tbuckley/cabot-search huggingface dataset:
Leucovorin (LV) pharmacokinetics in patients receiving high dose methotrexate (HDMTX), with or without glucarpidase treatment.
Authors: Stefan Schwartz, Thomas King, Suzanne Ward, Angela Ogden, Nikhil Chauhan, Scott C. Howard
Journal: Journal of Clinical Oncology (2013)

e20521 Background: Glucarpidase is a recombinant form of carboxypeptidase G2 and hydrolyzes MTX into inactive metabolites and provides alternate clearance in pts with delayed elimination and acute kidney injury. It is administered with IV hydration, urinary alkalinization, and LV. The primary objective was to investigate whether glucarpidase reduces exposure to LV and its active metabolite (5EMeTHF) to below the level achieved in pts who have not received glucarpidase, by assessing the PK of the active L-isomer of LV (6S-LV) following administration of HDMTX and LV. Methods: Open-label, multicenter PK study in pts treated with HDMTX (≥1 g/m 2 ) and LV (either ≥15 mg or ≥10 mg/m 2 ) with subsequent glucarpidase where indicated for renal impairment (Arm A) or without glucarpidase (Arm B). Plasma samples for LV and 5EMeTHF were taken pre-LV and at 5, 30, 60, 120, and 180 min after LV to calculate the area under the concentration curve of 6S-LV over 0-3 hours (AUC 0-3 ) following the LV dose. Results: 17 pts (8 Arm A, 9 Arm B) were analyzed. The median pre-glucarpidase methotrexate (MTX) plasma concentration was higher for Arm A 7.5 µmol/L) than B (1.1 µmol/L). Similarly, median LV doses were 89.88 mg/m 2 (Arm A) and 13.51 mg/m 2 (Arm B). Mean 6S-LV AUC 0-3 values (µmol*h/L) for Arm A were 8.70±5.56, compared with 1.31±0.78 for Arm B, consistent with Arm A receiving a higher LV dose than Arm B. Mean 6S-5MeTHF AUC 0-3 values (µmol*h/L) were similar in arms A and B (0.68 and 0.73). When normalized for LV doses, mean 6S-LV AUC 0-3 values (µmol*h/L) were similar between arms:10.02±4.83 in Arm A versus 9.79±5.18 for Arm B. Conclusions: Glucarpidase does not reduce exposure to 6S-LV and 5-MeTHF to below the level achieved in patients with normal renal function who did not receive glucarpidase. Adequate LV exposure is achieved if LV dosing is based on pre-glucarpidase plasma MTX concentration for at least 48 hours after glucarpidase administration. Clinical trial information: NCT00634504.
Results of NRG oncology/RTOG 9813: A phase III randomized study of radiation therapy (RT) and temozolomide (TMZ) versus RT and nitrosourea (NU) therapy for anaplastic astrocytoma (AA).
Authors: Susan Marina Chang, Peixin Zhang, J. Gregory Cairncross, Mark R. Gilbert, Jean-Paul Bahary, Carol Dolinskas, Kenneth D. Aldape, Arnab Chakravarti, David Schiff, Kurt A. Jaeckle, Paul D. Brown, Geoffrey Barger, Maria Werner-Wasik, Helen Alice Shih, David Brachman, Marta Penas-Prado, H. Ian Robins, Karl Belanger, Christopher J. Schultz, Minesh P. Mehta
Journal: Journal of Clinical Oncology (2015)

2002 Background: TMZ is efficacious in recurrent anaplastic glioma and newly diagnosed glioblastoma. The primary objective was to compare the overall survival (OS) of patients with AA treated with RT and either TMZ or NU. Secondary endpoints were to compare the time to tumor progression (TTP), relative toxicities of the 2 arms and correlate molecular analyses with clinical outcome. Methods: Eligibility: age ≥ 18 years, central histological confirmation of AA and KPS ≥ 60. Patients were randomized 1:1 to RT 59.4 Gy with TMZ 200 mg/m2daily on days 1-5 of the first week of RT with adjuvant TMZ every 28 days for 12 cycles versus NU (BCNU or CCNU). Median survival time (MST) for the NU arm was assumed to be 3 years with an estimated increase in the TMZ arm to 4.5 years- hazard ratio (HR) 0.67. A sample size of 216 patients per arm would provide an overall statistical power of 90% with a one-sided significance level of 0.05. The distribution of the OS of the 2 arms was compared using the Cox proportional hazard model and the log-rank test. Results: Because accrual goals were not met, the trial was closed in 2007.From 2002-2007, 196 eligible patients were randomized, 97 (RT+TMZ) and 99 (RT+NU). Stratification factors (age, KPS, surgery) were balanced between the 2 arms. 65% of patients have died at the time of this report and the median follow-up time for patients still alive was 9.1 years (1.9-11.6 years). There was no difference in OS between the RT+TMZ and the RT+NU arm (p-value 0.37). The MST for the RT+TMZ arm is 3.9 years (95% CI 3.0-7.0) and the MST for the RT+NU arm is 3.8 years (95% CI 2.2- 7.0). The associated HR is 0.94 (95% CI 0.67-1.33). The differences in PFS and TTP between the 2 arms were not statistically significant. The RT+NU arm had a significantly higher rate of worse overall grade ≥ 3 toxicity (75.8% versus 47.9% p < .001), mainly related to bone marrow toxicity. Conclusions: RT+TMZ did not appear to significantly improve OS or TTP for AA compared with RT+ NU. RT+TMZ was better tolerated. Correlative molecular, genetic and epigenetic analyses with clinical outcome are pending. NCT00004259 Support: U10CA21661, U10CA180868, U10CA180822 (NCI) and Schering Plough. Clinical trial information: NCT00004259.
Health workers are vital to sustainable development goals and universal health coverage
Authors: Lara Fairall, Eric Bateman
Journal: BMJ (2017)

Interventions to support a bigger and better trained work force must be prioritised

On international woman’s day earlier this month many major news outfits carried the story of Salome Karwah, who in 2014 featured on the cover of Time magazine for her work during the Ebola outbreak in west Africa.1 Karwah has died at the age of 28 from complications arising during the birth of her fourth child. Tragic for many reasons, her death highlights persistently high maternal mortality rates, especially in Africa, which contributes 20% of the world’s births but 40% of the world’s maternal deaths.2 It also highlights that stigma can be lethal; her husband reported that hospital workers avoided her because she had worked with and survived Ebola. And it highlights that providers can be patients too.

But perhaps most importantly, Karwah’s premature death is a reminder that the health system improvements promised during crises such as the Ebola outbreak are slow to materialise. Responses such as fast tracking the development of an Ebola vaccine tend to eclipse the scaling up of proved, cost effective interventions to meet the health related sustainable development goals. These identify maternal health as …
Gene expression profiling in renal cell cancer (RCC) during tumor vaccination with a gene-modified allogeneic cancer vaccine: Tumor-induced immunosuppression and a key role for NF-κB.
Authors: Anne Flörcken, Michael Grau, Annette Wolf, Andre Weilemann, Joachim Kopp, Bernd Dörken, Thomas Blankenstein, Antonio Pezzutto, Peter Lenz, Georg Lenz, Jörg Westermann
Journal: Journal of Clinical Oncology (2014)

e15555 Background: Tumor-induced immunosuppression is a hallmark of cancer and a major obstacle for immunotherapies. It includes impaired T cell function, reduced antigen presentation, and diminished humoral and innate immune responses. Therefore, the gene expression profile (GEP) of peripheral blood mononuclear cells (PBMCs) is very likely to reflect the immunological state and might give insights into the underlying molecular mechanisms of immunosuppression. A previously performed phase-I trial with an allogeneic, human leucocyte antigen (HLA)-A2-matched RCC cell line transfected with interleukin-7 (IL-7) and CD80 as a vaccine in RCC patients was feasible and safe, however, clinical responses and/or significant TH1-polarized immune responses were not observed. Methods: To further elucidate why our allogeneic gene-modified RCC vaccine failed to induce TH-1-polarized immune responses, PBMCs of RCC patients (n=9) and healthy controls (n=9) were analyzed by GEP both prior and after vaccination in order to identify differences in the expression of immunologically relevant genes and cellular processes. Results: At baseline, a profound and statistically significant downregulation of gene signatures associated with antigen presentation, immune response/T cells, cytokines/chemokines, and signaling/transcription factors was observed in RCC patients as compared to healthy controls. Vaccination led to a partial reversion of preexisting immunosuppression, however, GEP did not show appropriate TH-1 polarization. Moreover, various central components and a variety of known target genes of the nuclear factor-kappa B (NF-κB) signaling pathway were significantly downregulated in RCC patients´ PBMCs, implying that suppression of this signaling cascade plays a key role for the impairment of immunological responsiveness. Conclusions: Our data implicate that the GEP of PBMCs may serve as a surrogate parameter for interactions between tumor and immune system. GEP of PBMCs appears to be a useful tool for the characterization of a) tumor-induced immunosuppression and b) systemic immunological effects of immunotherapeutics.
An easily mistaken pulmonary opacity
Authors: Timothy Shao Ern Tan, Omar Abdulla
Journal: BMJ (2017)

A 54 year old male smoker of 20 pack years presented with a six week history of fever, anorexia, worsening cough, and dyspnoea. He had previously undergone coronary artery bypass grafting. A chest radiograph showed previous sternotomy, borderline cardiomegaly, pulmonary oedema, right lower zone consolidation, and a right mid zone oval density (fig 1⇓). What is the diagnosis for this oval density?



Fig 1  Chest radiograph



Encysted pleural fluid in the right oblique fissure.

Apart from the right sided encysted pleural fluid, fig 1 also shows left subpulmonic and right lamellar effusions. Overall, the radiological findings suggest congestive heart failure with coexisting right lobar pneumonia caused by Mycoplasma pneumoniae (organism confirmed on laboratory testing).

On …
Phase I study of safety, tolerability, and pharmacokinetics of pazopanib in combination with oral topotecan in patients with advanced solid tumors.
Authors: Bojana Milojkovic Kerklaan, Martijn P. J. K. Lolkema, Lot A. Devriese, Emile E. Voest, A. Nol-Boekel, M. Mergui-Roelvink, Kristine Mykulowycz, Joseph E Stoebenau, Lei Fang, Philippe Legenne, Paul Stephen Wissel, Deborah A. Smith, Bruce J. Giantonio, Jan HM Schellens, Petronella Witteveen
Journal: Journal of Clinical Oncology (2013)

2536 Background: To determine the maximum-tolerated dose (MTD), safety, tolerability and pharmacokinetics of the oral anti-angiogenic drug pazopanib in combination with oral topotecan, an inhibitor of topoisomerase-I. Methods: Two-stage, two-arm, dose escalation and pharmacokinetic phase I study of pazopanib and oral topotecan in patients with advanced solid tumors, (NCT00732420, www.clinicaltrials.gov). This interim report describes the bioavailability and safety results for daily pazopanib combined with oral topotecan (days 1, 8, 15) in a 28-day cycle. Results: Twenty-eight of 32 patients completed at least one cycle and were evaluable for analysis. Three dose-limiting toxicities (DLTs) occurred: grade 3 hand-foot-syndrome, diarrhea and neutropenia. Pazopanib 800 mg/topotecan 10 mg exceeded the MTD with two DLTs in six patients. The most frequent treatment-related toxicities were grade 3 anemia (3/28), leukocytopenia, neutropenia and fatigue (2/28 each). One death due to hepatic failure occurred at pazopanib 800mg/toptecan 2mg in a heavily pre-treated patient with sarcoma that may have been related to paracetamol ingestion but attribution to the pazopanib can not be excluded. Topotecan AUC 0-∞ increased 1.58-fold (90%CI: 1.09–1.29) and C max increased 1.78-fold (90%CI: 1.08-2.92) when given with pazopanib compared to single administration (n=7). Pazopanib AUC 0-24 and C max ratios were not increased when co-administered with topotecan: 0.98 (90%CI: 0.95-1.02) and 0.96 (90%CI: 0.92-1.01). Twenty-three patients were evaluable for response (RECIST): PR (2/23; 9%, both ovarian cancer); SD (13/23; 57%) and PD (8/23; 35%). Pazopanib 800 mg/topotecan 8 mg is currently being explored in an expansion cohort. A second treatment arm of pazopanib 800 mg with topotecan daily x5 is ongoing and will be reported separately. Conclusions: Daily pazopanib and weekly oral topotecan is tolerable with handfoot syndrome, neutropenia and fatigue as dose limited side effects. Pazopanib increased topotecan exposure 1.58-fold (AUC 0-∞ ) and 1.78-fold (C max ). Clinical trial information: NCT00732420.
Review of pathologic diagnosis in head and neck cancer patients: Why do it?
Authors: Gefei Alex Zhu, Ruth R Lira, A. Dimitrios Colevas
Journal: Journal of Clinical Oncology (2014)

6032 Background: Our hospital mandates review of outside pathology prior to treatment. Previous studies of inter-institution pathology consultations have demonstrated discordance rates of approximately 10%. We examined the overall rate of as well as predictors of discordant interpretations in patients seen at the Stanford Head and Neck Oncology program. Methods: The study cohort was identified using a retrospective search of the Stanford Cancer Center Research Database for head and neck cancer patients from 2005-2010 with outside pathology reviews. Discordance was manually assessed by a board-certified medical oncologist. We captured interpretation differences in histology, depth of invasion, margin positivity, presence of high-risk features, and results of special studies. The impact of tumor type (squamous, thyroid, or other), biopsy site, and type of specimen (cytology vs. histology) were assessed using chi-squared testing. Results: Of the 1,003 cases in the final cohort, 306 have been reviewed to date. There was an overall 18% discordance rate (56 cases), of which 68% (38 cases) were due to differences in histology. Discordance was associated with tumor type (p = 0.004), with lower rates for squamous (13%) and thyroid tumors (17%), and higher rates for other tumors (30%). Tumor biopsy site was also associated with discordance (p = 0.011), with lower rates in tumors of the oral cavity and lip (12%), oropharynx (12%), and hypopharynx (14%) and higher rates in those of the paranasal sinuses (42%), salivary glands (38%), and thyroid (26%). Fine needle aspiration specimens were not associated with discordant review (p = 0.14). Conclusions: Discordance rates of initial versus referral center diagnosis of head and neck tumor biopsies is substantial and clinically relevant. We could not identify any subset by site or initial histology where concordance exceeded 90%. Therefore we conclude that review is clinically relevant for all head and neck cancer patient specimens. Data for all 1,003 cases will be presented at the annual meeting.
Systemic chemotherapy for the treatment of advanced biliary tract carcinoma (BTC).
Authors: Susanna V. Ulahannan, Osama E. Rahma, David J. Liewehr, Seth M. Steinberg, Austin G. Duffy
Journal: Journal of Clinical Oncology (2014)

e15129 Background: The combination of gemcitabine (G) and cisplatin (C) is considered the standard of care in inoperable BTC based on the ABC-02 trial that showed an increased median progression free survival, and median overall survival compared to single agent G. BTC are rare malignancies, and hence the paucity of randomized trials. We therefore performed a comprehensive analysis of published prospective clinical trials in BTC. Methods: Data for this analysis was collected by searching PubMed using the combination of the following terms: “chemotherapy” and “biliary tract cancer, cholangiocarcinoma, or gallbladder cancer”. In addition, we reviewed relevant abstracts (2008-2013) presented in ASCO, GI ASCO, ESMO and ECCO. In each treatment arm, RR, the median PFS and OS, were obtained and the distributions between the different pre-defined treatment groups were analyzed. Results: 83 trials encompassing 92 treatment arms and 3809 patients were included in our analysis. The pooled analysis demonstrated a median RR 29%, PFS 4.8m and OS 9.5m for G in combination with C (10 trials, 655 patients). The combination of G with platinum agents (24 treatment arms treating 1403 patients) compared with other regimens showed a strong trend toward improved RR (p= 0.047) but no significant difference in PFS or OS. All regimens containing G (OS 9.7m, PFS 5.0m and RR 26.1%) were compared to regimens without G (OS 8.9m, PFS 3.8m and RR 19.0%). The global effect of G on OS showed a strong statistical trend p= 0.014 and a significant improvement in PFS (p=0.003). In the same manner, platinum-based regimens were compared to platinum-free regimens but did not reveal any superior outcomes. In order to study the treatment effect over the past two decades we plotted RR, PFS and OS for each of the analyzed regimens, the median RR was 21.4%, the median PFS was 4.4m and the median OS 9.4 m, no discernable trends in any of the data over time. Conclusions: Based on our analysis of first line treatments in non-operable BTC, G remains the backbone of chemotherapy treatment, a finding which is consistent with randomized data from the ABC-02 study.
Central validation of HER2 status to determine heterogeneity of marker expression in HER2-positive gastric cancer (GC).
Authors: Ivonne Haffner, Birgit Luber, Dieter Maier, Albrecht Kretzschmar, Ludwig Fischer von Weikersthal, Miriam Ahlborn, Jorge Riera-Knorrenschild, Beate Rau, Florian Weissinger, Stefan Fuxius, Steffen Neumann, Thomas Decker, Katrin Schierle, Christian Wittekind, Florian Lordick
Journal: Journal of Clinical Oncology (2017)

12 Background: 10-20% of GC overexpress HER2, a membrane-bound receptor tyrosine kinase (RTK) which belongs to the epidermal growth factor receptor (EGFR) family. Drugs directed against HER2 have shown mixed success in the treatment of advanced GC. While trastuzumab, a monoclonal antibody addressing HER2 has been approved for 1 st -line treatment of stage IV HER2+ GC, trastuzumab-emtansine failed to improve outcomes in 2 nd -line and lapatinib, a small molecular RTK inhibitor of HER2 and EGFR was not effective in 1 st - and 2 nd -line. Until now, primary and secondary resistance against HER2-directed treatment of GC is not well understood. The VARIANZ study aims to assess mechanisms influencing efficacy of trastuzumab in HER2+ GC. Methods: In this multicenter study, patients who receive medical treatment for advanced GC are recruited in 31 sites. The HER2 status is verified centrally by two dedicated GI pathologists using immunohistochemistry (IHC, DCS, HI608C0I) and chromogenic-in-situ hybridization (CISH, Zytomed Systems, C-3022-40). Results: From May 2014 to August 2016, we have enrolled 316 patients in this ongoing project (72% male, median age 64 years). At present, 281 samples were fully characterized for the HER2 status. According to criteria from the Trastuzumab for Gastric Cancer (ToGA) study, 53 of 281 samples were characterized HER2+ by central testing. In 38 samples that were diagnosed as HER2+ by local pathologists the HER2 status could not be verified centrally. 7 HER2- probes in local testing were characterized as HER2+ by central testing. The overall deviation rate between local and central testing is 27%. HER2 gene amplification in HER2+ tumors with deviating local report (mean HER2/CEP17: 2.8 ± 0.9, range between 1.9 and 4.5) is lower compared to HER2+ tumors and confirmed local report (mean HER2/CEP17: 5.5 ± 2.6; range between 2.2 and 11.0; p = 0.014). Conclusions: HER2-expression in GC is heterogeneous and still not easy to assess. Variability between local and central HER2 assessment is significant. Robust biomarkers predicting response or resistance to HER2 and other target therapies are needed. Clinical trial information: NCT02305043.
Prospective screening for human epidermal growth factor receptor 2 (HER2) positivity in patients with inoperable locally advanced or metastatic gastric or gastro-esophageal junction cancer. AGMT gastric-5.
Authors: Ewald Woell, Peter Regitnig, Wolfgang Eisterer, Josef Thaler, Horst Oexle, Bernd Lorenz Hartmann, Johannes Andel, Alois Wuestner, Bjoern Jagdt, Christoph Tinchon, Michael A. Fridrik, Richard Greil
Journal: Journal of Clinical Oncology (2016)

e15501 Background: Trastuzumab plus chemotherapy is the treatment of choice for locally advanced or metastatic gastric cancer patients. Pathological assessment of gastric cancer specimens however still remains difficult albeit it is a crucial prerequisite for optimal treatment. Methods: This registry was designed as a prospective, observational, multi-center research initiative comparing HER2 test results obtained from the local pathology department and to reevaluate HER2 testing in a central pathology laboratory. HER2 testing was performed by means of immunohistochemistry (IHC) and in equivocal cases (Score 2+) in addition by in-situ hybridization (ISH).In the central laboratory HER2 IHC was carried out using the HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody. In the local pathologies up to four different kits were used.The rate of HER2 positive locally advanced or metastatic gastric or GEJ cancer is the primary study objective. Comparison of HER2 results from local and central labs, safety, PFS, OS and type of chemoimmunotherapy in HER2 positive patients are additional objectives. Results: Up to now samples of 127 patients have been tested in local and central pathology respectively. Median age was 68 years, median weight 68 kg. 59 patients already had at least one prior treatment for metastatic disease. 20 out of 127 tested samples (15.7%) showed discordance between central and local testing with 6/127 (4.7%) false negative results and 14/127 (11.0%) false positive results. 37 patients (29.0%) tested HER2 positive in local pathology. 30 of which were treated with trastuzumab in combination with different chemotherapy backbones (53.3% first line). Median PFS was 6.5 months, overall survival was 12.0 months. PFS and OS were shorter in patients with false positive results (5.7 and 7.6 months, respectively). Conclusions: This ongoing registry points to the fact that HER2 testing in gastric cancer is difficult, and highlights the necessity for quality insurance to optimize individual treatment options. Although different chemotherapy backbones are used PFS is similar to published data.