4,393 BM patients (mean age of 65.6 years, 97% male), divided into 5 most prevalent primary cancer cohorts - 2,783 lung cancer, 574 skin, 568 prostate, 236 kidney, and 232 colorectal cancer patients. Median time to death after BM diagnosis was 103 days for lung, compared to 84 (p&lt;0.01) for skin, and 127, 109, 99 days (all p&gt;0.05) for kidney, prostate and colorectal cohorts respectively. Patients with ≥3 comorbidities ranged from 50% (skin) to 62% (colorectal). Compared to lung, the kidney cohort reported higher emergency room visits (21.6% vs. 16.3%, p=0.04), prostate and colorectal cohorts reported higher inpatient visits (65.3%, 69.4% vs. 59.6%, p=0.011, 0.003, respectively). Whole brain radiotherapy was the most common brain-directed treatment, ranging from 24% (kidney) to 37% (lung); brain-surgery ranged from 7% (lung) to 10% (colorectal); 89% to 94% used corticosteroid supportive therapy. Conclusions: High unmet need exists in the brain metastases population in terms of poor survival, high comorbidity burden and significant healthcare resource utilization. Patient outcomes vary significantly by primary cancer sites reflecting the heterogeneity of this disease.
Trastuzumab-induced cardiotoxicity in Uruguayan HER2-positive breast cancer patients.
Authors: Andrea Schiavone, Mariana Diaz, Natalia Camejo, Natalia Reborido, Horacio Vazquez, Gabriel Parma, Alvaro Vazquez, Cecilia Castillo, Gabriel David Krygier, Lucia Beatriz Delgado
Journal: Journal of Clinical Oncology (2015)

143 Background: To evaluate the incidence, severity and outcome of Trastuzumab-induced cardiotoxicity in HER2 positive Uruguayan breast cancer (BC) patients. Methods: Retrospective observational analysis of HER2 positive BC patients who were treated with Trastuzumab (TTZ) from January 2007 to December 2013 at two Uruguayan centers. Cardiac monitoring included physical examination and assessment of left ventricular ejection fraction (LVEF) by echocardiography that was evaluated before TTZ administration and every 12 weeks thereafter during the duration of therapy. Cardiovascular risk factors analyzed were: obesity (BMI ≥ 30 kg/m2), hypertension, diabetes, sedentary lifestyle and high cholesterol. Results: Sixty nine female patients were found in the databases of our institutions. Median age was 48 years (range: 27-73). Stage at diagnosis was as detailed: 19 % EI, 46 % EII, 29 % EIII and 4 % EIV. Eighty nine percent of patients received adjuvant TTZ , 4 % neoadjuvant TTZ and 7 % received it as a palliative therapy. Thirty patients (43, 5%) had at least one cardiovascular risk factors: 26% hypertension, 16% obesity, 9% sedentary lifestyle, and 4% high cholesterol. Median number of TTZ cycles was 15. Cycles were administered every 3 weeks at standard dose. Nineteen patients (27%) developed cardiotoxicity, of whom 12 had a transient suspension because of a reversible fall in LVEF, 2 had a irreversible reduction in LVEF, and 5 had a symptomatic heart failure. Eighty-nine percent of our patients (62 patients) completed treatment and the rest had a definitive suspension due to a irreversible reduction in LVEF or symptomatic heart failure. Most patients that developed cardiotoxicity (15 out of 19) had cardiovascular risk factors and also most of them (16 out of 19) had received anthracyclines before TTZ. Conclusions: Cardiotoxicity incidence was similar to the incidence reported in the literature and when it was present, in most cases was transient, asymptomatic, and reversible.
Randomized phase III study of 5-fluorouracil/folinate/oxaliplatin given continuously or intermittently with or without cetuximab, as first-line treatment of metastatic colorectal cancer: The NORDIC VII study (NCT00145314), by the Nordic Colorectal Cancer Biomodulation Group.
Authors: K. Tveit, T. Guren, B. Glimelius, P. Pfeiffer, H. Sorbye, S. Pyrhonen, E. Kure, T. Ikdahl, E. Skovlund, T. Christoffersen
Journal: Journal of Clinical Oncology (2011)

365 Background: The role of anti-EGFR therapy in first-line treatment of metastatic colorectal cancer (mCRC) is not established. In the present study pts were randomized to FLOX or FLOX + cetuximab until progression or FLOX intermittently + cetuximab continuously. Methods: Treatment arm A: Nordic FLOX (q2w): oxaliplatin 85 mg/m 2 day 1, 5-FU bolus 500 mg/m 2 and FA 60 mg/m 2 day 1-2; B: FLOX + cetuximab, initial dose 400 mg/m 2 , then 250 mg/m 2 /week; C: FLOX for 16 weeks + cetuximab continuously, with FLOX added at progression. Primary endpoint was progression-free survival (PFS). Results: Between May 05-Oct 07, 571 pts were randomized, 566 pts evaluable in intention to treat (ITT) analyses. Median age was 61 (24-74). ECOG status: 0=67%, 1=29%, 2=4%. KRAS and BRAF mutation (mut) analyses were obtained in 498 (87%) and 457 pts (81%), respectively. 40% of tumors had KRAS mut, 12% had BRAF mut. Cetuximab combined with Nordic FLOX did not significantly improve RR, PFS or OS compared to FLOX. KRAS mutation was not predictive for cetuximab effect. OS was similar for patients treated with FLOX intermittently and cetuximab continuously as for patients treated until progression. BRAF mutation was a strong negative prognostic factor (median OS 7.6 vs. 20.4 mo). Conclusions: Cetuximab did not add significant benefit to the Nordic FLOX regimen in first-line treatment of mCRC, irrespective of KRAS-mut. [Table: see text] [Table: see text]
Toxicity and tolerability of dose dense (q 14 days) docetaxel (T)/ doxorubicin (A)/ cyclophosphamide (C) (TAC) in stage II - III breast cancer
Authors: J. H. Margolis, R. Zekman
Journal: Journal of Clinical Oncology (2005)

795 Background: Dose dense chemotherapy has shown improved clinical outcomes in breast cancer therapy (Citron, et al. JCO, 2003). Dose density has not been evaluated using TAC. Methods: From April 2003 to September 2004, 16 women mean age 43 with newly diagnosed stage II - III breast cancer received TAC q 14 days (T=75 mg/m2, A=50 mg/m2, and C=500 mg/m2) and Pegfilgrastim 6 mg every 14 days for 6 cycles. The planned cumulative dose over 6 cycles was T=450 mg/m2, A=300 mg/m2, and C=3000 mg/m2. Results: The mean treatment interval was 11 weeks (range, 10 to 15 weeks). The mean delivered dose intensity was T=90% (405 mg/m2), A= 96% (288 mg/m2), and C=98% (2940 mg/m2). There were a total of 93 cycles of chemotherapy administered of which 61(66%) were administered without dose reduction. 9 patients required a dose reduction of at least one cycle. Hand-foot syndrome (HFS) required a dose reduction in 7(44%) patients, and accounted for 12(13%) cycles reduced. Mucositis required a dose reduction in 4(25%) patients, and accounted for 16(17%) cycles reduced. Febrile neutropenia was noted in only one patient. 79(85%) cycles were given successfully without a dose delay. 9 patients required a dose delay in at least one cycle most commonly due to HFS or mucositis, an average of 7 days. Other toxicities noted were, grade 1–2 anemia 16(100%) and thrombocytopenia 5(31%), nausea 11(69%), and fatigue in 11(69%) patients were treated successfully with supportive care. Heart failure was not noted in any patients, and currently all patients are alive at short term follow up. Conclusions: TAC q 14 days is feasible in patients with stage II - III breast cancer. Despite the dose reductions and delays, patients received most of the planned protocol dose and maintained dose density. An unexpected unique toxicity, HFS was apparent which was not noted in TAC q 21 days. Interestingly, febrile neutropenia was not a major toxicity in this group as compared to traditional TAC q 21 days. A randomized controlled trial should be done to compare the efficacy of TAC q 21 days to TAC q 14days. No significant financial relationships to disclose.
Prognostic significance of the PSA nadir after salvage radiotherapy following radical prostatectomy in prostate cancer.
Authors: Thomas Wiegel, Detlef Bartkowiak, Dirk Bottke, Alessandra Siegmann, Volker Budach, Wolfgang Hinkelbein
Journal: Journal of Clinical Oncology (2015)

207 Background: Salvage radiotherapy (SRT) is a curative approach in recurrent prostate cancer after radical prostatectomy. The outcome depends on various parameters. We report the long term results of SRT with special respect to the course of PSA after SRT. Methods: Between 1997 and 2007, 307 patients received SRT with 66.6 (N=240) or 70.2 Gy (N=67) using CT-based 3D planning. The median pre-SRT PSA was 0.297 ng/ml. Post-SRT progression was defined as either PSA rising &gt;0.2 ng/ml above nadir, or hormone treatment, or clinical recurrence. Data were analyzed with the Kaplan-Meier method (Logrank-test) and with multivariate Cox regression. Results: Patients were followed up for median 7.2 (max. 14.4) years. Recurrence occurred in median 9.4 months post-RP. In 112 patients, SRT was administered before their PSA reached 0.2 ng/ml, 195 men were above that threshold. After SRT, 222 patients achieved a PSA nadir &lt;0.1 ng/ml, 85 retained higher values. SRT given at a PSA &lt;0.2 ng/ml correlated with achieving a post-SRT nadir &lt;0.1 ng/ml (p&lt;0.0001) and with improved freedom from progression (p=0.0133). Men with a post-SRT nadir &lt;0.1 ng/ml (undetectable range) had significantly less recurrences (p&lt;0.0001) and a better overall survival (p=0.0248). In multivariate analysis of pre-SRT parameters, pT≥3, Gleason Score ≥7, a post-RP PSA nadir ≥0.1 ng/ml and pre-SRT PSA ≥0.2 ng/ml increased the risk of progression. If failing the post-SRT nadir &lt;0.1 ng/ml was included in the model, then this was the strongest risk factor (hazard ratio 7.93). Conclusions: Our data suggest early salvage RT at a PSA level below 0.2 ng/ml to be a favorable treatment option for post-RP PSA recurrence. It increases the chances of achieving a post-SRT PSA-nadir &lt;0.1 ng/ml, which is associated with an improved outcome in terms of PSA progression and overall survival.
Correlation of clusterin with pancreatic endocrine tumors' size and stage.
Authors: P. Allam-Nandyala, J. Djeu, D. Coppola
Journal: Journal of Clinical Oncology (2011)

291 Background: Clusterin, a ubiquitous multifunctional cytoplasmic and secretory sulfated glycoprotein (sCLU), plays a role in prevention of apoptosis and it is overexpressed in a variety of tumors. The role of sCLU in pancreatic neuroendocrine tumors (PET) has not been investigated. In this study sCLU expression was evaluated in a subset of PET, and the results were correlated with the clinical pathological features of the tumors. Methods: sCLU expression was immunohistochemically evaluated in 106 cases of PET using the avidin-biotin-complex method and the tissue microarray analysis technology. The immunohistochemical reactions were qualitatively and semiquantitatively evaluated by 2 pathologists. Results: Strong sCLU reactivity was identified in 36/65 (51%) PETs. In 23/65 (35%) cases the sCLU score was 3 or less. sCLU expression scores significantly correlated with tumor size (p-value= 0.03) and with tumor stage (p-value= 0.02). The IHC score index did not correlate with tumor grade (p= 0.15). Conclusions: We report the novel expression of sCLU in PET. The correlation of sCLU with PET size and stage involves this molecule in pancreatic neuroendocrine tumorigenesis. sCLU may represent a new target of therapy for PET. No significant financial relationships to disclose.
Adjuvant chemoradiation for resected gallbladder cancer.
Authors: B. G. Muller, J. A. Sola, M. Carcamo, A. Sola, A. M. Ciudad, C. Trujillo
Journal: Journal of Clinical Oncology (2011)

319 Background: Gallbladder cancer (GBC) is the leading cause of cancer death in women in Chile. Even after curative surgery, prognosis is grim. To evaluate acute and late toxicity and efficacy in terms of overall survival of adjuvant chemoradiation (CR) after curative resection of GBC. Methods: We retrospectively analyzed the cohort of patients with curatively resected GBC diagnosed between January 1999 and April 2009, treated with adjuvant CR at the Instituto Nacional del Cáncer, Santiago de Chile. Treatment protocol considered external beam radiation therapy (RT) (45–54 Gy) to tumor bed and regional lymphnodes with concurrent 5-fluorouracil (5-FU) (500 mg/m 2 /day by 120-h continuous infusion on days 1-5 and 29-33). Data was obtained from medical records, mortality from death certificates. NCI CTC v 3.0 was used for toxicity grading, and 6th Edition of AJCC Cancer Staging Manual for staging. Survival was estimated by Kaplan- Meier curves. Results: 45 patients with curatively resected GBC received adjuvant CR. Mean age was 56 years (range 33-75), 38 patients were female. All patients had PS 0 or 1 at baseline. After diagnosis a second surgery was performed in 41 patients. Cholecystectomy with hepatic segmentectomy and lymphadenectomy was the curative surgery in 40 patients. For tumor and staging details see the Table. All patients received RT with a planned dose of 45 Gy in 25 fractions. 9 patients received a boost to the tumor bed up to 54 Gy. Three patients stopped RT early. 33 patients had concurrent 5-FU, 31 completed treatment as planned. Therapy was well tolerated, only 4 grade 3 toxicities were observed (1 neutropenia, 1 thrombocytopenia, 2 elevated alkaline phosphatase). No grade 4 or 5 toxicity was observed. No grade &gt;2 late toxicity was observed. Twenty two patients have died. Median survival was 26 months, with 3- and 5-year overall survival of 64% and 46% respectively. Conclusions: Adjuvant chemoradiation with 5-FU is well tolerated and might impact favorably on survival in patients with curatively resected GBC. [Table: see text] No significant financial relationships to disclose.