tbuckley/cabot-search huggingface dataset:
Randomized phase II/III study of docetaxel/S-1 (DS-1) versus CDDP/5FU (FUP) in advanced or recurrent gastric cancer: Updated phase II results
Authors: R. Ikeda, K. Yoshida, Y. Satou, M. Takahashi, Y. Une, W. Yamamoto, K. Tanimoto, K. Hiyama, Y. Sasaki, M. Nishiyama
Journal: Journal of Clinical Oncology (2009)

4595 Background: Our previous single arm phase II trial demonstrated that the combination of DS-1 was one of the most powerful candidates to become a standard regimen for metastatic gastric cancer (K. Yoshida, et al: Clin Cancer Res 2006). This trial evaluated DS-1 and FUP in advanced or recurrent gastric cancer, and the primary objective of the phase II part was to evaluate activity and safety of the 2 regimens. Methods: Patients with advanced or recurrent gastric cancer, who had not received any chemotherapy except one regimen (not including taxanes), were eligible for this trial. Patients were randomized to either: DS-1, intravenous administration of 40 mg/m 2 docetaxel on Day1 and oral administration of 80–120 mg/m 2 /day S-1 on Days 1 to 14 every 3 weeks, or FUP, intravenous continuous administration of 800 mg/m 2 /day 5-FU on Day 1 to 5 and intravenous administration of 80 mg/m 2 /day CDDP on Day 2 every 4 weeks. Results: Between June 2005 and August 2008, forty-nine of 54 patients (ECOG PS 0–2) were randomized to DS-1 (n=24) or FUP (n=25). Response rates (CR+PR) assessed by RECIST were 88.3% (CI;62.6–95.3) vs 52.0% (CI; 31.3–72.2, P=0.032), median times to treatment failure (TTF) were 122 days (CI; 75.2–168.8) vs 85 days (CI;67.9–102.1, P=0.003), median progression free survivals (PFS) were 198 days (CI;117.8–278.4) vs 105 days (CI;90.3–119.7, P=0.066). Median overall survival times (MSTs) were 369 days (CI; 359.6–378.4) vs 371 days (CI; 297.2- 444.8, P=0.281), but as of today, 14 pts (8 in DS-1 and 6 in FUP) are still alive. Grade 3/4 adverse events assessed by CTCAE v3.0 occurring in ≥20% patients, were neutropenia (58.3% vs 28.0%), nausea (4.2% vs 20.0%), leucopenia (33.0% vs 4.0%), fatigue (0% vs 20.0%) and anorexia (8.3% vs 32.0%). All treatment-related adverse events were resolved and no toxic death was reported. Conclusions: DS-1 significantly improved the RR and TTF in advanced or recurrent gastric cancer patients. To clarify the survival benefit, a phase III continuation of the study is in preparation. No significant financial relationships to disclose.
Neoadjuvant treatment evaluation in soft tissue sarcomas (STS): Looking for news in radiologic and pathologic response.
Authors: N. Sala, L. Robert, A. Lopez-Pousa, M.J. Quintana, J. Llauger, S. Baguã, O. Gallego, M. Vega, I. Gracia, J.M. Mazarico, A. Sebio.
Journal: Journal of Clinical Oncology (2010)

e20509 Background: Chemotherapy (CT) and combined chemoradiotherapy (CRT) have been explored for preoperative management of locally advanced soft tissue sarcomas (STS). Pathological and radiological changes could be a predictor of behaviour and predictor factor in STS. Objective: To correlate pathological and radiological patterns of response to neoadjuvant chemotherapy (CT) or chemoradiotherapy (CRT) in localized high grade STS. Methods: Between 2001 and 2009, 34 patients stage III STS were treated in two consecutive neoadjuvant trials with high-dose ifosfamide or epirubicine + ifosfamide (22 patients received CRT 44 Gy) before surgery (70% conservative surgery). Adjuvant treatment consisted in CT in 13 p (4 high- dose ifosfamide, 9 ifosfamide-epirrubine) and RT in 10 p. Median follow-up was 33 months (4.2-99). Histological types: 15 pleomorphic, 8 synovial, 4 leiomiosarcoma, 7 others. Median tumor size 11cm (5-25cm). Patients were evaluated with MRI basal and before surgery, analizing size, necrosis, contrast uptake and signal (T1 and T2). Pathological response includes size, margins, tumor viability, distribution and necrosis (according Huvos score). Results: Response rate (RECIST) was PR 12 p (36%), SD 19 p (57%), PD 2 p (6%) and it correlates with survival (p 0.03). Overall survival was 83.6m (1,2,3-year survival: 97.1%, 89.6%, 78.4% respectively). Disease-free survival (DFS) was 78.29m (65.28-91.30). Induced tumoral necrosis (≥95%) after treatment didn't show statistical significance. Positive margins (p 0.03) and size increase (p 0.017) correlates with worse prognosis. Only T1 signal change to hiperintensity was significant with better survival (p 0.001), relapse (p 0.02) and time to relapse (p 0.004); decrease in contrast uptake was not significant. Conclusions: After neoadjuvant treatment in STS, analizing MRI tumor size and T1 signal changes to hiperintensity should be considered in response evaluation. Optimal surgery should include negative margins. However tissue necrosis does not seem to predict outcome. No significant financial relationships to disclose.
Long-term follow-up of limited stage small cell lung cancer patients treated with carboplatin-based chemotherapy and radiotherapy by the Minnie Pearl Cancer Research Network (MPCRN)
Authors: D. R. Spigel, J. D. Hainsworth, H. A. Burris, C. Dannaher, J. Hon, L. H. Morrissey, F. A. Greco
Journal: Journal of Clinical Oncology (2004)

7222 Background: Cisplatin plus etoposide and radiotherapy (RT) is considered standard therapy for good performance status (PS) patients with limited stage small cell lung cancer (SCLC) with a 5-year survival rate of about 20%. From 1993 through 2001, 180 patients with limited-stage SCLC were entered on 4 sequential phase II trials of carboplatin-based chemotherapy with RT (see Table). Methods: The primary objective of this analysis was to evaluate the long-term survival of carboplatin-based RT regimens. Eligible patients had limited stage SCLC; no prior systemic therapy; ECOG PS 0–2 (trials 1, 2, 3); PS 0–1 (trial 4), and adequate organ function. Results: 101 women and 79 men were enrolled with a median age of 60 years (range 35–85) years. The median survival of all patients was 17.4 months. The minimum follow-up is 2.25 years (range 2.25–10.4 years). Overall noncensored survival at 2 and 5 years was 38% and 20%, respectively. Actuarial survival at 10 years is 10%. Conclusions: Carboplatin-based/RT regimens given in a community setting by the MPCRN for patients with limited stage SCLC produced a 5-year survival rate of 20%, which is comparable to standard cisplatin-based/RT regimens. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb; GlaxoSmithKline
Outcomes after autologous stem cell transplantation in relapsed or refractory Hodgkin disease: The Duke experience
Authors: D. W. Kim, D. Misra, R. W. Clough, G. D. Long, R. G. Prosnitz
Journal: Journal of Clinical Oncology (2007)

8100 Background: High dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) offers patients with relapsed or refractory Hodgkin's disease (HD) the possibility of durable long term remission. We examined the characteristics and outcomes of patients treated at Duke University Medical Center between May 1997 and May 2006. Methods: We performed a retrospective chart review on all patients with relapsed or refractory HD who received HDT followed by ASCT at our institution. Various prognostic factors were also analyzed for their impact on overall survival (OS) and disease free survival (DFS). Results: Sixty-one patients received HDT followed by ASCT for relapsed or refractory HD. Median age was 33 years (range: 16 years to 64 years). The patient population was comprised primarily of males (64%), Caucasians (80%), and patients with nodular sclerosing histology (77%). Fifty-six percent of patients had primary refractory HD. At the time of relapse, 44% of patients had stage I-II disease, and 21% had B symptoms. For patients with relapsed disease, the median time from initial diagnosis to relapse was 17 months. Most patients (64%) received cyclophosphamide, etoposide, and BCNU chemotherapy as HDT. Thirty-one percent of patients received consolidative radiotherapy after HDT. Twenty-eight percent of patients had chemotherapy- responsive disease prior to undergoing HDT. Following ASCT, 46/61 (75%) of patients achieved a complete response. Transplant-related deaths occurred in 2/61 (3%) patients. With a median follow-up of 2.5 years (range: 3 months to 8.8 years), the actuarial 5-year OS and DFS were 79% and 50%, respectively. The most common post-therapy complication was pneumonitis, which occurred in 62% of patients. Three (5%) patients developed second malignancies. On univariate analysis, gender, stage at diagnosis, stage at relapse, presence of B symptoms at relapse, and the interval to first relapse did not significantly affect OS or DFS. Conclusions: Our results confirm that HDT followed by ASCT offers an excellent chance for long-term DFS and OS in patients with relapsed or refractory HD, with a low risk of treatment-related mortality. No significant financial relationships to disclose.
Early Palliative Care in Cancer Patients. Systematic Review of Literature, with Meta-Analysis of Randomized Clinical Trials
Authors: A. Affatato, L. Stocchi, F. Drudi, S. Nicoletti, M.C. Monterubbianesi, C. Ridolfi, E. Barzotti, C. Santelmo, F. Carloni, D. Tassinari
Journal: Annals of Oncology (2014)
Use of colony stimulating factors (G-CSF and GM-CSF) after allogeneic stem cell transplantation in adult patients: A meta-analysis of published studies
Authors: R. S. Komrokji, E. G. Dib, J. L. Liesveld, G. L. Phillips, G. H. Lyman
Journal: Journal of Clinical Oncology (2004)

6638 Background: Use of colony stimulating factors (CSFs) accelerate the hematopoietic recovery after allogeneic stem cell transplant (allo-SCT). The impact of using CSFs after allo-SCT on survival and duration of hospitalization is unclear. The primary objectives of our meta-analysis were the effect of CSFs on 100-day survival, long-term survival, and duration of hospitalization. The secondary objectives were hematopoietic recovery, GVHD, febrile neutropenia, use of parenteral antibiotics, transplant related mortality, relapse rate, and DFS. Methods: Data search of published studies included Medline (1966–2003), Embase, Cochrane library and hand search of references. Studies were included if they were randomized or controlled trials of using CSFs after allo-SCT versus placebo or no treatment. A quality score was generated to assess the studies (7 points score based on predetermined quality items). All data extraction and quality assessment were done in duplicate independently. . Results: Eight randomized or controlled clinical trials were included (n = 458)(G-CSF = 4, GM-CSF = 4). The mean quality score was 4 / 7. Hematological malignancies were the underlying disease in most studies (one study included solid tumors). CSFs group and placebo / no treatment group were balanced in age, sex, disease status, conditioning regimens, number of stem cell infused, and GVHD prophylaxis. There was no difference on 100-day mortality between the CSFs group and the placebo / no treatment group (odds ratio 1.21 [95% CI 0.76, 1.92]; P value = 0.41). The long term mortality was also not different (odds ratio 0.79 [95% CI 0.54, 1.16]; P value = 0.23). Results on duration of hospitalization, the other secondary endpoints, and an economic analysis will be presented. Conclusions: CSFs improve hematopoietic recovery when used after allo-SCT. There is no evidence CSFs have impact on 100-day survival or long-term survival. Larger sample size and better quality studies are needed to address this question. Economic analysis will be presented. We are conducting a similar meta-analysis addressing the role of CSFs in autologous SCT. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Amgen
A phase I dose escalation and pharmacokinetic (PK) study of intravenous (iv) aflibercept (VEGF Trap) plus weekly gemcitabine (Gem) in patients (pts) with advanced solid tumors: preliminary results
Authors: A. Patnaik, M. Pipas, L. S. Rosen, L. Wood, K. Phipps, M. Mulay, C. Garay, M. Korc, J. Sarantopoulos
Journal: Journal of Clinical Oncology (2008)

3558 Background: Aflibercept (AF) is a recombinant fusion protein that is a potent inhibitor of vascular endothelial growth factor (VEGF). This study was designed to assess the safety/tolerability, dose-limiting toxicities (DLTs), recommended Phase II dose, and PK of AF plus Gem. Methods: This combination trial explored escalating iv doses of AF, administered every 2 weeks(q2w), followed by standard weekly iv Gem (7w on/1w off, then 3w on/1w off every 4w). Results: 32 pts (M/F 9/23, median age 58 [38–75], ECOG-PS 0/1/2: 10/21/1) were enrolled in 2 AF dose levels: 4.0 (n = 20) and 6.0 (n = 12) mg/kg. Primary tumors included pancreas (11), breast (7), sarcoma (3), and others (11). Most (9/11) pancreatic pts were first-line. Other pts were heavily pre-treated, with a median of 3[1–11] prior lines. Pts received a median of 2 [1–9] 4w treatment cycles (cy). During the dose escalation phase, no AF-related DLT (first 4w cy) was observed. Gr > 3 NCI-CTCAE toxicities observed across doses included: neutropenia (34%), thrombocytopenia (22%), hypertension (HTN) (22%), proteinuria (PrU) (6%), pulmonary embolus (6%, including one Gr 5 at 4 mg/kg in a pancreatic cancer pt), and unstable angina, hemorrhage, blurred vision (3% each). In 4/12 pts (33%) at 6 mg/kg, Gr 3 HTN not controlled despite 4w treatment and/or Gr 3 PrU contributed to early treatment discontinuation. One partial response was noted (breast at 4mg/kg) and 10 pts had stable disease. Free and bound AF concentrations with Gem are comparable to those observed with AF alone. At both doses, free AF exceeds bound AF over dosing interval, suggesting sustained effective trapping of VEGF. Conclusions: AF 4 mg/kg q2w combined with weekly gemcitabine was selected for further investigations. Updated data will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis
Comparative Genomics of Candidate Phylum TM6 Suggests That Parasitism Is Widespread and Ancestral in This Lineage
Authors: Yun Kit Yeoh, Yuji Sekiguchi, Donovan H. Parks, Philip Hugenholtz
Journal: Molecular Biology and Evolution (2015)

Candidate phylum TM6 is a major bacterial lineage recognized through culture-independent rRNA surveys to be low abundance members in a wide range of habitats; however, they are poorly characterized due to a lack of pure culture representatives. Two recent genomic studies of TM6 bacteria revealed small genomes and limited gene repertoire, consistent with known or inferred dependence on eukaryotic hosts for their metabolic needs. Here, we obtained additional near-complete genomes of TM6 populations from agricultural soil and upflow anaerobic sludge blanket reactor metagenomes which, together with the two publicly available TM6 genomes, represent seven distinct family level lineages in the TM6 phylum. Genome-based phylogenetic analysis confirms that TM6 is an independent phylum level lineage in the bacterial domain, possibly affiliated with the Patescibacteria superphylum. All seven genomes are small (1.0–1.5 Mb) and lack complete biosynthetic pathways for various essential cellular building blocks including amino acids, lipids, and nucleotides. These and other features identified in the TM6 genomes such as a degenerated cell envelope, ATP/ADP translocases for parasitizing host ATP pools, and protein motifs to facilitate eukaryotic host interactions indicate that parasitism is widespread in this phylum. Phylogenetic analysis of ATP/ADP translocase genes suggests that the ancestral TM6 lineage was also parasitic. We propose the name Dependentiae (phyl. nov.) to reflect dependence of TM6 bacteria on host organisms.
Association of reduced intraepithelial CD3+/regulatory T-cell ratio with poor outcome in human colon cancers
Authors: F. A. Sinicrope, R. L. Rego, N. R. Foster, D. J. Sargent, S. M. Ansell, E. D. Kwon
Journal: Journal of Clinical Oncology (2008)

11023 Background: Colon cancers elicit a host-mediated anti-tumor response that is characterized by tumor infiltrating lymphocytes (TILs). Regulatory T cells (Treg) are a T cell subset that express the forkhead box transcription factor (FoxP3) and can inhibit anti-tumor immune responses. We analyzed the frequency and localization of Treg cells, as indicated by FoxP3 expression, and the pan T lymphocyte marker CD3+ in human colon cancers and their relationship to clinical outcome. Methods: TNM stage II and III colon carcinomas (n= 160) from patients treated in 5-fluorouracil-based adjuvant therapy trials were analyzed for FoxP3 and CD3 expression in lymphocytes infiltrating tumor epithelium and stroma by immunohistochemistry. The CD3+/ FoxP3+ ratio was calculated, grouped by quartile, and dichotomized at the 1st quartile for analysis. CD3+, FoxP3+ and their ratio were then correlated with tumor stage, disease-free (DFS) and overall survival (OS) rates. Results: FoxP3+ lymphocytes were significantly increased in tumor epithelium and stroma compared to autologous normal colonic mucosa (p< 0.0001). No association was found between CD3+, FoxP3+ or their ratio and stage. Increased CD3+ T cells in the epithelium, but not stroma, showed improved DFS [(5 yr. 68.1 vs. 51.1%; HR 0.54 (0.32, 0.91); p=0.018]. Calculation of the CD3+/ FoxP3+ ratio enabled an assessment of Tregs as a proportion of T cells. While FoxP3 alone was not prognostic, a lower intraepithelial CD3+/FoxP3 ratio was associated with worse DFS 5 yr. 47.5 vs, 68.3%); HR 0.52 (0.31, 0.89); p= 0.016)], but not OS [5 yr. 67.5 vs. 71.7%; HR 0.67 (0.39, 1.14); p= 0.135)]. The CD3+/FoxP3+ ratio in tumor stroma was not prognostic. Conclusions. FoxP3+ infiltrating T lymphocytes are significantly increased in colon carcinomas compared to autologous normal mucosa. Increased intraepithelial CD3+ T cells were associated with a more favorable outcome. However, a reduced ratio of CD3+/FoxP3+ cells was associated with worse survival rates consistent with a role for regulatory T cells in suppressing the anti-tumor immune response. Prognostic Impact of CD3+ and CD3+/FoxP3+ Ratio Intraepithelial Total (N= 160) 5-yr DFS % Hazard Ratio (95% CI) P-value 5-yr OS % Hazard Ratio (95% CI) P-value CD3+_ 1st quartile other 47113 51.1% 0.54 0.0180 63.8% 0.68 0.1492 68.1% (0.32, 0.91) 73.5% (0.41, 1.15) CD3+/FoxP3+ 1st quartile other 40120 47.5% 0.52 0.0159 67.5% 0.67 0.1345 68.3% (0.31, 0.89) 71.7% (0.39, 1.14) No significant financial relationships to disclose.
A phase I and pharmacokinetic study of nolatrexed dihydrochloride, a potent thymidylate synthase (TS) inhibitor, combined with docetaxel in patients with advanced cancer
Authors: S. Syed, E. Calvo, K. P. Papadopoulos, A. Ricart, T. Dufresne, J. Cooper, C. Takimoto, G. Suplick, J. Garcia-Vargas, E. K. Rowinsky
Journal: Journal of Clinical Oncology (2005)

2115 Background: Thymitaq (Th) is a potent and direct inhibitor of TS which has shown activity in patients with head and neck tumors or hepatocarcinoma, as well as in breast, ovarian, and lung cancer models. Because of its lipophilicity and absence of a glutamate moiety, it is not susceptible to certain resistance mechanisms implicated in classical antifolate TS inhibitors, including impaired transport or decreased polyglutamylation. In addition of accumulative evidence of synergism between taxanes and antifolates, Th and docetaxel (Doce) have different mechanisms of action and activity spectrum, as well as nonoverlapping toxicities, which provide a rationale for their evaluation in combination. Methods: Escalating doses of 120-hour IV infusion of Th from a starting dose level of 600 mg/m2/day, and Doce from an initial dose of 30 mg/m2 IV on D1 every 28 days were administered to minimally-pretreated patients with advanced solid malignancies. Folic acid and vitamin B12 supplementation was provided during the study. Results: To date, 8 pts (median age 58, [45–72]; 3 male/5 female; hepatocarcinoma [3], gall bladder, esophagus, stomach, and kidney carcinoma, and soft tissue sarcoma [1, each]) have received 13 courses (range 1–4) at Doce dose levels of 30 mg/m2 (3 pts), and 45 mg/m2 (5 pts) with 600 mg/m2/day of Th. DLTs have been G3 fatigue (1 pt), and G3 mucositis and G4 neutropenia, febrile, in a patient with cirrhosis and hepatocarcinoma, which might have resulted in decreased clearance of the drugs, especially Doce. Toxicities are mostly mild to moderate, including G3 neutropenia, G2 thrombocytopenia, and G2 nausea/vomiting, diarrhea and bilirubin elevation, each in 12.5% of pts. Css of Th (mean, 5.51 μg/mL; ranges 2.86 to 6.19 μg/mL; n=5 pts), were in the same range as prior PK studies at a similar dose and, at the present dose level, already portend biologic activity based on animal models. Conclusions: The MTD and recommended dose of Th in combination with Doce for disease-directed studies with this regimen has not been determined yet. Expanded accrual continues at 600 mg/m2/day of Th and 45 mg/m2 of Doce as the potential recommended dose. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eximias
Abnormal pulmonary arterial remodelling in patients with combined pulmonary fibrosis emphysema (CPFE) and idiopathic pulmonary fibrosis (IPF)
Authors: Elisabetta Balestro, Francesca Lunardi, Emanuela Rossi, Nazarena Nannini, Giuseppe Marulli, Monica Loy, Federico Rea, Fiorella Calabrese
Journal: European Respiratory Journal (2011)

CPFE is a syndrome with distinct clinical, functional and radiological characteristics. Recent works have demonstrated the impact of pulmonary hypertension (PH) on worse survival but little is known about the morphological and molecular substrates. The aim of our study was to evaluate the arterial remodelling and expression of transforming growth factor-beta1 (TGF-β) in the lungs of patients with CPFE compared to IPF without PH. The study was performed on lung samples or native lungs (2007-10 recruitment period): 7 CPFE patients (mean age 59±5.8 yrs), 15 IPF patients (mean age 53±10yrs) and 5 non-implanted donors (mean age 30±10yrs) as a normal control group. In all cases morphometry was used to measure arterial intimal, medial, and total thickening and immunohistochemical evaluation of TGF-β was quantified in macrophages and alveolar epithelial cells. In CPFE, FEV1%pred and FVC%pred were significantly less reduced than in IPF (p=0.004 and p=0.003, respectively), while DLCO%pred was similar. Intimal and total thickening were significantly increased in CPFE than IPF (p=0.004 and p=0.03, respectively). A trend of increased alveolar TGF-β expression was detected in CPFE compared to IPF (p=0.07) while its expression in macrophages was similar. As expected, arterial remodelling and TGF-βexpression were significantly increased in both IPF (p=0.001; p=0.001 respectively) and CPFE (p=0.004; p=0.003, respectively) compared to controls. In conclusion, our study demonstrated that lungs with CPFE display significant arterial remodelling which may represent pathological substrate for the increased occurrence of PH.