tbuckley/cabot-search huggingface dataset:
Bone metastases in germ cell tumors: Results from an international data base.
Authors: Christoph Oing, Karin Oechsle, Andrea Necchi, Yohann Loriot, Ugo De Giorgi, Aude Flechon, Gedske Daugaard, Mikhail Fedyanin, Gabriella Elisabeth Cohn-Cedermark, Teodoro Sava, Anja Lorch, Eric Winquist, Jourik A. Gietema, Marcus Hentrich, Elena Farè, Carsten Bokemeyer
Journal: Journal of Clinical Oncology (2014)

4559 Background: Bone metastases (BM) are rare in germ cell tumor (GCT) patients (pts). Systematic data on risk factors, treatment and outcome are largely lacking. Methods: An international data base including 272 GCT pts with BM (140 at primary diagnosis, 132 with first BM occurrence at relapse) diagnosed between 1983 - 2013 from 23 centers was retrospectively analyzed. Results: BM at primary diagnosis mostly affected spine (71%) and pelvis (24%), 40% had a single and 60% multiple lesions. Pts had a primary gonadal / retroperitoneal / mediastinal GCT in 68% / 16% / 16% and seminoma / nonseminoma in 25% / 74%. Primary treatment was standard dose chemotherapy in 90% (SD-CTX) and dose intensified CTX in 10% (DI-CTX). Secondary resection (SR) / radiotherapy (RTX) of BM was performed in 10 pts (7%) / 20 pts (14%). Histology was necrosis / mature teratoma / vital tumor in 6 / 2 / 1 pts. 45% of pts relapsed, 79% again with BM. Median FU was 21 months (mos). Calculated median PFS and OS were 31 mos (range, 0-225) and 98 mos (95%CI, 14–182). No survival benefit was achieved by DI-CTX (PFS p=.29; OS p=.96) or SR of BMs (PFS p=.25; OS p=.99). 132 pts developed BM at relapse: Mostly in spine (67%) and pelvis (24%). 47% had a single, 53% multiple lesions. Median time from initial GCT diagnosis to detection of BM was 20 mos (95%CI, 16-24). Salvage treatment was SD-CTX / DI-CTX in 86% / 14%. SR / RTX of BM were performed in 14% / 42%. Histology was necrosis / mature teratoma / vital tumor in 1 / 2 / 14 pts. Overall, 52% of pts progressed during salvage CTX. After a median FU of 45 mos (range, 2-335), median OS was 13 mos (95%CI, 8 – 17). PFS and OS seem to be improved by DI-CTX (2yr-PFS 37% vs 14%, p=.006; 2yr-OS 47% vs 25%, p=.008) and / or SR of residual bone lesions (2yr-PFS 37% vs 14%, p=.016; 2yr-OS 74% vs 20%, p<.001). Additional RTX of BM did not impact survival in the salvage setting (PFS p=.73; OS p=.15). No other characteristics (tumor markers, non-bone metastases) were associated with the occurrence of BM in both cohorts. Conclusions: Pts with BM at primary diagnosis will achieve long-term survival (median OS 98 mos), but pts relapsing with BM have a dismal prognosis (median OS 13 mos). In patients relapsing with BM intensification of salvage therapy and resection of residual bone lesions may improve survival.
Cisplatin/5-fluorouracil (CF) versus carboplatin/paclitaxel (CT) chemoradiotherapy (CRT) for locoregionally advanced esophageal cancer (LAEC).
Authors: Michael Marquardt, Carryn M. Anderson, Sarah L Mott, Muhammad Furqan, Gerald H. Clamon, Kalpaj Parekh, Bryan G. Allen, John Michael Buatti, John Morgan Watkins
Journal: Journal of Clinical Oncology (2017)

140 Background: Disease control and survival outcomes for LAEC are poor despite multimodality treatment with CRT with or without esophagectomy. Without comparative trial data, oncologists select a chemotherapy regimen based on clinical experience and toxicity profile. The present investigation compares LAEC progression free survival (PFS) and overall survival (OS) for CF versus CT. Methods: A retrospective analysis was performed for patients with LAEC from 2003-2012, treated with curative-intent neoadjuvant or definitive concurrent CRT with either CF or CT. Chi-squared tests, Fisher’s exact tests, and t-tests were used to identify significant differences between treatment groups. The Kaplan-Meier method was used to estimate PFS and OS. Results: Of 149 patients with non-metastatic LAEC, 82 met inclusion criteria (n=38 CF, n=44 CT), with 63, 2, and 2 excluded for non-CF/CT CRT, missing data, and &lt;1 month follow-up, respectively. Treatment groups were well balanced, excepting fewer females, lower prior cancer rate, and longer follow-up for the CF group (Table 1). At a median follow-up of 22.7 months (range, 1.8-132.1, median follow-up 58.6 for survivors), 48 patients experienced recurrence (22 CF, 26 CT), and 63 patients died (29 CF, 34 CT). No differences in PFS or OS were demonstrated between treatment groups (Table 1). Conclusions: The present study failed to detect a disease control or survival difference between CF and CT as a component of CRT in neoadjuvant or definitive settings for LAEC. Until randomized trial data are available, oncologists may elect CF or CT based on clinical situations and anticipated sequelae. [Table: see text]
Sixty seconds on . . . Zavicefta
Authors: Nigel Hawkes
Journal: BMJ (2017)

It is. Growing antimicrobial resistance is a serious threat, so any evidence that the drug industry is focusing on new antibiotics is cheering.

That’s the claim. Zavicefta combines an established antibiotic, ceftazidime, with a second component, avibactam, designed to inhibit one of the pathways by which antibiotics acquire resistance.

No. Beta lactamase inhibitors …
Education and gender differences in perception of prognosis among advanced cancer patients (ACP) in hospice
Authors: S. W. Gray, F. Hlubocky, C. K. Daugherty
Journal: Journal of Clinical Oncology (2004)

6022 Background: Prior research documents that social attributes and preferences for involvement in medical decision making (MDM) influence doctor-patient communications. Little is known about how these attributes and preferences may effect ACP perceptions of prognosis in the hospice population. Methods: We interviewed 64 functional ACP (cognitively intact; KPS of 0,1 or 2).The majority were interviewed within one week of hospice enrollment (median age 72.5: range 38–89; 53% female; 75% white; 65% widowed, divorced or single; 32% <high school education). The ACPS' subsequent median survival was 13 weeks (0–43 weeks, data unavailable for 5 ACP). Greater than 90% of those approached agreed to and completed semi-structured interviews using a standardized survey that addressed multiple issues related to hospice enrollment decisions. Preferences for participation in MDM were measured using a validated instrument. Results: 44 ACP gave closed-ended answers regarding the possibility of their death at some unspecified time in the future, while 20 patients refused to answer the question or gave open-ended answers. Of those giving closed-ended answers, 70% were certain death would occur while 30% felt it probable, possible or not possible. Of the certain responders, 39% were male, 61% female. When asked about the specific possibility of death within one year, 35% of certain responders were male, 65% female (p= 0.056). Uneducated (<high school) ACP responded that death was certain 50% of the time, while highly educated patients (college or graduate degree) responded that death was certain 100% of the time. Conclusions: Differences in stated perceptions of prognosis among women and the less educated were present regardless of ACP preferences for participation in MDM. One hypothesis to explain this is that physicians communicate information about prognosis based more on social attributes and assumptions about ACP preferences for information rather than on elicited or known preferences for MDM. Other explanations include that women and the less educated may have more fatalistic attitudes about their health that relates to prior, poor health care experiences. No significant financial relationships to disclose.
Evaluating the cost-effectiveness of low-level laser therapy (LLLT) in head and neck cancer patients submitted to concurrent chemoradiation.
Authors: Heliton Spindola Antunes, Daniel Herchenhorn, Isabele Avila Small, Carlos Manoel Araujo, Elida Cabral, Mariana Pereira Rampini, Pedro Carvalho Rodrigues, Tereza Giannini Pereira da Silva, Elza Maria de Sa Ferreira, Fernando Luiz Dias, Nelson Teich, Vanessa Teich, Luciene Fontes Schluckebier, Carlos G. M. Ferreira
Journal: Journal of Clinical Oncology (2013)

6071 Background: Oralmucositis (OM) is a main factor for increasing treatment costs in head and neck squamous cell carcinoma (HNSCC) patients (pts) treated with chemoradiation (CRT). This study was designed to estimate the cost-effectiveness of LLLT to prevent oral mucositis in HNSCC patients submitted to CRT. Methods: From June 2007 to Dec 2010, 94 patients with HNSCC of nasopharynx, oropharynx and hypopharynx entered a prospective, randomized, double blind, placebo-controlled, phase III trial (47 LLLT (LG) and 47 placebo (PG)). CRT consisted of conventional RT 70.2 Gy (1.8Gy/d, 5 times/wk) + concurrent cisplatin 100 mg/m 2 every 3 wks. The LLLT used daily was a diode InGaAlP (660nm-100mW-4J/cm²). OM evaluation was done by WHO and OMAS scale. The resources used by patients in both groups were documented during the trial. Unit costs for procedures were obtained from a public reference list (SIGTAP / SUS) as of Jan 2012 and unit costs for drugs were based on ex-factory prices. The cost per laser session was US$ 34.00 (exchange rate from Brazilian currency to US dollar = 1.95) for the baseline analysis. Costs of RT, chemotherapy, fluconazole and chlorhexidine 0.12% were equivalent in both groups and therefore not included in the analysis. Hospitalization rates associated with the treatment of oropharyngeal or oral mucositis were not documented in the study and were estimated according to previously published data. Results: Under the perspective of the Brazilian public healthcare system (SUS), total costs were higher in PG than LG on opioide use (LG= US$ 29.45; PG= US$143.72, gastrostomy (LG= US$ 41.69; PG= US$107.22 ) and hospitalization (PG= US$ 63.59). In LG costs were higher with laser therapy (US$ 1,549.50). The total incremental cost associated with the use of LLLT was US$ 1,306.61 per patient. The incremental cost-effectiveness ratio (ICER) was US$ 3,838.16 per case of grade 3 and 4 mucositis avoided when compared with no treatment. Conclusions: Our results indicate that laser group had a smaller morbidity during treatment and LLLT is cost-effective when compared to pacebo under a threshold of at least US$ 4,000 per avoided mucositis case. Clinical trial information: NCT01439724.
Rapid Genetic Adaptation during the First Four Months of Survival under Resource Exhaustion
Authors: Sarit Avrani, Evgeni Bolotin, Sophia Katz, Ruth Hershberg
Journal: Molecular Biology and Evolution (2017)

Many bacteria, including the model bacterium Escherichia coli can survive for years within spent media, following resource exhaustion. We carried out evolutionary experiments, followed by whole genome sequencing of hundreds of evolved clones to study the dynamics by which E. coli adapts during the first 4 months of survival under resource exhaustion. Our results reveal that bacteria evolving under resource exhaustion are subject to intense selection, manifesting in rapid mutation accumulation, enrichment in functional mutation categories and extremely convergent adaptation. In the most striking example of convergent adaptation, we found that across five independent populations adaptation to conditions of resource exhaustion occurs through mutations to the three same specific positions of the RNA polymerase core enzyme. Mutations to these three sites are strongly antagonistically pleiotropic, in that they sharply reduce exponential growth rates in fresh media. Such antagonistically pleiotropic mutations, combined with the accumulation of additional mutations, severely reduce the ability of bacteria surviving under resource exhaustion to grow exponentially in fresh media. We further demonstrate that the three positions at which these resource exhaustion mutations occur are conserved for the ancestral E. coli allele, across bacterial phyla, with the exception of nonculturable bacteria that carry the resource exhaustion allele at one of these positions, at very high frequencies. Finally, our results demonstrate that adaptation to resource exhaustion is not limited by mutational input and that bacteria are able to rapidly adapt under resource exhaustion in a temporally precise manner through allele frequency fluctuations.
Analysis of KRAS and BRAF mutant colorectal cancers in a multiracial population.
Authors: Jared David Acoba, Christopher A. Lum, Lambert T Leong
Journal: Journal of Clinical Oncology (2012)

1599 Background: We previously demonstrated racial disparities in colorectal cancer (CRC) survival despite adjustments for tumor and socioeconomic factors. Molecular differences in breast and lung tumors contribute to racial survival inequality, yet in CRC, molecular tumor characteristics have not been studied extensively in a racially diverse cohort. We performed a comprehensive evaluation of KRAS and BRAF mutations in a multiracial population to determine the prevalence in CRC and the degree to which these molecular traits impact survival. Methods: A retrospective cohort study of patients diagnosed with CRC between 2008 and 2011 from hospital tumor registries was performed. The prevalence of KRAS and BRAF mutations was determined for the study population and individual racial groups. Multivariable Cox proportional hazards regression models for survival were built for KRAS and BRAF mutation status while adjusting for age at diagnosis, race, and stage of disease. Results: Of 706 patients diagnosed with CRC, KRAS mutational analysis was performed on 148 subjects. 14% of subjects were white (W), 64% Asian (A), and 21% Native Hawaiian/Pacific Islander (NH). KRAS mutation was identified in 48 subjects (32%). The prevalence of mutant tumors among racial groups was W 33%, A 36%, and NH 30%. Analysis for KRAS G13D mutations revealed a prevalence of W 11%, A 9%, and NH 7%. When compared to published datasets of predominantly white patients, our multiracial cohort had a significantly higher rate of KRAS G13D mutant tumors, p=0.039. Of 74 subjects tested for the BRAF mutation, two mutant tumors were detected (3%). The prevalence of the BRAF mutation by race was 10% W, 3% A, and 0% NH (p=0.18). BRAF and KRAS G13D mutations were adverse prognostic factors in a multivariate analysis, although the odds ratios failed to meet statistical significance. Conclusions: The prevalence of BRAF and KRAS mutations in this multiracial cohort is similar to what has been previously reported. However the rates of KRAS G13D and BRAF mutant tumors in our cohort are higher than prior reports. Furthermore, KRAS G13D which has been postulated to be a favorable prognostic factor for CRC, may adversely impact survival of minority patients.
Tumor stage and primary treatment selection among a large cohort patients with hepatocellular carcinoma.
Authors: Xue-Mei You, Jian-Hong Zhong, Ning-Fu Peng, Liang Ma, Le-Qun Li
Journal: Journal of Clinical Oncology (2017)

256 Background: This study reviewed the distribution of each tumor stage and each type of primary treatment modality among patients with primary hepatocellular carcinoma (HCC) treated at a tertiary tumor hospital between January 2003 and October 2013. Methods: Baseline data of patients with primary HCC treated between January 2003 and October 2013 were retrospectively collected. Tumor stage was determined according to the Barcelona Clinic Liver Cancer (BCLC) staging system and Hong Kong Clinic Liver Cancer (HKLC) staging system. Results: A total of 6241 patients with primary HCC were included in the analysis. In accordance with the BCLC, 28.9% of patients were in stage 0/A, 16.2% in stage B, 53.6% in stage C, and 1.3% in stage D. According to the HKLC stage system, 8.4% patients were in stage I, 1.5% in stage IIa, 29.0% in stage IIb, 10.0% in stage IIIa, 33.6% in stage IIIb, 3.4% in stage IVa, 2.5% in stage IVb, 0.2% in stage Va, and 11.4% in stage Vb. Treatment modalities applied to this patient group were as follows: 33.3% of patients underwent hepatic resection, 36.7% underwent transarterial chemoembolization (TACE), 2.2% underwent radiotherapy, 0.9% underwent local ablated therapy, 8.8% underwent systemic chemotherapy, 4.2% underwent traditional herbal medicine therapy, 0.1% underwent targeted drug therapy, and 13.8% received no treatment. Hepatic resection was the most frequent therapy for patients with BCLC 0/A/B disease, and TACE was the first-line therapy for patients with BCLC C disease. In the HKLC stage, the main treatments for HKLC I to IIIb disease is hepatic resection and TACE. Systemic chemotherapy was the first-line therapy for patients with HKLC IVa/IVb disease. Most HKLC Va/Vb patients received traditional Chinese medicine (TCM) treatment. Conclusions: Prevalence of stage BCLC B and C disease was high among our HCC patients. In HKLC stage, HKLC I to IIIb disease was high among our HCC patients. Hepatic resection and TACE are first-line therapies.
Correlation of pharmacokinetics of CPT-11 in FOLFIRI with phenotyping of CYP3A4 and UGT1A1 activity.
Authors: Daniel Boon Yeow Chan, Lawrence Soon-U Lee, Ling-Zhi Wang, Wei-Peng Yong, Lu Fan, Benjamin Chuah, Kim-Hor Hee, Winnie Hui Yee Ling, I Peng Thomas Soh, Thambidurai Ganesh Babu, Pei Fen Cheong, Pei Jye Voon, Ross A. Soo, How-Sung Lee, Soo-Chin Lee, Boon C. Goh
Journal: Journal of Clinical Oncology (2012)

e13002 Background: CPT-11 has complex PK and PD; genotyping of UGT1A1 is recommended for higher doses in *28 carriers (Caucasian) and *6 carriers (Asian) because of a higher risk of toxicity. Raltegravir is mainly metabolized to raltegravir glucuronide by UGT1A1. CPT-11 is mainly eliminated by cytochrome P450 isoform 3A (CYP3A)-mediated oxidation and by esterase cleavage to form SN-38, which is further conjugated by uridine-diphosphate glucuronosyltransferase (UGT) isozymes to the inactive SN-38 glucuronide. We prospectively explored the correlation of midazolam and raltegravir PK with CPT-11 clearance (CL) and SN-38 levels respectively and toxicity in patients undergoing chemotherapy with CPT-11. Methods: Twenty-five Asian patients with advanced cancer received CPT-11 as a 2-weekly 90-minute infusion (180 mg/m 2 ) as part of the FOLFIRI regimen. Subjects were administered raltegravir 400 mg orally (as a UGT1A1 probe) and intravenous midazolam 1 mg (as a CYP3A4 probe) one day before the first dose of their chemotherapy. Blood sampling for drug concentrations was performed for 2 days after probe drug administration. Non-compartmental PK analyses were performed using WinNonLin. Genomic DNA was isolated and screened for the known genetic variants in UGT1A1*6. Results: One patient developed grade 3 diarrhea and 16 developed grade 3-4 neutropenia. The mean CPT-11 CL was 21.9 + 7.8L/h. SN-38G/SN-38 AUC ratio was highly correlated with Raltegravir glucuronide/ Raltegravir AUC ratio (r=0.784 p&lt;0.01). Midazolam CL was highly correlated with CPT-11 CL (r=0.563 p&lt;0.01). SN38 AUC correlated well with neutropenia (Log 10 Nadir Absolute Neutrophil Count (ANC) (r=-0.397 p&lt;0.05). Neither CPT-11 nor midazolam CL correlated with Log 10 Nadir ANC. Of the 24 patients with genotyping of UGT1A1*6 done, 17 were wild type (GG), 7 heterozygotes (AG) and 0 were mutant (AA). No differences in toxicity or SN38 pharmacokinetics were observed in the UGT1A1*6 variants. Conclusions: Raltegravir glucuronide ratio is a good predictor of SN-38 glucuronidation, and has potential to predict neutropenia from FOLFIRI treatment. Prospective studies with dose adjustments should be done to develop raltegravir as a probe to optimize CPT-11 therapy.
A phase I/II study of radiation therapy, paclitaxel poliglumex, and cetuximab in locally advanced head and neck cancer.
Authors: Seung Shin Hahn, Jeffrey Bogart, Chung Taik Chung, Jack Hsu, Robert Kellman, Jung-AH Kim, Steve Graziano, Dena Martin, Ajeet Gajra
Journal: Journal of Clinical Oncology (2012)

e16047 Background: In patients with locally advanced head and neck cancer (LA-HNC), radiotherapy (RT) + cisplatin showed survival benefit over RT alone, but with significant toxicity. The addition of cetuximab to RT demonstrated survival benefit without increased RT-related toxicity. Paclitaxel poliglumex (PPX) is a novel conjugate consisting of paclitaxel linked to a biodegradable, water-soluble polymer of glutamic acid. PPX has a radiation enhancement factor of ≈8 and improved curability in a murine carcinoma model. In a phase I study of PPX + RT in esophageal cancer, no dose-limiting toxicities (DLTs) occurred at PPX doses up to 70 mg/m 2 /week and an encouraging rate of pathological CRs was observed. This phase I/II study addresses the combined use of intensity modulated RT (IMRT), PPX, and cetuximab in patients with LA-HNC. Methods: Eligible patients had untreated stage III or IV squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx; ECOG PS 0-1; and adequate bone marrow function. In the phase I portion, patients received cetuximab 400 mg/m 2 day 1 and 250 mg/m 2 days 8, 15, 22, 29, 36, 43, and 50. PPX was administered at 40 mg/m 2 days 8, 15, 22, 29, 36, 43, and 50 for Cohort 1 (n = 3) then escalated or decreased for Cohorts 2-5 (3 patients each) until the maximum tolerated dose (MTD) was established. IMRT began on day 8 and consisted of 69.96 Gy delivered in 2.12 Gy daily fractions. In the phase II portion, patients received PPX at the MTD + cetuximab and IMRT at the phase I dose and schedule. Results: In total, 14 patients were treated (9 phase I, 5 phase II). The PPX MTD was determined to be 40 mg/m 2 . The majority of adverse events (AEs) were grade 1/2 and consistent with known toxicities of individual agents. The most common grade 3 AEs were mucositis (n = 8), radiation dermatitis (n = 4), and cetuximab rash (n = 3). Of 13 patients evaluable for response, 9 had CR and 4 had PR. After a median 17-month follow up, the local control rate was 11/11 and the median survival was 20 months. Two patients with stage IVC disease were excluded for local control and survival analysis. Conclusions: The combination of IMRT, PPX, and cetuximab is tolerable and shows promising clinical activity in patients with LA-HNC.