tbuckley/cabot-search huggingface dataset:
A New Sign of Intracerebral Hematoma Expansion—Reply
Authors: Gregoire Boulouis, Andreas Charidimou, M. Edip Gurol
Journal: JAMA Neurology (2017)

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Health-related quality of life outcomes in a phase I/II study of stereotactic hypofractionated once-weekly radiation therapy (SHORT) for nonmetastatic prostate cancer.
Authors: Indranil Mallick, Moses Arunsingh, Sujoy Gupta, Satyadip Mukherjee, Sanjoy Chatterjee, Raj K Shrimali, Rimpa Achari
Journal: Journal of Clinical Oncology (2017)

126 Background: Stereotactic Radiation Therapy (SRT) for prostate cancer offers an opportunity to exploit the low alpha/beta ratio of prostate cancer. We present patient reported health-related Quality-of-life (HR-QoL) outcomes of an SRT schedule with once-weekly fractionation in an unselected cohort of non-metastatic prostate cancer. Methods: In a Phase I/II study 30 patients with non-metastatic prostate cancer (multiparametric MRI cT1-4N0, M0, Gleason 6-10, PSA &lt; = 60 ng/ml) were treated to a dose of 35Gy in 5 fractions delivered once a week (along with simultaneous elective nodal radiotherapy at 25Gy/5Fr to patients high-risk by NCCN criteria). Androgen deprivation therapy given to intermediate and high-risk patients. Treatments were planned using volumetric intensity modulated arc therapy. Quality of life was assessed using the EORTC QLQ C30 and PR25 questionnaires. HR-QoL parameters at baseline (before start of SRT) was compared to those at treatment completion and 3 months post-SRT. The raw QoL scores were converted to a scale of 0-100 by convention. A scale difference of 10 or higher was considered clinically meaningful. Results: All of the 30 recruited patients completed treatment and HR-QoL data were available at 3 time points for all patients. The ratio of low, intermediate and high risk patients was 1:9:20. SRT was well tolerated with no acute Grade 3 GI or GU symptoms by NCI CTC v4 (separately reported). Twenty one parameters were studies within the QLQ C30 and PR25 framework. At the end of treatment, only the urinary symptom score showed a clinically meaningful worsening (mean of 20/100 at baseline vs 34/100 at end of treatment, p &lt; 0.001). At 3 months, the urinary symptom score had returned close to baseline (26/100, p = 0.08). There was no clinically meaningful deterioration in the remaining HR-QoL parameters. Conclusions: Patient perception of function and symptoms with once-weekly SRT was good, with only a temporary worsening of the urinary symptom score, and subsequent recovery by 3 months. Compared to baseline scores, other QoL parameters did not show a clinically meaningful difference at end of treatment or at 3 months. Clinical trial information: CTRI/2016/02/006671.
A phase 1b dose-escalation trial of erlotinib, capecitabine and oxaliplatin in metastatic colorectal cancer (MCRC) patients
Authors: J. P. Delord, P. Beale, E. Van Cutsem, S. Clarke, C. Verslype, R. Bugat, A. Rakhit, S. Fettner, U. Brennscheidt, A. Feyereislova
Journal: Journal of Clinical Oncology (2004)

3585 Background: Epidermal growth factor receptor (HER1/EGFR) overexpression occurs in 45–80% of CRC patients (pts). Erlotinib (Tarceva™) is a potent HER1/EGFR inhibitor. Capecitabine and oxaliplatin have proven activity in MCRC pts. This trial determined the safety, the maximum tolerated dose (MTD) and pharmacokinetics (PK) of erlotinib in combination with capecitabine and oxaliplatin. Methods: MCRC pts were previously untreated or had received first-line treatment with 5-FU ± irinotecan. Patients were to receive escalating doses of daily oral erlotinib, capecitabine (days 1–14) (100mg + 1,650mg/m2 [Cohort 1]; 100mg + 2,000mg/m2 [Cohort 2]; 150mg + 2,000mg/m2 [Cohort 3]) and i.v. oxaliplatin 130mg/m2, every 21 days. Dose-limiting toxicity (DLT) was defined according to NCI-CTC criteria (2.0) in cycle 1 or 2. The MTD was the dose below which >1/3 pts had a DLT. Results: The first 6 pts in Cohort 1 had no DLTs. In Cohort 2, 2/6 pts had DLTs: one with G3 diarrhea and G3 intolerable rash; one with G3 diarrhea. Cohort 2 was expanded to 11 pts and two more pts experienced DLTs: one pt had G4 diarrhea and one pt had G3 pruritic rash. As 4/11 pts had DLTs, this cohort exceeded the definition of MTD. Thus, Cohort 1 was expanded to 12 pts and there were no DLTs in the additional pts. The most common adverse events (AEs) were diarrhea and rash. Preliminary evidence of antitumor activity was seen in both cohorts. Overall, 5 pts had a partial response (PR) and 14 had stable disease (SD). There was no evidence of PK interaction between erlotinib, capecitabine and oxaliplatin. Conclusions: These data indicate that capecitabine 1,650mg/m2 and oxaliplatin 130mg/m2 in combination with erlotinib 100mg/d is the recommended dose for phase II trials in MCRC pts. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Roche Roche
Tumor perivascular PDGFBR as an independent prognostic factor in metastatic colorectal cancer.
Authors: Maja Bradic Lindh, Artur Mezheyeuski, Bengt Glimelius, Per Pfeiffer, Elin Kure, Tone Ikdahl, Eva Skovlund, Halfdan Sorbye, Kjell Magne Tveit, Kristian Pietras, Helgi Birgisson, Jan Mulder, Tormod Kyrre Guren, Arne Ostman
Journal: Journal of Clinical Oncology (2013)

3571 Background: New vessel formation is an essential factor for tumor growth and metastasis. Tumor vessels show reduced and variable pericyte coverage. Several pericyte markers have been identified, including platelet-derived growth factor receptor beta (PDGFbR), smooth muscle α-actin (ASMA) and desmin. Variability in pericyte status and its prognostic significance remains largely uncharacterized in colorectal cancer (CRC). The aim of the present study was to perform a preliminary analysis of the variability in expression of the three pericyte markers and to investigate the potential prognostic significance of perivascular PDGFbR (PV-PDGFbR). Methods: A population-based cohort was used for double-staining, performed on 100 tumors with CD34 and above-named pericyte markers. For the rest of the study a metastatic CRC (mCRC) collection from the phase III NORDIC-VII study was used. Analyses were performed on a tissue microarray with tumor material from 328 out of the 566 patients in the intention to treat population. All tumors and corresponding normal tissue were scored by immunohistochemistry (IHC) with regard to PV-PDGFbR. 255 and 97 cases were analyzed by IHC with regard to perivascular ASMA and microvessel density (MVD), respectively. Results: Analyses of the double-staining revealed independent and variable expressions of all three pericyte markers. Analyses of the NORDIC-VII cohort revealed two prognostic groups with low and high PV-PDGFbR expression. Median OS was 14.3 mo for PV-PDGFbR-low tumors (N=22) vs. 22.9 mo for PV-PDGFbR-high (N=306) tumors (HR=1.95; 95% CI 1.20-3.16; log-rank p=0.007). Multivariate analysis, including WHO performance status, alkaline phosphatase level and BRAF mutation status confirmed PV-PDGFbR as an independent prognostic factor of OS (HR=1.75; 95% CI 1.07-2.84; p=0.025). PV-PDGFbR was not significantly linked to perivascular ASMA or MVD. PV-PDGFbR in normal tissue was not associated with survival. Conclusions: CRC display a previously un-recognized variability in pericyte characteristics. Low tumor PV-PDGFbR level is associated with worse prognosis in patients with mCRC, in a manner independent of performance status, alkaline phosphatase levels and BRAF status.
Caesarean section controversy
Authors: Katie Groom, José Belizan, Fernando Althabe, Fernando Celso F F.C. Barros, Sophie Karlin, Christine Nuttall, Sara Paterson Brown, Luis G A Quadros, Kathy Eftekhar, Philip Steer, Madhukar Pai, Nilofer Sabrine, M.P. O'connell, W. Lindow
Journal: BMJ (2000)
Treatment patterns among patients with metastatic GEP-NET treated at a tertiary referral center.
Authors: Jessica J Jalbert, Roman Casciano, Biwen Tao, Trevor Dutton, Lauren K. Brais, Sonia J. Pulgar, Anthony Berthon, Sylvie Gabriel, Jerome Dinet, Matthew H. Kulke
Journal: Journal of Clinical Oncology (2017)

397 Background: Treatment options for patients with advanced gastroenteropancreatic neuroendocrine tumors (GEP-NET) have been increasing. We describe treatment patterns among patients with advanced GEP-NET evaluated at a tertiary referral center. Methods: We conducted a cohort study of patients with well-differentiated GEP-NET recruited between June 2003-May 2015 from Dana-Farber Cancer Institute’s (DFCI) gastrointestinal clinic, using data from an institutional research database and the electronic healthcare records of DFCI and partner hospitals. Patients were required to have been evaluated ≥ 2 at DFCI and to be diagnosed with metastatic GEP-NET. Medications were categorized as cytotoxic agents (CA), angiogenesis inhibitors (AI), mTOR inhibitors (mTORI), interferons (IFN), somatostatin analogues (SSA), or investigational therapies (IT). Combination therapy (combo) was defined as treatment overlap by ≥ 30 days. Results: Among 682 patients (mean age [SD]: 58.5 [11.9], 50.1% male, 96.5% white, 44.9% midgut NET, 28.7% pancreatic NET, 38.9% carcinoid symptoms, and 62.6% with &lt; 1 year since metastatic GEP-NET diagnosis), 89.0% initiated ≥ 1 GEP-NET medication. First line treatment distribution was: 59.5% SSA, 17.5% SSA combo, 14.8% CA, 3.0% IT, 2.8% non-SSA combo, 1.2% AI, 0.7% IFN, and 0.5% mTORI. Among patients on first line SSA monotherapy, 68.4% remained on treatment until death or end of follow-up. Of the 296 patients advancing to second line treatments, 90.5% took SSAs (13.5% monotherapy and 77.0% combo), of which 95.9% were continuing their first line SSA treatment. 86.7% of third line therapy patients (157/181) were on SSAs (6.6% monotherapy and 80.1% combo), all of which had initiated SSAs as first or second line treatment. Most common SSA combo therapy was with CA, followed by with AI. Conclusions: SSA monotherapy and SSA combination therapy with CA were the most common treatments for metastatic GEP-NET between 2003 and 2015. Sustained SSA use was frequent, reflecting the continuous nature of SSA use throughout the disease course.
Autophagy determines efficiency of liver‐directed gene therapy with adeno‐associated viral vectors
Authors: Marianna Hösel, Anke Huber, Susanne Bohlen, Julie Lucifora, Giuseppe Ronzitti, Francesco Puzzo, Florence Boisgerault, Ulrich T. Hacker, Wilhelmus J. Kwanten, Nora Klöting, Matthias Blüher, Alexander Gluschko, Michael Schramm, Olaf Utermöhlen, Wilhelm Bloch, Federico Mingozzi, Oleg Krut, Hildegard Büning
Journal: Hepatology (2017)

Use of adeno-associated viral (AAV) vectors for liver-directed gene therapy has shown considerable success, particularly in patients with severe hemophilia B. However, the high vector doses required to reach therapeutic levels of transgene expression caused liver inflammation in some patients that selectively destroyed transduced hepatocytes. We hypothesized that such detrimental immune responses can be avoided by enhancing the efficacy of AAV vectors in hepatocytes. Because autophagy is a key liver response to environmental stresses, we characterized the impact of hepatic autophagy on AAV infection. We found that AAV induced mammalian target of rapamycin (mTOR)-dependent autophagy in human hepatocytes. This cell response was critically required for efficient transduction because under conditions of impaired autophagy (pharmacological inhibition, small interfering RNA knockdown of autophagic proteins, or suppression by food intake), recombinant AAV-mediated transgene expression was markedly reduced, both in vitro and in vivo. Taking advantage of this dependence, we employed pharmacological inducers of autophagy to increase the level of autophagy. This resulted in greatly improved transduction efficiency of AAV vectors in human and mouse hepatocytes independent of the transgene, driving promoter, or AAV serotype and was subsequently confirmed in vivo. Specifically, short-term treatment with a single dose of torin 1 significantly increased vector-mediated hepatic expression of erythropoietin in C57BL/6 mice. Similarly, coadministration of rapamycin with AAV vectors resulted in markedly enhanced expression of human acid-α-glucosidase in nonhuman primates.We identified autophagy as a pivotal cell response determining the efficiency of AAVs intracellular processing in hepatocytes and thus the outcome of liver-directed gene therapy using AAV vectors and showed in a proof-of-principle study how this virus-host interaction can be employed to enhance efficacy of this vector system. (Hepatology 2017;66:252-265).
Hospitalization rates in elderly, newly diagnosed acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) patients treated with azacitidine.
Authors: Masumi Ueda, Divya Gupta, Paolo Fabrizio Caimi, Richard Creger, Jane Little, Basem M. William, Hillard M. Lazarus, Marcos J.G. De Lima, Brenda W. Cooper
Journal: Journal of Clinical Oncology (2015)

e18040 Background: Azacitidine is a common treatment for elderly AML and MDS patients. We describe rates of hospitalization in an older cohort of AML or high-risk MDS patients initially treated with azacitidine. Methods: We retrospectively reviewed 310 consecutive patients evaluated for AML and MDS at our institution from January 2010 to April 2014. We identified 56 newly diagnosed AML or high-risk MDS patients > 65 years old deemed unfit for standard chemotherapy and who received azacitidine as initial treatment. Total duration of hospitalization from treatment initiation to death was collected. Log-rank test was used to compare baseline patient characteristics such as performance status, laboratory profile, cytogenetics and survival. Results: Median survival of the 56 patients treated with azacitidine was 8.8 months (range 3.5-11.4). Median age was 72 years (range 67-78). 47% had response to therapy as defined by International Working Group criteria for MDS. Twenty-six patients (46%) were hospitalized at initiation of azacitidine, with median duration of stay of 14.5 days. 82% were hospitalized at least once after start of treatment, with median total inpatient stay of 17 days. The median number of admissions per patient was 2. Common reasons for admission after start of therapy were febrile neutropenia (36%) and localized infection (19%); bleeding, cardiac issues, and progressive disease comprised 9% of first admissions each. Only 5 (9%) patients received ICU care during the follow-up period. Median proportion of days spent inpatient out of total days of follow-up was 8.7% (range, 2.9-20.9). Median survival did not differ between those who did or did not have a response to azacitidine therapy (10 vs. 9.5 months, p = .3) nor between those receiving first course of azacitidine as outpatient vs. inpatient (10 vs. 7.5 months, p = .1). Conclusions: Despite a high rate of hospitalization after therapy initiation in this high-risk population, the proportion of time spent inpatient was relatively low. Although it is unclear how this compares to other therapies, we conclude that managing this cohort of elderly patients in the outpatient setting is an attainable goal.
Phase IB trial of ADI-PEG 20 (A) plus nab-paclitaxel (nab-P) and gemcitabine (gem) in patients with advanced pancreatic cancer (PC).
Authors: Maeve Aine Lowery, James J. Harding, Kenneth H. Yu, David Paul Kelsen, John S. Bomalaski, Danielle C. Glassman, Christina M. Covington, Robin Brenner, Ellen Hollywood, Adalberto Barba, Amanda Johnston, Kay Chia-Wei Liu, Marinela Capanu, Ghassan K. Abou-Alfa, Eileen Mary O'Reilly
Journal: Journal of Clinical Oncology (2017)

295 Background: ADI-PEG 20 (A) is a pegylated form of arginine depleting enzyme, arginine deaminase. Normal cells synthesise arginine using the enzyme argininosuccinate synthetase (ASS). A selectively targets malignant cells which lack ASS. A has shown encouraging pre clinical activity as monotherapy in PC, and synergistic activity with gem and taxanes. Methods: Eligibility: Metastatic PC, up to one line of prior treatment (dose escalation cohort:ct) no prior treatment (expansion ct), ECOG 0-1.Treatment: gem 1,000 mg/m2, nab-P 125mg/m2 3 out of 4 weeks, A 18 mg IM weekly (ct 1), A 36mg weekly (ct 2 and expansion ct). Primary endpoint: determine MTD of A in combination with nab-P and gem. Statistical plan: Single arm, non-randomized, open-label, phase IB, standard 3 + 3 dose escalation with expansion ct of 9 patients at MTD. Secondary endpoints: progression-free survival (PFS), response rate, overall survival (OS), safety, tolerability, blood and archival tumor analyses for ASS expression and immunogenicity. Pts treated at MTD and on expansion cohort were eligible for primary and secondary endpoints. Results: Between 11/14 and 09/15, 18 pts enrolled. 4 pts (22%) had 1 prior line of therapy. Toxicity attributable to A was limited to grade 1 rash/erythema at injection site (n = 3). Cohort 2 was expanded to 6 pts due to DLT of elevated LFTs, no further DLTs observed. ≥ grade 3 toxicity attributable to gem and/or nab-P included elevation in AST/ALT, hematologic toxicity, fatigue, diarrhea, neutropenic fever, alopecia as expected. No A related grade 3-5 toxicities were observed. Response: 6 pts (40%) PR, including one previously treated pt, 8 pts (53%) stable disease (SD), 1 pt inevaluable. Two pts continue on study, median PFS 6.5 months (95% CI 5.3 – 15.2), median OS 11.3 months (95% CI 4.9- . ). Eight of 15 pts treated at MTD received 2 nd -line chemotherapy at progression. Five of 11 archival tumors samples tested for ASS1 expression by IHC were deficient. Conclusions: A was well tolerated in combination with gem and nab-P. Activity was observed in treated and untreated pts, and in pts with ASS deficient and proficient tumors; synergy of A with cytotoxics may be independent of ASS status and future investigation in an unselected population is warranted. Clinical trial information: NCT02101580.
Radiotherapy for intubated patients with malignant airway obstruction: Futile, or facilitating extubation?
Authors: Alexander V. Louie, Sophia Lane, David Palma, Andrew Warner, Jeffrey Quoc Cao, George Rodrigues
Journal: Journal of Clinical Oncology (2013)

e19120 Background: There is uncertainty as to the appropriate management of intubated patients with malignant airway obstruction (MAO). Radiotherapy (RT) may be delivered but requires substantial resources in this patient population. In the absence of evidence, it is unknown if radiotherapy facilitates extubation or prolongs ICU stays, resulting in a delay in the appropriate transition to end-of-life care. Methods: We performed a 10-year retrospective review of patients in the ICU treated with RT for MAO. Primary study endpoints were overall survival (OS) and extubation success (ES) defined as ≥48 hours without reintubation or death. Secondary endpoints included rates of discharge from the ICU and to home. Logistic regression and Cox regression analyses were performed to identify factors associated with ES and OS. Results: Twenty-six patients were eligible for analysis. Patients waited an average of 2.9 days (±4.5) from intubation and MV until receiving RT. Seven patients (27%) achieved ES, occurring between days 4 and 22 after RT initiation. All of these patients were discharged from the ICU, and most (n=6) were discharged home. There was a trend for a higher chance of ES in patients who received higher radiation doses (OR per 5 Gy increase: 0.63, p = 0.080). Median OS was only 0.36 months (range 0–113 months), and 6-months OS was 11%. On Cox regression analysis, increased radiation dose was predictive of improved OS (HR per 5 Gy increase: 0.74, p = 0.016). Conclusions: Although median survival is short, in a minority of intubated patients with MAO, RT is associated with ES. Survival beyond six months is uncommon, although improved OS is associated with higher delivered doses of RT.
Surgery alone or in a multi-modality approach in the management of patients (pts) with Malignant Pleurant Mesothelioma (MPM): A 15-years experience
Authors: O. Nascimben, V. Pagan, A. Paccagnella, G. Pizzi
Journal: Journal of Clinical Oncology (2004)

7197 Background: The role of surgery, chemotherapy (CT) and radiotherapy (RT) in MPM remain controversial. We retrospectively reviewed all the pts with MPM referred to our Hospital between 1988 and 2003 and analysed the survival (S) by prognostic factors and modalities of treatment. Methods: 147 pts (M/F =117/30; median age =63) had histologically confirmed diagnosis of MPM (epithelial =100, mixed =23, sarcomatoid =13, not definable =11). 64 pts, with stages I-III and favourable P.S., underwent surgery: 29/64 pleurectomy (P) and 35/64 extrapleural pneumonectomy (EPP). P was the prevalent surgical approach in the period 1988–1996 and in 14/29 pts it was followed by palliative CT and/or RT. Since 1997 EPP has became the main surgical option and in 32 pts it was considered within a tri-modality approach including 4 cycles of CT with carboplatin + paclitaxel and thoracic RT, given with concurrent weekly paclitaxel. Results: The median S of all 147 pts was 10 months (m.). Epithelial tumours and female sex were associated with significantly improved S. The median S of the 64 operated pts was 18 m. compared to 7 m. of pts not surgically treated. Among the operated pts the median S was similar for P (18 m.) and EPP (16 m.), with 1 perioperative death in P and 3 in EPP. For the 30/32 pts surviving EPP and candidate to the tri-modality approach, the median S was 20 m. and the 2- and 5-year S was 38% and 19%. Conclusions: Despite our experience confirmed the results of the tri-modality approach seen in more consistent series, the prognosis of the operated pts, not different in P and EPP groups, seems mainly to reflect the favourable selection, regarding stage and P.S., for surgery eligibility. No significant financial relationships to disclose.