tbuckley/cabot-search huggingface dataset:
Therapeutic effects and pharmacokinetics of recombinant human granulocyte-macrophage colony-stimulating factor in childhood cancer patients receiving myelosuppressive chemotherapy.
Authors: W L Furman, D L Fairclough, R D Huhn, C B Pratt, N Stute, W P Petros, W E Evans, L C Bowman, E C Douglass, V M Santana
Journal: Journal of Clinical Oncology (1991)

Twenty-five children with refractory solid tumors were given recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in escalated doses of 60 to 1,500 micrograms/m2 as 2-hour intravenous infusions, beginning 24 hours after myelosuppressive treatment with cisplatin and etoposide. Tolerance to rhGM-CSF was exceptional even at dose levels that exceeded the maximum-tolerated dosage (MTD) reported for adults. The agent produced dose-related increases in platelet and neutrophil counts, resulting in significantly shorter durations of severe neutropenia and thrombocytopenia (P less than .01 for each analysis). At the higher dosages (greater than or equal to 750 micrograms/m2), treatment with rhGM-CSF reduced the median number of days of antibiotic therapy for fever and neutropenia by approximately one half. We conclude that rhGM-CSF is well tolerated by leukopenic children in doses as high as 1,500 micrograms/m2. An MTD was not reached in this study. The ability of the growth factor to reduce severe neutropenia and thrombocytopenia suggests it will have an important role in the management of childhood solid tumors.
EMD121974 (NSC 707544, cilengitide) in asymptomatic metastatic androgen independent prostate cancer (AIPCa) patients (pts): A randomized trial by the Prostate Cancer Clinical Trials Consortium (NCI 6372)
Authors: D. A. Bradley, R. Dunn, C. Ryan, R. DiPaola, D. C. Smith, K. A. Cooney, P. Mathew, M. Gross, A. D. Colevas, M. Hussain
Journal: Journal of Clinical Oncology (2007)

5137 Background: Integrins a v β 3 and a v β 5 are essential to PCa metastasis by regulating cell adhesion, migration, invasion and motility. Cilengitide is a potent and selective a v β 3 and a v β 5 integrin receptor antagonist that in phase I studies has shown clinical activity. Methods: Pts with asymptomatic, metastatic chemo-naive AIPCa with PSA or objective progression, no visceral disease, minimum PSA of 5ng/ml, and adequate organ function were randomized to cilengitide 500 mg or 2,000 mg IV 2X weekly in 6-week cycles, using modified randomized selection design. Disease status was assessed every 12 weeks. The primary end point is objective progression rate (not including PSA) at 6 months. The Simon 2-stage optimal design is used to accrue 53 pts/arm. After first stage (20 pts/arm), accrual continues if ≥ 6 pts have not progressed. If second stage accrual is initiated, at end of study, the better performing arm will be chosen for further study provided at least 18/53 pts in that arm have not progressed. Secondary end points include safety, response rates and correlative measures of cilengitide effect on circulating and bone marrow tumor and endothelial cells and on bone remodeling markers. Results: First stage accrual is complete with 42 pts registered. Median performance status is 0, median age is 71 years (range 52–85), and median PSA is 44ng/ml (range 5–870). Disease progression at registration was defined by PSA in 90%, soft tissue in 36% and bone in 31% of pts. Median number of cilengitide cycles is 3 (range 1–8). To date, 32/42 pts have received ≥ 2 cycles. The most common (&gt;5%) treatment related adverse events (AE): fatigue (38%), constipation (13%), anorexia (10%), leucopenia (8%) and nausea (8%). There were only 3 grade (G) 3 AEs (neutropenia, lymph node pain, lymph NOS) and no G4 AEs. Only 3 pts required dose modification. 25/42 pts were removed from protocol on or before 6 months, 6 pts received therapy for more than 6 months, and 11 are too early to assess. Conclusions: Cilengitide is well tolerated. Final results (efficacy, safety, correlative studies) of the first stage of accrual will be reported. Supported by CTEP, Prostate SPORE Grant P50 CA069568- 09, PC051375, Merck KGaA, PC051382. [Table: see text]
Analysis of a panel of serum biomarkers in patients with metastatic lung cancer.
Authors: E. Lou, M. L. Johnson, C. Sima, R. Gonzalez-Espinoza, M. G. Kris, C. G. Azzoli, M. Fleisher
Journal: Journal of Clinical Oncology (2010)

e18080 Background: To date, there is no blood test or panel of serum biomarkers commonly used for diagnosis, prognosis or management of patients with lung cancer. We hypothesized that selected protein biomarkers measured in the serum of patients with metastatic lung cancer may correlate with patient survival, or assist in distinguishing between histologic subtypes (squamous vs. adenocarcinoma vs. small cell). Methods: After informed consent, we compiled and analyzed baseline samples of serum prior to chemotherapy from 52 patients with metastatic non-small cell (NSCLC) or small cell lung cancer (SCLC). ELISA was performed on 96-well plates using a robotic plate analyzer in the MSKCC Clinical Laboratory. Selected biomarkers tested to date include: pro-GRP, SCCL, neuron-specific enolase (NSE), CyFra-21. Baseline (pre-treatment) levels have been correlated with patient outcome (proportional hazards method) and tumor histology (logistic regression method) using a prospectively maintained clinical database. Results: Baseline serum levels of CyFra-21 significantly predicted increased risk of mortality (HR 1.4, 95% CI 1.1-1.9, p = 0.01). No association was found between baseline NSE, pro-GRP, and SCCL levels and survival. Preliminary results comparing NSCLC versus SCLC indicate significantly higher levels of NSE (p < 0.03) and pro-GRP (< 0.001), and lower levels of CyFra-21 (p < 0.02), in SCLC. A multivariate logistic model that includes NSE, pro-GRP and CyFra-21 distinguished between SCLC and NSCLC with almost perfect accuracy (C Index = 0.98). Conclusions: Serum biomarkers may be useful in predicting patient survival and distinguishing NSCLC from SCLC. Increased levels of CyFra-21 at the time of diagnosis may be associated with increased mortality. SCLC is associated with higher levels of NSE and pro-GRP, and with lower levels of CyFra-21. There is indication that a valuable prediction instrument can be built using these three markers. Serum analysis is ongoing using samples from 4 timepoints in up to 230 patients. Measurements of the following additional_serum markers are planned: HE-4, mesothelin, osteopontin, CEA, alpha-1 antitrypsin, TTF-1, VEGFR and EGFR. No significant financial relationships to disclose.
Patterns of use of docetaxel in stage IV prostate cancer (PCa) patients in SEER-Medicare.
Authors: E. Onukwugha, M. Grabner, C. D. Mullins, B. S. Seal, A. Hussain
Journal: Journal of Clinical Oncology (2010)

4658 Background: To date, docetaxel (D) is the only chemotherapy agent that has provided a survival benefit to metastatic castration resistant PCa patients (pts). The objective of this study was to determine usage patterns of D in a large observational dataset, with stratification by demographics, treatment regimen, and time. Methods: We analyzed pts aged 66 or older from the linked Surveillance, Epidemiology, and End Results and Medicare (SEER-Medicare) database who received any type of chemotherapy. Pts were diagnosed with PCa between 2000 and 2005 and were followed until death or the end of the study period (December 31, 2007). We restricted the cohort to those with incident Stage IV disease (according to the AJCC-TNM classification). Using weekly and monthly data we calculated summary statistics and chi-square tests on D usage patterns by race groups, by age groups, and over time. Results: Application of the inclusion/exclusion criteria resulted in 1,248 Stage IV PCa pts on chemotherapy with 788 on D, of which 97% (N=761) also report receipt of androgen deprivation therapy (ADT). Docetaxel use increased from 55% in 2000 to 71% in 2005 (p-value <0.001). Among D pts, similar increases over time were noted for the proportion with M1 disease (73% to 91%; p- value <0.001), while the proportion using ADT remained high (97%) and stable over time. The distribution of D pts according to race (White; African American; Other) and age (66-74; 75-84; 85+) were [85%; 11%; 4%] and [59%; 38%; 3%], respectively. Among D pts, the vast majority (97%) received only D. A histogram of the average time between D claims followed a right-skewed, bimodal distribution with peaks at 1 week (34%) and 3 weeks (27%). The peaks were more defined by conditioning on ADT receipt, in the 66-74 year old (v. 75+) and 2003-2005 (v. 2000-2002) patient subgroups. Conclusions: The SEER-Medicare data set allows a rich characterization of docetaxel usage patterns. We find that the use of docetaxel varies over time and patient subgroups. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis Amgen, Bayer, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Lilly, Merck, Novartis, Pfizer, sanofi-aventis sanofi-aventis Pfizer, sanofi-aventis GlaxoSmithKline, Novartis, Pfizer, sanofi-aventis
Co-exposure to refractory ceramic fibres and asbestos and risk of pleural mesothelioma
Authors: Aude Lacourt, Mickael Rinaldo, Céline Gramond, Stéphane Ducamp, Annabelle Gilg Soit Ilg, Marcel Goldberg, Jean Claude Pairon, Patrick Brochard
Journal: European Respiratory Journal (2014)

The aim of this study was to investigate the hypothesis of an increased risk of pleural mesothelioma due to co-exposure to asbestos and refractory ceramic fibres (RCF) compared to asbestos exposure alone. Males were selected from a French case–control study conducted in 1987–1993 and from the French National Mesothelioma Surveillance Program in 1998–2006. Two population controls were frequency matched to each case by year of birth. Complete job histories were collected and occupational asbestos and RCF exposures were assessed using job exposure matrices. The dose–response relationships for asbestos exposure were estimated from an unconditional logistic regression model in subjects exposed to asbestos only (group 1) and subjects exposed to both asbestos and RCF (group 2). A total of 988 cases and 1125 controls ever-exposed to asbestos were included. A dose–response relationship was observed in both groups but it was stronger in group 2. In comparison with subjects exposed at the minimum value of the cumulative index of exposure, the odds ratio was 2.6 (95% CI 1.9–3.4) for subjects exposed to 75 fibres·mL −1 ·year −1 in group 1 increasing to 12.4 (95% CI 4.6–33.7) in group 2. Our results suggest that the pleural carcinogenic effect of occupational asbestos exposure may be modified by additional exposure to RCF.
Predictive utility of molecular markers for efficacy of preoperative gemcitabine and pemetrexed in lung cancer
Authors: K. E. Sommers, J. Zhou, A. Canter, X. Li, A. Sharma, L. Robinson, G. Bepler
Journal: Journal of Clinical Oncology (2008)

7544 Background: A phase II single-institution trial of preoperative gemcitabine and pemetrexed (GP) in patients with resectable NSCLC was conducted. The primary molecular objective was to assess associations between individual patients’ disease response and the level of expression of genes associated with GP metabolism at the RNA level. The primary clinical objective was to assess therapeutic efficacy and tolerability. Methods: Patients had to have stage IB, II, IIIA and selected IIIB disease that was surgically respectable by CT, PET, brain MRI, and mediastinoscopy. G (1,500 mg/m2) and P (500 mg/m2) were given on days 1, 15, 29, and 43. CT and PET were repeated, and patients with resectable disease had surgery. Fresh tumor specimens were processed as frozen sections for laser-capture microdissection (LCM) of tumor cells. Real-time RTPCR was used to quantify expression of target genes at the mRNA level. Results: 52 pts started therapy. The age ranged from 41–83 y; 26 were women; 21 had adenocarcinoma; and the disease stages were IB in 16, II in 18, and III in 18 pts. The RECIST response rates were 2% CR, 33% PR, 59% SD, and 6% PD. GP was well tolerated, 6 pts had G3 clinical toxicities, and 42 had all 4 cycles on time without dose modification. There was a significant correlation between the percentage of tumor response to GP and the levels of RRM1 (p ≤ 0.001; regulatory subunit of ribonucleotide reductase) and TS (p = 0.006; thymidylate synthase). Low levels of expression were associated with tumor shrinkage. The expression levels of all other genes were not significantly correlated with disease response. In vitro cytotoxicity of P, methotrexate, and G were similarly influenced by RRM1 expression; high levels were associated with resistance and low levels with sensitivity. P and G were moderately synergistic, and the degree of synergism was not influenced by RRM1 expression. Conclusions: Bi-weekly preoperative GP is well tolerated and produces an objective RR of 35%, which is similar to the 33–64% RR for platinum-containing doublets. Tumoral RRM1 and TS levels are predictive of disease response and should be included in future trials for chemotherapy selection in patients with resectable disease. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eli Lilly Eli Lilly Eli Lilly, sanofi-aventis
Outcome of patients with advanced GIST achieving a complete remission (CR) with imatinib (IM) before interruption: Pooled analysis of two consecutive prospective randomizations of the French Sarcoma Group BFR14 phase III trial
Authors: C. Chevreau, I. Ray-Coquart, B. Bui, A. Adenis, M. Rios, F. Duffaud, S. Darnis, A. Le Cesne, C. Moneron, J. Blay
Journal: Journal of Clinical Oncology (2009)

10549 Background: Patients (pts) experiencing a major response under IM treatment seem to have a better outcome than others (Cioffi, ASCO 08). IM interruption in responding patients after 1 and 3 yrs of treatment results in a high risk of rapid progression after a few months. The influence of pattern of response on PFS before IM discontinuation is unknown. Methods: Since June 2002, 415 pts were included in this trial. Fifty-eight, 50 and 12 (ongoing) non progressive pts at 1, 3 and 5 yrs respectively were randomly offered to continue (C arm) or interrupt (I arm) IM. Sixty-four pts were randomized in the I arm, 32, 25 and 7 after 1, 3 and 5 yrs of IM treatment respectively. Time to progression (TTP) of pts achieving a CR or a major PR (residual tumor &lt; 10mm) before IM interruption was compared to outcome of pts experiencing others patterns of response. Results: Twenty-three pts achieving a CR or a major PR (36%) before randomization in the I arm, 9 after 1 yr, 10 after 3 yrs and 4 after 5 yrs of IM treatment. As of December 2008, 15 relapses were observed in the CR group (65%) versus 36 in the other cohort of pts (90%). The median TTP were 10.5 months (IC95%: 9–16 months) for the CR group and 6.1 months (IC95%: 4–9.2 months) for the non CR group (p=0.058). The median TTP were 9.4 months for the CR group vs 6 months for pts randomized after 1 yr of treatment, 12.3 months versus 5.7 months for pts randomized after 3 yrs of treatment respectively. One third of pts achieving a CR before randomization in the I arm was free of disease in December 2008. Conclusions: A CR achieved under IM is not a prerequisite for a prolonged disease-free survival in advanced GIST after 1 or 3 yrs of treatment. Despite a trend for a favourable outcome, prognosis of pts with a CR or a major PR is similar to those achieving a PR or a disease stabilisation. A selected group of advanced GIST pts in CR could be cured with IM alone. New radiological assessments or response critera have to be implemented in order to define a real CR. [Table: see text]
Type 3 innate lymphoid cells maintain intestinal epithelial stem cells after tissue damage
Authors: Patricia Aparicio-Domingo, Monica Romera-Hernandez, Julien J. Karrich, Ferry Cornelissen, Natalie Papazian, Dicky J. Lindenbergh-Kortleve, James A. Butler, Louis Boon, Mark C. Coles, Janneke N. Samsom, Tom Cupedo
Journal: The Journal of Experimental Medicine (2015)

Disruption of the intestinal epithelial barrier allows bacterial translocation and predisposes to destructive inflammation. To ensure proper barrier composition, crypt-residing stem cells continuously proliferate and replenish all intestinal epithelial cells within days. As a consequence of this high mitotic activity, mucosal surfaces are frequently targeted by anticancer therapies, leading to dose-limiting side effects. The cellular mechanisms that control tissue protection and mucosal healing in response to intestinal damage remain poorly understood. Type 3 innate lymphoid cells (ILC3s) are regulators of homeostasis and tissue responses to infection at mucosal surfaces. We now demonstrate that ILC3s are required for epithelial activation and proliferation in response to small intestinal tissue damage induced by the chemotherapeutic agent methotrexate. Multiple subsets of ILC3s are activated after intestinal tissue damage, and in the absence of ILC3s, epithelial activation is lost, correlating with increased pathology and severe damage to the intestinal crypts. Using ILC3-deficient Lgr5 reporter mice, we show that maintenance of intestinal stem cells after damage is severely impaired in the absence of ILC3s or the ILC3 signature cytokine IL-22. These data unveil a novel function of ILC3s in limiting tissue damage by preserving tissue-specific stem cells.
Doxorubicin (Dox), cyclophosphamide (Cyc) and weekly docetaxel (Doc) as first-line treatment of advanced breast cancer (ABC)
Authors: T. Ibrahim, P. Serra, B. Vertogen, M. Marangolo, D. Amadori
Journal: Journal of Clinical Oncology (2007)

11516 Background: The breast is one of the leading cancer sites in women. ABC is essentially incurable with standard therapy and have a median survival of approximately 2 years. Dox, Cyc and Doc showed better efficacy results but also an increased rate of neutropenia and febrile neutropenia with respect to FAC (which is considered one of the most used standard option). The substitution of 5- fluorouracil with docetaxel resulted in an increase in the efficacy parameters but showed a higher hematological toxicity. One possible approach to reduce the rate of neutropenia is the administration of weekly docetaxel wich demostrated efficacy in ABC. Methods: ABC patients (pts) were enrolled in an open, single arm, non-randomized phase I escalation trial in 3 to 6 pts/cohorts. MTD dose was identified on the basis of DLT defined according to WHO grade classification of toxicity. * The treatment schedule was: Doc 20 mg/m 2 (or 25, depending on dose level assignment) on day 1, 8, 15; Dox 40 mg/m 2 (or 50, depending on dose level assignment) and Cyc 500 mg/m 2 on day 1, every four weeks. Results: Eleven pts, median age 56 yrs, were enrolled. Five pts were allocated to dose level 20/50 (Doc/Dox) and six pts to dose level 20/40. At the dose level 20/50 febrile neutropenia (DLT) occurred in 2 pts. Other 3 pts experienced neutropenia WHO grade 4 (not DLT). Six patients were allocated at previous dose level and MTD was defined at Doc 20 mg/m 2 in combination with Dox 40 mg/m 2 and Cyc 500 mg/m 2 Conclusions: We didn’t observe toxic deaths and all the toxicity was limited and resolved. The accrual was stopped and we are waiting for one patient to end the treatment in order to analyse the final data and to design the phase II study a the dose Doc 20 mg/m 2 (days 1, 8 and 15) in combination with Dox 40 mg/m 2 and Cyc 500 mg/m 2 (day 1) every 4 weeks. No significant financial relationships to disclose.
Epidermal growth factor receptor (EGFR) inhibitor–related skin toxicity: Review of interim data from a phase II study (20060314) of panitumumab (pmab) with FOLFIRI in the first-line treatment of metastatic colorectal cancer (mCRC)
Authors: M. Karthaus, R. Hofheinz, L. Mineur, H. Letocha, R. Greil, J. Thaler, E. Gamelin, L. Wright, C. Köhne
Journal: Journal of Clinical Oncology (2009)

e20634 Background: Skin toxicity that can impact quality of life as well as treatment adherence is commonly associated with EGFR therapy. Despite their particular importance in terms of making decisions regarding supportive care, time to onset and maximum grade of skin toxicity are seldom reported. Pmab is a fully human monoclonal antibody directed against the EGFR with demonstrated monotherapy activity in patients (pts) with wild-type KRAS expressing, chemotherapy refractory, mCRC. Methods: In this single-arm study, first-line pts with histologically confirmed mCRC were enrolled to receive pmab (6mg/kg) and FOLFIRI every 2 weeks. This trial is ongoing to evaluate the primary endpoint of objective response rate and secondary endpoints including disease control rate, duration of response, time to response, progression-free survival, time to progression and other safety aspects. The focus of this abstract is skin toxicity. Results: Cutoff for the initial interim analysis was 27 June 2008. Of the 154 pts enrolled, 68% are male; median age is 64 years (range 21–84) and 95% of pts had ECOG PS 0–1. A total of 97% of pts had experienced at least one adverse event (any grade) and 55% of pts had experienced a grade 3/4 event. Grade 3/4 skin and subcutaneous toxicities were observed in 20% of pts ( Table ). Median time to first cutaneous toxicity and median time to most severe toxicity were 9 (95%CI, 7–13) and 14 (95%CI, 13–16) days, respectively. The most severe toxicity was grade 4 in one pt. Conclusions: Combining pmab with FOLFIRI in the first-line setting is a well-tolerated regimen. Skin toxicity was observed in 92% of patients; onset, incidence, and severity of which appears to be comparable to published data. Management of skin toxicities will be presented. [Table: see text] [Table: see text]