tbuckley/cabot-search huggingface dataset:
Efficacy and safety of PF299804 versus erlotinib (E): A global, randomized phase II trial in patients (pts) with advanced non-small cell lung cancer (NSCLC) after failure of chemotherapy (CT).
Authors: M. J. Boyer, F. H. Blackhall, K. Park, C. H. Barrios, M. J. Krzakowski, I. Taylor, J. Q. Liang, L. J. Denis, J. P. O'Connell, S. S. Ramalingam
Journal: Journal of Clinical Oncology (2010)

LBA7523 Background: PF299804, a potent, irreversible inhibitor of human epidermal growth factor receptor (HER)-1/EGFR, -2, and -4 tyrosine kinases (TK), is active in E-sensitive and -resistant preclinical models. PF299804 had clinical activity in phase I/II trials in EGFR TK inhibitor (TKI)-refractory NSCLC; a phase III trial is ongoing (BR26). The current trial compared efficacy and safety of PF299804 vs.E in pts with NSCLC after CT failure. Methods: Eligible pts (any histology, ECOG performance status [PS] 0–2, 1/2 CT regimen failures, no prior E, available tumor tissue) were randomized 1:1 to oral PF299804 45 mg or E 150 mg once daily and treated until progression/toxicity. Endpoints included progression-free survival (PFS; primary), overall survival (OS), objective response rate (ORR), safety, and KRAS/EGFR mutation (mu) status. Results: 188 pts (median age 60 years, 87% PS 0/1, 41% female, 65% adenocarcinoma (adeno), 25% East Asian, 21% non-smoker, 16% EGFR mu, 16% KRAS mu) were randomized. Baseline characteristics were balanced between arms except for PS 2 ( PF299804 , 20; E, 3 pts). Mu status determination rates were high (KRAS, 81%; EGFR, 77%). Median follow-up was 12 weeks. PF299804 showed significantly longer PFS vs. E in the overall population (p=0.017), with benefit consistent across several subgroups (SG) including EGFR wild type (wt). ORR favored PF299804 (17% vs. 4%; p=0.008). Frequent treatment-related adverse events (TRAEs) for PF299804 vs. E (grade, any/3 or 4): diarrhea (71%/11% v 48%/3%), acne (53%/7% vs. 34%/5%), and rash (26%/4% vs. 37%/2%). Eight pts discontinued due to TRAEs: PF299804 , 6; E, 2 pts. Conclusions: PF299804 showed significant improvement in PFS (primary endpoint) vs. E in all enrolled pts with NSCLC. Common EGFR TKI AEs were more frequent with PF299804. [Table: see text] [Table: see text]
Meta-analysis of effects of zoledronic acid (ZOL) on survival in metastatic bone disease (MBD): Survival in patients with high bone turnover
Authors: R. J. Cook, V. Hirsh, P. P. Major, F. Saad, R. Dias, A. Lipton, R. E. Coleman
Journal: Journal of Clinical Oncology (2008)

20562 Background: ZOL is an integral component of therapy for patients (pts) with MBD to reduce the risk of skeletal-related events (SREs) and preserve physical function. Recent reports suggest that pts with high N-telopeptide of type I collagen (NTX) levels that normalize during therapy have improved survival compared with persistently high NTX (Lipton A, et al. Oncologist 2007, Cancer 2008). In this study we evaluate the outcomes of pts included in 3 placebo (PLA)-controlled trials of ZOL in solid tumors. Methods: Pts with MBD from solid tumors were included in randomized trials of ZOL (4 or 8/4 mg every 3–4 wk; n = 1071) vs PLA (n = 571) in addition to standard cancer therapies. Baseline NTX and bone-specific alkaline phosphatase (BALP) levels were available for 1345 pts (218 breast, 608 prostate, 519 other). Relative risks (RR) of death and associated 95% confidence intervals (CI) for ZOL vs PLA in the entire population (ITT), all pts with NTX and BALP data, and those ≥ and < the upper limits of normal (ULN) for NTX (64 nmol/mmol creatinine [Cr]) or BALP (146 IU/L) were assessed using a Cox regression model. Results: Survival was similar between treatment groups in the ITT population. However, although there was not statistically significant heterogeneity between the different bone marker groups, pts with NTX ≥ ULN who were treated with ZOL had significantly longer survival compared with PLA (Table 1). Further exploratory subset analyses revealed a 26.4% reduction in the risk of death for ZOL vs PLA among pts with especially high NTX levels (NTX > 100 nmol/mmol Cr [n = 498; RR = 0.736; 95% CI = 0.592, 0.916; P = .006]). Conclusions: The relationships between normalization of high baseline NTX at 3 mo and survival have been described previously. For the first time, this exploratory analysis investigates the effects of ZOL on survival in pts based on baseline bone turnover rates associated with MBD. Potential survival benefits are currently being investigated in multivariate models of the pooled dataset. Population ZOL, n PLA, n RR 95% CI P ITT 1071 571 0.939 0.828, 1.064 .323 Marker data 866 466 0.924 0.801, 1.067 .283 NTX < ULN 351 180 1.137 0.880, 1.469 .328 NTX ≥ ULN 518 286 0.828 0.696, 0.985 .034 BALP < ULN 304 162 1.039 0.795, 1.358 .781 BALP ≥ ULN 567 302 0.882 0.744, 1.046 .148 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Pharmaceuticals Inc. Novartis Pharmaceuticals Inc. Novartis Pharmaceuticals Inc. Novartis Pharmaceuticals Inc. Novartis Pharmaceuticals Inc. Novartis Pharmaceuticals Inc. Novartis Pharmaceuticals Inc. - Speaker's Bureau
Reply
Authors: Salvatore Piano, Paolo Angeli
Journal: Hepatology (2016)

Potential conflict of interest: Nothing to report. We appreciate the interest of Fiore et al. in our article recently published in Hepatology.1 In our clinical trial, fluconazole was added in patients with nosocomial spontaneous bacterial peritonitis (SBP) with no response to meropenem and daptomycin (MER/DAPTO). First, we want to point out that in our trial, for the first time, an antifungal agent was proposed in an empirical treatment protocol for SBP. Indeed, even in the most recent guidelines on management of infections in cirrhosis, antifungal treatment has not been suggested in nonresponders to broad‐spectum antibiotics.2 Therefore, our strategy appears a step forward with respect to available guidelines. Before planning the protocol, we reviewed microbiological data in our center from 2007 to 2009. Of 69 episodes of culture‐positive SBP, only 2 (3%) were attributable to fungi. In both episodes, fluconazole susceptible Candida albicans strains were isolated. This is why we chose fluconazole as empirical fungal treatment in our trial. Furthermore, no fungal isolation was found in our study and treatment failures in the MER/DAPTO group cannot be clearly attributed to fungal infection.1 In addition, there is no clear evidence that echinocandins are better than fluconazole in treating "suspected" invasive candidiasis, such as spontaneous peritonitis.3 Thus, according to both American and European guidelines, our strategy was acceptable and cost‐effective.3 However, we definitely agree with Fiore et al. that echinocandins represent the treatment of choice in patients with microbiological evidence of candidiasis, given that echinocandins have been shown to be more effective than fluconazole in these patients.5 The empirically based addition of echinocandins in patients with cirrhosis and spontaneous peritonitis who failed to respond to a broad‐spectrum antibiotic treatment needs to be further investigated in a controlled, clinical trial. Meanwhile, there is no doubt that echinocandins should be used in this clinical setting in patients previously exposed to an azole and/or in centers with a high prevalence of fluconazole‐resistant Candida spp.
The lung cancer journey - a review from the prince charles hospital pulmonary malignancy unit
Authors: Lj J. Rassam, Np P. Sinhal, H. Mackenzie, Rv Bowman, Km M. Fong, Ia A. Yang, G. Pratt, M. Fay, B. Hughes, M. F. Windsor, K. Matar
Journal: Journal of Thoracic Oncology (2011)
The Orkdal model: Development, implementation, and evaluation of collaboration between specialist and community care within cancer palliative care.
Authors: Anne-Tove Brenne, Anne Kari Knudsen, Cinzia Brunelli, Vidar Halsteinli, Stein Kaasa
Journal: Journal of Clinical Oncology (2014)

73 Background: Palliative care early in the cancer disease trajectory may improve health related quality of life for patients and their families. Collaboration between community and specialist health care professionals is paramount to achieve optimal cancer care. The objective of this study is to develop and to implement this model into our health care system.The target population is cancer patients with metastatic and/ or loco-regional disease. Methods: The study takes place in a rural district of 13 municipalities with a local hospital (Orkdal) in Mid Norway. It is designed as a prospective controlled observational pre- post cohort study with four main interventions: 1. Development and implementation of a standardized care pathway across health care levels, 2. Educational programme for health care professionals, 3. Information about cancer and palliative care to the public, 4.Information,education and support to family members.Outcomes are patient’s time spent at home, family member’s health related quality of life, improvement of health care providers’ knowledge and skills and distribution of health care service use. Results: A standardized care pathway for all palliative cancer patients including home care, care in nursing homes, and specialist care in hospitals (in- and outpatients) is developed. It focuses on access to palliative care services, transfer of medical data, and symptom assessment. The educational program consists of two parts; one to inform about the project and the standardized care pathway, and one to improve competence and skills in cancer palliative care. To the general public, information regarding chemo- and radiotherapy, symptom diagnosis and treatment and palliative care services in general is given. Conclusions: A total integrated model to improve care for cancer patients was developed focusing on collaboration between community and specialist health care, and on early integration of palliative care in the traditional cancer care trajectory. Improved care for cancer patients and their families in the Orkdal region to equal costs is expected. The Orkdal Model may be applied in other regions and for other chronic diseases. Clinical trial information: NCT02170168.
A pilot study of a home-based exercise intervention for adult patients with AML.
Authors: K. Fisher-Schlombs, S. N. Culos-Reed, J. Brandwein, M. D. Minden, G. A. Tomlinson, S. M. Alibhai
Journal: Journal of Clinical Oncology (2010)

e19570 Background: Fatigue is the most common and disabling symptom that negatively affects quality of life (QOL) and daily function in patients who have completed treatment for acute myeloid leukaemia (AML). Many studies conducted in patients with solid tumours have reported improved fatigue and QOL following an exercise intervention, however there have been no studies in AML patients post treatment. Methods: Post-treatment AML patients aged 40+ who were medically cleared for exercise and not already exercising were randomly assigned to either an exercise or wait-list control group. Patients assigned to the exercise group were provided with equipment and an individualized 12-week home-based exercise program with weekly support from a certified exercise physiologist. Patients assigned to the wait-list control group were encouraged to maintain their regular activity for 12 weeks, following which they were crossed over to the exercise group. Fitness was measured at baseline, 6, 12 and 24 weeks. QOL, fatigue, anxiety, and depression were measured at baseline, 3, 6, 9, 12, 18 and 24 weeks. Between-group differences in 12-week change scores were calculated using linear regression and adjusted for age and baseline function. Results: 32 of a target 40 patients (mean age 56 y, SD 8.6) have been enrolled and randomized to date (18 exercise, 14 wait-list control). The groups had similar age and gender distributions as well as baseline fitness, global QOL, fatigue, anxiety, and depression scores. Subjects improved in 6-minute walk test distance, sit and reach distance, most QOL domains, and fatigue scores over 12 weeks. Anxiety and depression scores decreased slightly. Exercise was associated with clinically important but statistically non-significant improvements in grip strength and role function. Improvement in global QOL was seen in control subjects, but this was not statistically significant. Compliance was generally high and the intervention was safe and well-tolerated. Conclusions: A home-based exercise program for post- treatment AML patients age 40+ is feasible and safe. It may be associated with modest improvements in grip strength and role function but further recruitment and follow-up are required to determine QOL and fitness benefits. No significant financial relationships to disclose.
Phase I study to characterize pharmacokinetics (PK) of topotecan (T) at 4 mg/m<sup>2</sup> administered weekly as a 30-minute IV infusion
Authors: K. K. Curtis, R. C. Jewell, J. T. Hartney, P. P. Griffin, T. R. Fitch, D. W. Northfelt
Journal: Journal of Clinical Oncology (2008)

13551 Background: T inhibits topoisomerase-I, causing lethal DNA damage during replication. T is approved for daily X5 treatment of ovarian & SCLC, with encouraging activity/safety in weekly dosing. PK has not been studied in this dose/schedule, but is dose- proportional at other doses/schedules. We report a PK & safety study at this dose/schedule in patients with advanced cancer. Methods: Eligibility: ECOG ≤2; ≥18 yrs; advanced cancer failing or having no standard therapy; >4 wks since last therapy & without post-treatment toxicities; no concurrent therapy; adequate hematologic/renal/hepatic function; non-pregnant; adequate contraception; no active infection or concurrent severe illness. Dose: T 4 mg/m2 over 30 minutes IV weekly x3 every 28d; PK after first dose only; Dose Escalation: none; Safety Assessments: Clinical, hematologic, biochemical parameters assessed per CTCAE v3.0 as adverse/serious adverse events (AE/SAE); PK assays: Plasma concentrations of total T (lactone + carboxylate) measured by HPLC/MS/MS; noncompartmental methods to derive CL, Vss, t½, Cmax, & AUC(0-∞) of total T. Results: Accrual: 6 F, 10 M; all metastatic; 2 each of breast, colon, uterine, kidney, prostate; 1 each of esophagus, head/neck, liver, NSCLC, ovary, small bowel; SAEs grade 5/4/3: n=1/5/3; 3 (grade 4 thrombocytopenia, neutropenia, leukopenia) attributed to T; AEs: anemia 11, thrombocytopenia 10, fatigue 8, nausea 5, neutropenia 5, vomiting 4. Conclusions: PK of T at 4 mg/m2 is similar to that seen at lower doses (Kuppens, 2007). This T dose/schedule was tolerable in patients with advanced cancer. Total Topotecan Pharmacokinetic Parameters Parameter N Geometric Mean (%CVb) CL(L/h) 15 20.6(33%) Vss(L) 15 101(27%) t½(h) 15 4.95(12%) Cmax(ng/mL) 16* 144(40%) AUC(0-∞)(ng.h/mL) 15 365.7(26%) * t½ could not be estimated for one patient; thus, only Cmax was available for that patient. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline
Length polymorphism in the promoter of the thymidylate synthase (TS) gene is associated with prognosis but not with response in neoadjuvant treated locally advanced (NTLA) gastric cancer (GC)
Authors: K. Ott, H. Vogelsang, K. Becker, M. Kolbl, U. Fink, F. Lordick, H. Höfler, J. R. Siewert, G. Keller
Journal: Journal of Clinical Oncology (2004)

4038 Background: The TS gene promoter possesses regulatory repeated polymorphic sequences that have been reported to influence TS expression. High levels of TS expression have been associated with poor response to 5-FU based chemotherapy (CTx) and poor survival. Therefore we investigated whether the TS genotype was associated with response or prognosis in NTLA GC. Methods: DNA was isolated from blood of 135 patients (pts.) with locally advanced GC staged uT3/4 any N cM0 before treatment with 5-FU based neoadjuvant CTx: 33 responder, 102 nonresponder, 106 complete (R0) resected pts., median follow up 30.3 months (m.). TS genotype was determined by a polymerase chain reaction (PCR) and subsequent electrophoresis in a 2% agarose gel obtaining products of 144 bp (3R/3R), 116 bp (2R/2R) or both (2R/3R). All TS genotypes were confirmed at least once by a separate PCR. Results: 61 pts. had the 2R/3R, 33 the 2R/2R and 41 the 3R/3R genotype. There was no correlation between response and TS genotype (p=0.96). Pts. with the 2R/2R genotype showed a significant improved survival (median: not reached) compared to those with 2R/3R (median: 87.9 m.) and 3R/3R (median: 33.4 m.) (p=0.002). Analyzing only the R0 resected pts. the median survival for 2R/2R (reference) and 2R/3R (relative risk [RR]=2.0, 95% confidence interval [95% CI]: 0.6–6.2) is not yet reached, for 3R/3R (RR=5.8, 95% CI: 1.9–18.4) is 31.3 m. after resection (p=0.007). Multivariate analysis revealed lymphnode metastases (ypN) (p<0.001) and TS genotype (p=0.003) as statistically significant factors for the R0 pts. Conclusions: The TS genotype is not a useful marker for response prediction, but is an independent prognostic factor in this group of GC patients treated with 5-FU based CTx. The 3R/3R genotype identifies a subgroup of patients who are unlikely to benefit from a neoadjuvant 5-FU based regimen. No significant financial relationships to disclose.
Cancers involving the lung mediate human marrow cell phenotype change.
Authors: P. J. Quesenberry, J. Aliotta, M. Del Tatto, M. Dooner, G. A. Colvin
Journal: Journal of Clinical Oncology (2010)

10618 Background: Microvesicles from different tissues can mediate genetic phenotype changes of adjacent normal marrow cells. Methods: We have evaluated excised tissue from cancers involving the lung for their capacity to change the genetic phenotype of co cultured human marrow cells. thirteen cancers were evaluated: 11 were primary non-small cell lung cancers and there was one sarcoma and one melanoma of the lung. Excised tissue was co cultured opposite normal volunteer human bone marrow for 2 or 7 days with the cancer tissue separated from the human marrow by a cell impermeably 0.4 um membrane. Real-time RT-PCR for the following lung specific genes, aquaporin 1, aquaporin 2, aquaporin 3, aquaporin 4, aquaporin 5, surfactant A, B, C, and D, and clara cell-specific protein was carried out on 9 tumors. Results: In each instance, including the sarcoma and the melanoma, lung specific genes were highly expressed in the marrow cells. There was expression of from 1-8 lung-specific genes from different cancers ranging from over 2 fold to over 1000 fold of control. Expression was seen in co cultured whole marrow, ficol separated marrow and marrow subjected to ammonium chloride lysis. Human marrow exposed to conditioned media from lung cancer cells expressed high levels of pulmonary specific genes. Ultracentrifugation (28,000 g) of lung cancer conditioned media, pelleted large numbers of microvesicles (diameter 100-180 nm as shown by electron microscopy). Tumor-derived microvesicles also induced expression of lung-specific mRNA in target marrow cells. Pelleted microvesicles stained by the supravital dyes CFSE (green fluorescence) and PKH26 (red fluorescence) were shown to be taken up by human bone marrow cells. Conclusions: These studies indicate that cancer cells are capable of transferring a lung genetic phenotype to marrow cells. Whether this represents genetic information transferred primarily from lung to cancer cells and then secondarily to target co cultured cells or priamry genetic information from the cancer cells ia at present unknown. The capacity of cancer cells to transfer genetic phenotype suggests important possible modes of cancer progression, resurrence and metastases. It also suggests therapeutic strategies to block these occurrences. No significant financial relationships to disclose.
P-100 The Rhesus D - negative phenotype is one of the major risk factors for postoperative complications after gastrectomy for gastric carcinoma
Authors: A. Baušys, D. Klimas, A. Kilius, K. Pauža, G. Rudinskaite˙, Ž. Sinkevičius, N. Samalavičius, E. Sangaila, R. Baušys
Journal: Annals of Oncology (2015)
Pilot Study To Evaluate The Prevalence Of Actionable Oncogenic Mutations In Patients With Relapsed Refractory Multiple Myeloma
Authors: Alexander Lesokhin, Mithat Gonen, Kaitlyn Redling, Nikoletta Lendvai, Hani Hassoun, Heather Landau, David J Chung, Guenther Koehne, Minal Patel, Kristina W. Brennan, Kai Wang, Eric M Sanford, Tim Brennan, Geoff A. Otto, Michelle K. Nahas, Doron Lipson, Philip J. Stephens, Roman Yelensky, Vincent A. Miller, Marcel Van Den Brink, Ross L. Levine, Ahmet Dogan, Sergio A Giralt
Journal: Blood (2013)
Point mutation of C-terminal region of CD20 molecule predicts rituximab-induced complement-dependent cytotoxicity and clinical response to rituximab in non-Hodgkin’s lymphoma
Authors: Y. Terui, Y. Mishima, Y. Mishima, M. Yokoyama, K. Hatake, N. Sugimura, K. Kojima, T. Sakurai, K. Takeuchi
Journal: Journal of Clinical Oncology (2006)

7563 Background: Although rituximab is commonly used as induction and maintenance therapy for malignant lymphoma, some patients become refractory to treatment and the mechanism of resistance is unclear. The aim of this study was to investigate the relationship between CD20 mutations and rituximab resistance. Methods: To investigate whether CD20 mutations affect response to rituximab, fresh CD19+ lymphoma cells were isolated from the lymph nodes, or bone marrow of 68 patients with NHL. The cells were subsequently sorted by flow cytometry. RNA was prepared from the isolated cells and RT-PCR was performed. The PCR products were sequenced, subcloned into an expression vector pTARGET, transfected into K562 cells. CD20 expression was examined by flow cytometry and laser scanning confocal microscopy. Results: In all 68 patients, overall response rate (CR+CRu+PR) to rituximab was 91.2% (62/68), but t four cases became PD after PR. DNA sequence analysis revealed that point mutations were mostly observed in three CD20 domains - extracellular/cytoplasmic domains, the third transmembrane domain and the C-terminal cytoplasmic domain. Two cases had point mutations in extracellular/cytoplasmic domains, one patient had point mutations in the transmembrane domain, four cases showed point mutations in the C-terminal cytoplasmic domain and six cases had non-specific CD20 mutations, which did not affect CD20 expression. 56 patients showed no mutations of CD20 gene. CD20 expression was very weak in patients with point mutations in the C-terminal cytoplasmic domain, whereas expression was increased in patients with point mutations in the transmembrane domain. Conclusions: Point mutations in CD20 may cause rituximab resistance and identification of CD20 mutations upon diagnosis may help to predict a patient’s response to rituximab. No significant financial relationships to disclose.