tbuckley/cabot-search huggingface dataset:
Evaluation of the impact of gut microbiota on uremic solute accumulation by a CE-TOFMS–based metabolomics approach
Authors: Eikan Mishima, Shinji Fukuda, Chikahisa Mukawa, Akinori Yuri, Yoshitomi Kanemitsu, Yotaro Matsumoto, Yasutoshi Akiyama, Noriko N. Fukuda, Hiroki Tsukamoto, Kei Asaji, Hisato Shima, Koichi Kikuchi, Chitose Suzuki, Takehiro Suzuki, Yoshihisa Tomioka, Tomoyoshi Soga, Sadayoshi Ito, Takaaki Abe
Journal: Kidney International (2017)

Gut microbiota is involved in the metabolism of uremic solutes. However, the precise influence of microbiota to the retention of uremic solutes in CKD is obscure. To clarify this, we compared adenine-induced renal failure and control mice under germ-free or specific pathogen-free (SPF) conditions, examining the metabolite profiles of plasma, feces, and urine using a capillary electrophoresis time-of-flight mass spectrometry-based approach. Mice with renal failure under germ-free conditions demonstrated significant changes in plasma metabolites. Among 183 detected solutes, plasma levels of 11 solutes, including major uremic toxins, were significantly lower in germ-free mice than in SPF mice with renal failure. These 11 solutes were considered microbiota-derived uremic solutes and included indoxyl sulfate, p-cresyl sulfate, phenyl sulfate, cholate, hippurate, dimethylglycine, γ-guanidinobutyrate, glutarate, 2-hydroxypentanoate, trimethylamine N-oxide, and phenaceturate. Metabolome profiling showed that these solutes were classified into three groups depending on their origins: completely derived from microbiota (indoxyl sulfate, p-cresyl sulfate), derived from both host and microbiota (dimethylglycine), and derived from both microbiota and dietary components (trimethylamine N-oxide). Additionally, germ-free renal failure conditions resulted in the disappearance of colonic short-chain fatty acids, decreased utilization of intestinal amino acids, and more severe renal damage compared with SPF mice with renal failure. Microbiota-derived short-chain fatty acids and efficient amino acid utilization may have a renoprotective effect, and loss of these factors may exacerbate renal damage in germ-free mice with renal failure. Thus, microbiota contributes substantially to the production of harmful uremic solutes, but conversely, growth without microbiota has harmful effects on CKD progression.
A national treatment survey on the chemotherapy (CTX) treatment for patients (Pts) with metastatic breast cancer (MBC) in Germany.
Authors: Christian Jackisch, Michael Untch, Peter Dall, Christoph Thomssen, Ute-Susann Albert, Hans-Joachim Lueck, Ingo Bauerfeind, Anton J. Scharl
Journal: Journal of Clinical Oncology (2013)

e17544 Background: The optimal CTX regimens and their sequence is the subject of ongoing debates esp. on the use of anthracycline/taxane (AT)-based adjuvant therapy (tx). Methods: Since 2004 a biennial survey is performed to evaluate routine CTX practice in MBC A total of 1,966 German sites were contacted. From 515 (26.2%) patient data were used for evaluation in order to achieve a representative sample for a chart review between June and August 2012. The current analysis is based on data from 291 sites on characteristics and tx of 741 pts undergoing first (1L), second (2L) or third (3L) line CTX for MBC in May 2012. Results: Data from 417 pts in 1L, 203 pts in 2L, and 121 pts in 3L were evaluated. Median age was 60 years (yrs). Patient characteristics were: 74% hormone receptor positive, 24% HER2-positive at primary diagnosis, 67% premenopausal, 60% had metastases in ≥ 2 organs, 66% had visceral disease. Prior tx (excluding M1 pts) was: no systemic tx 10%, endocrine tx only 13%, adjuvant CTX 58% (40% A and 44% AT-based), neoadjuvant CTX 20% (12% A and 75% AT-based). Median time from primary diagnosis to start of any treatment for MBC was 4.5 yrs for node-negative and 2.1 yrs for node-positive disease. Median time from primary diagnosis to current CTX was 4.9 yrs in 1L, 5.1 yrs in 2L and 5.8 yrs in 3L. Combination CTX was given in 21% of 1L, 12% of 2L and 9% of 3L pts, and its use decreased with increasing age. Agents used most frequently in 1L were taxanes in 61% (paclitaxel (P) 52%, docetaxel (D) 6%, nab-paclitaxel (Nab) 3%), capecitabine (X) 21%, vinorelbin (V) 19%, Epirubicin 6%, carboplatin 5%. 1L taxane tx was given to 73% of pts with prior A-based and 46% of pts with prior AT-based (neo-)adjuvant tx. Agents used most frequently in 2L were X 31%, P 20%, V 20%, gemcitabine (G) 7%, Nab 6% and in 3L V 27%, X 22%, eribulin 15%, Nab 12% P 7%, G 5%. Targeted tx was given in 54% of pts (20% trastuzumab, 4% lapatinib, and 30% bevacizumab), additional tx were bisphosphonates in 58%, and radiotherapy in 20%. Conclusions: The survey showed a high concordance of routine treatment and the existing national guidelines regarding CTX. Taxanes still dominate CTX in MBC including a significant amount of taxane rechallenge after their use in (neo-)adjuvant tx.
Palliative care utilization in patients with newly diagnosed, incurable solid tumor malignancies: The experiences of an institution new to palliative care.
Authors: Adrian REYES Bersabe, Joshua Romain, Wilfred P. Delacruz
Journal: Journal of Clinical Oncology (2017)

92 Background: Early palliative care (PC) referral can enhance quality of life (QOL) in patients with metastatic cancer and even improve overall survival in non-small cell lung cancer. Despite compelling data showing benefits of early integration of PC, barriers to care exist. Our institution recently established an outpatient PC service. To improve utilization of this new service we identified clinicians’ attitudes and barriers to PC, and provided education on the PC referral process. The effects of this intervention on PC utilization were assessed. Methods: We conducted a retrospective chart review of outpatient Hematology/Oncology (HO) referrals to identify patients referred for newly diagnosed, solid tumor malignancies with no curative options. Hospice referrals were excluded. We then formally surveyed clinicians participating in multi-disciplinary tumor boards to identify PC referral practices and attitudes/barriers to PC referrals. Education on PC and instruction on PC referral process were provided during this period. Post-intervention review of PC referrals over 4 months was conducted. Results: Prior to our intervention, of the 53 new consultations reviewed meeting study criteria only three (5.7%) patients were referred to PC. Our survey revealed that 66% (31/47) of oncology providers did not know the institution had onsite PC available and only eight (17%) knew how to place a referral. After education was provided, a second cohort revealed 24.1% (7/29) of patients were appropriately referred for early outpatient PC representing an 18.4% absolute increase. Conclusions: We significantly increased early PC referrals for HO patients with advanced or metastatic disease. However, other efforts to improve institutional awareness and change the culture of care to ensure that majority of these patients are appropriately referred. Longitudinal evaluation will further ensure that timely adjustments are made and that effects are permanent.
Ciclosporin compared with prednisolone therapy for patients with pyoderma gangrenosum: cost-effectiveness analysis of the STOP GAP trial
Authors: J.M. Mason, K.S. Thomas, A.D. Ormerod, F.E. Craig, E. Mitchell, J. Norrie, H.C. Williams
Journal: British Journal of Dermatology (2017)

Background Pyoderma gangrenosum (PG) is a painful, ulcerating skin disease with poor evidence for management. Prednisolone and ciclosporin are the most commonly used treatments, although not previously compared within a randomized controlled trial (RCT). Objectives To compare the cost‐effectiveness of ciclosporin and prednisolone‐initiated treatment for patients with PG. Methods Quality of life (QoL, EuroQoL five dimensions three level questionnaire, EQ‐5D‐3L) and resource data were collected as part of the STOP GAP trial: a multicentre, parallel‐group, observer‐blind RCT. Within‐trial analysis used bivariate regression of costs and quality‐adjusted life years (QALYs), with multiple imputation of missing data, informing a probabilistic assessment of incremental treatment cost‐effectiveness from a health service perspective. Results In the base case analysis, when compared with prednisolone, ciclosporin was cost‐effective due to a reduction in costs [net cost: −£1160; 95% confidence interval (CI) −2991 to 672] and improvement in QoL (net QALYs: 0·055; 95% CI 0·018–0·093). However, this finding appears driven by a minority of patients with large lesions (≥ 20 cm2) (net cost: −£5310; 95% CI −9729 to −891; net QALYs: 0·077; 95% CI 0·004–0·151). The incremental cost‐effectiveness of ciclosporin for the majority of patients with smaller lesions was £23 374/QALY, although the estimate is imprecise: the probability of being cost‐effective at a willingness‐to‐pay of £20 000/QALY was 43%. Conclusions Consistent with the clinical findings of the STOP GAP trial, patients with small lesions should receive treatment guided by the side‐effect profiles of the drugs and patient preference – neither strategy is clearly a preferred use of National Health Service resources. However, ciclosporin‐initiated treatment may be more cost‐effective for patients with large lesions.
Randomized phase II study of concurrent gefitinib and chemotherapy versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer (NSCLC) with sensitive EGFR mutations: NEJ005/TCOG0902.
Authors: Satoshi Oizumi, Shunichi Sugawara, Koichi Minato, Toshiyuki Harada, Akira Inoue, Yuka Fujita, Makoto Maemondo, Hirohisa Yoshizawa, Kazuhiko Ito, Akihiko Gemma, Masaru Nishitsuji, Masao Harada, Hiroshi Isobe, Ichiro Kinoshita, Satoshi Morita, Kunihiko Kobayashi, Koichi Hagiwara, Minoru Kurihara, Toshihiro Nukiwa
Journal: Journal of Clinical Oncology (2014)

8016 Background: The first-line combination of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) plus platinum-based doublet chemotherapy has yet to be sufficiently evaluated for patients with EGFR-mutant NSCLC. This randomized phase II trial was designed to identify an effective combined regimen of gefitinib (G) plus carboplatin/pemetrexed (CP) for subsequent use in phase III study. Methods: Chemotherapy-naïve patients with advanced non-squamous EGFR-mutated NSCLC were randomly assigned to receive either a concurrent regimen (C group) or a sequential and alternating regimen (S group). Patients in the C group received concurrent G (250 mg daily) and CP (AUC = 6 and 500 mg/m2, day 1) of a 3-week cycle for 6 cycles, followed by concurrent G and P maintenance. Patients in the S group initially received G (days 1 to 28) and then CP (day 29 and 51); the cycle was repeated for 3 cycles, followed by alternating G and P maintenance. The primary endpoint was progression-free survival (PFS). Results: All 80 patients enrolled were eligible and evaluable for efficacy. Median PFS was 17.2 months in the C group and 15.1 months in the S group (p = 0.41). Although overall survival data are immature (with a median follow-up time of 24.6 months, 10 and 19 death events), median survival times were not reached in the C group, and were 30.0 months in the S group (p = 0.049). Response rates were similar in both groups (87.8% in the C group and 82.1% in the S group). The most common grade 3 or greater adverse events were neutropenia (48.8% and 46.2%), thrombocytopenia (41.5% and 28.2%), and anemia (34.1% and.12.8%). G-related skin rash or diarrhea was not severe, and interstitial lung disease was not frequent (two cases in each group; 5% of all patients). No treatment-related deaths occurred. Conclusions: To the best of our knowledge, this is the first randomized study to investigate the efficacy of a combination of EGFR-TKI and chemotherapy in the EGFR-mutated setting. Both regimens had promising efficacy with predictable toxicities, although concurrent regimens might provide better overall survival. Clinical trial information: UMIN000002789.
Adaptively randomized trial of neoadjuvant chemotherapy with or without the Akt inhibitor MK-2206: Graduation results from the I-SPY 2 Trial.
Authors: Debu Tripathy, Amy Jo Chien, Nola Hylton, Meredith Becker Buxton, Cheryl Ann Ewing, Anne M. Wallace, Andres Forero, Henry G. Kaplan, Rita Nanda, Kathy S. Albain, Stacy L. Moulder, Barbara B. Haley, Angela DeMichele, William Fraser Symmans, Laura van 't Veer, Melissa Paoloni, Laura Esserman, Donald A. Berry, Douglas Yee
Journal: Journal of Clinical Oncology (2015)

524 Background: A key node of growth and survival signaling pathways is the Akt serine/threonine kinase that activates mTOR and downstream effectors. I-SPY 2 is a randomized neoadjuvant trial to test agents and combinations added to standard chemotherapy. Pathological complete response (pCR) defined as absence of invasive cancer in breast and nodes is the primary endpoint. We report efficacy results for allosteric Akt inhibitor MK-2206. Methods: Women with invasive breast cancer ≥2.5 cm on exam or ≥2 cm on imaging were adaptively randomized to 12 weekly paclitaxel (and trastuzumab if HER2+) cycles (control) or in combination with one of several experimental agents followed by doxorubicin/cyclophosphamide x 4. Patients (pts) are stratified to 8 subsets based on hormone-receptor (HR), HER2, and MammaPrint statuses, with combinations of subsets defining agent signatures. MK-2206 135 mg daily by mouth was evaluated in all 8 subsets. Adaptive assignment to the experimental arms was based on current Bayesian probabilities of superiority over control. Graduation by signature and futility stopping was based on Bayesian predictive probability of success in a 2-arm, N=300 Phase 3 randomized 1:1 trial with pCR endpoint. Results: MK-2206 graduated in the first 3 signatures in the table. Accrual ended with 93 patients assigned to that arm and when 56 pts had been concurrently randomized to control. Final posterior and predictive probabilities are shown for all 10 signatures. Conclusions: MK-2206 improves pCR rates compared to standard chemotherapy in several breast cancer signatures, defined mostly by HR- and HER2+, sufficiently for evaluation in a Phase 3 neoadjuvant trial powered for event-free survival. Safety data will be presented. Clinical trial information: NCT01042379. Signature Estimated pCR Rate Probability MK2206 Superior to Control Predictive Probability Success Phase 3 MK-2206 N=93 Control N=56 Difference HR-/HER2+ 64.1 35.7 28.4 97.3 87.0 HR- 46.7 26.1 20.6 98.6 82.7 HER2+ 49.6 28.9 20.7 95.1 77.7 HR-/HER2- 40.2 22.4 17.8 96.8 75.9 MP+ 39.3 22.5 16.8 97.0 74.1 All 35.2 21.1 14.1 97.9 68.6 HR+/HER2+ 35.8 22.4 13.4 85.4 61.3 HER2- 29.3 18.0 11.3 95.0 59.0 HR+ 22.8 15.9 6.9 81.8 42.5 HR+/HER2- 17.1 13.0 4.1 72.7 31.7
Temozolomide (TMZ) and radiation (XRT) for aggressive pediatric CNS malignancies
Authors: K. C. Loh, J. Willert, H. Meltzer, W. Roberts, B. Kerlin, F. Kung, M. Levy, R. Kadota, A. Yu, M. A. Spear
Journal: Journal of Clinical Oncology (2004)

8566 Background: TMZ combined with XRT has gained widespread use in CNS tumors secondary to low toxicity, good CSF penetration and possible synergy. Prior reports have focused on adult patients. Thus, the outcomes of several uncommon and therapeutically challenging pediatric diagnoses treated with regimens combining TMZ and XRT are presented. Methods: Toxicity, survival, and response rate (CR, PR, SD, PD) were determined by chart review. Diagnoses were pathologically confirmed. Patient 1 (P1) (9 yr) had pilocytic astrocytoma (PA) exhibiting rapid local recurrences in spite of multiple resections. P2 (6 yr) presented with PA having both rapid local regrowth and CSF dissemination. P3 (15 yr) had glioblastoma. P4 (2 yr), presented with rapidly progressing recurrence and CSF dissemination of medulloblastoma. Patients with focal disease were treated with concomitant TMZ (daily 75 mg/m2) and 3D-conformal XRT (54–60 Gy) followed by TMZ (200 mg/m2 5 days / month). Those with disseminated disease were also treated with craniospinal XRT (39.6 Gy) prior to conformal boost, followed by TMZ (200 mg/m2 5 days / month). P4 was further treated with TMZ (90 mg/m2) concomitant to XRT. Results: P1 had grade 3 lymphopenia during treatment, initially demonstrated a PR with marked improvement of neurologic deficits, but died at 0.5 years from CSF dissemination. P2 suffered grade 3 neutropenia, thrombocytopenia, and lymphopenia, but is alive with an ECOG PS of 1 at 1.8 years post-diagnosis with a PR at all sites. P3 had increased neurologic symptomology (grade 2) during XRT, initially with SD, but died at 0.8 years from PD. P4 exhibited grade 1 lymphopenia with a PR, then died at 0.5 years from PD. No XRT related dermatologic toxicity beyond the expected (grade 1–2) was seen. Conclusions: TMZ combined with XRT is well tolerated in aggressive pediatric malignancies, even when full dose craniospinal radiation is utilized. Patient numbers are small, but outcomes appear to be at least as good as expected with frequent PR. No significant financial relationships to disclose.
Use of thalidomide as consolidation therapy in ovarian and primary peritoneal cancers
Authors: B. Ndubisi, F. Ciricano, N. Finkler
Journal: Journal of Clinical Oncology (2004)

5154 Background: Ovarian cancer represents 55% of all gyn cancer deaths. Over 70% are Diagnosed at stage III and IV with survival of 0 to 30%. Response rates of 70 to 80% and median survival of 38 months can be expected after surgical cytoreduction plus platinum-taxane based chemotherapy. The relapse rate approaches 75% after complete clinical response. This high relapse rate suggests persistent microscopic disease which requires neovascularization for regrowth. Following recurrence, survival is dismal. Methods: This is a pilot study to determine if thalidomide (T), an antiangiogenic agent and immunomodulator can affect time to recurrence and progression of advanced epithelial ovarian cancer (AEOC). Disease-free and overall survival, and tolerability are evaluated. Patients with stage III and IV AEOC with surgical resection and 6 to 8 cycles of P/T based chemotherapy with complete clinical response were included. Patients received 100 to 300 mg of T daily. Routine surveillance for recurrence was done. Side effects profiles were recorded. Results: To date, a total of 8 patients have been enrolled. 7 (82%) were papillary adenocarcinomas, 2 (13%) were endometrial adenocarcinomas. Age range 49 to 82 yrs. 1 patient discontinued after 21 weeks due to a new diagnosis of breast cancer. 2 patients progressed with ascites and elevated CA-125 level at 2 and 7 months respectively. 3 patients withdrew at 2 weeks, 3 weeks and 2 months due to vertigo and somnolence. One patient stopped at 14 months due to peripheral neuropathy and edema. 2 patients continue on therapy at 4 and 20 months. There were no serious adverse events. All evaluable patients are followed for recurrence. Conclusions: T has a potential role as consolidative therapy in patients AEOC. Patients experienced somnolence and vertigo at 200 to 300 mg, however, daily doses of 100 mg was well tolerated. In our study, the number of patients is small and median follow-up is short. However, we recommend a larger study with longer follow-up period. Newer IMID analogs of T should be considered in this setting. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celgene Corporation
Patient preference trial comparing capecitabine and S-1 in metastatic breast cancer patients.
Authors: Daigo Yamamoto, Satoru Iwase, Takuhiro Yamaguchi, Yu Tsubota, Takashi Kawaguchi, Hiroki Odagiri, Keisuke Ariyoshi, Kaoru Kitamura
Journal: Journal of Clinical Oncology (2014)

TPS2634 Background: Capecitabine and S-1 are an orally administered fluorinated pyrimidine with high activity in metastatic breast carcinoma (MBC). We reported the activity and safety of two oral fluoropyrimidines, capecitabine or S-1, in breast cancer patients (ASCO, 2013). While capecitabine was as efficacious as S-1 for the treatment of MBC, there were differences between the two drugs with respect to their toxicity profiles. Methods: This study is an open-label, multicentre, phase II patient preference trial with two treatment arms, comparing capecitabine and S-1 in patients with MBC. Patients are required to be between 25 and 75 years of age, with ECOG performance status <3. Patients are centralized by Japan Breast Cancer Research Network. Oral capecitabine is administered at a dose of 1,657 mg/m2 twice daily on days 1–21 every 4 weeks. S-1 is 40–60mg two times daily according to body surface area on days 1–28 every 6 weeks. In this cross-over study, patients receive either two cycles of S-1 followed by three cycles of capecitabine, or three cycles of capecitabine followed by two cycles of S-1 and then patients are asked about their preference. After 12 weeks patients are asked to choose which of the two regimens they preferred. Therapy is given unless there is any sign of progression or severe toxicity or the patient wants to discontinue the therapy. Patients with stable disease (SD) or partial response (PR) after two treatment cycles, could continue on their regimen of choice thereafter. Tumor response is assessed according to the RECIST criteria. The primary end point is to investigate patient preference. The secondary end point is PFS, OS, address quality of life (EORTC-30), and anxiety and depression (HADS). NCI-CTCAE, ver. 4.0 and PRO-CTCAE are used to assess toxicity. We estimate that 70% of the patients in S-1 treatment group and 30% in the capecitabine group would like to continue the same treatment after three months after the treatment initiation. About 30 patients in each group are needed to detect the difference of the preference proportion with two-sided significance level 0.05 and 80% power. Chi-squared test will be used to test the null hypothesis for the primary analysis. Clinical trial information: UMIN000013045.
Determination of a second-line chemotherapy agent for patients with colorectal cancer (CRC) after fluorouracil failure
Authors: K. Yamashita, Y. Hirabayashi, M. Ikeda, M. Yamamura, T. Kubozoe, K. Iki, H. Matsumoto, A. Urakami, T. Hirai, T. Tsunoda
Journal: Journal of Clinical Oncology (2004)

3638 Background: Fluorouracil-based chemotherapy, such as with 5-FU/leucovorin, is standard as first-line chemotherapy for advanced CRCs. However, the best agent for chemotherapy after fluorouracil failure is still unknown. The primary objective of this study was to determine the best agent for second-line chemotherapy. Methods: Seventy-eight tumor specimens from CRC patients with no prior chemotherapy were obtained operatively and their sensitivity against five anticancer drugs, 5-FU, Mitomycin C, Cisplatine, Decetaxel and CPT-11, in an in vitro chemosensitivity test using CD-DST methods was analyzed. The chemosensitivity was expressed as the percentage T/C ratio, where T was the total volume of the treated group and C was that of the control group. Pearson's correlation coefficients were used to assess the relationship. P<0.05; statistically significant. A statistically significant correlation between two drugs was defined as a correlation of cross-resistance between them. Conversely, non-positive correlation was defined a correlation of no cross-resistance between them, with each of them having an independent spectrum. Results: Fifty-four specimens (colon, 30; rectum, 24) were successfully analyzed. The mean T/C ratios of 5-FU, Mitomycin C, Cisplatine, Decetaxel and CPT-11 were 79.1%, 69.9%, 81.2%, 59.4% and 63.8%, respectively. Although each of the agents has a different functional mechanism from that of 5-FU, with the exception CPT-11, all of them had a closely positive correlation with 5-FU. Conclusions: Only CPT-11 expressed an independent spectrum from 5-FU, thus indicating it to be the best agent for second-line chemotherapy after fluorouracil failure. No significant financial relationships to disclose.