tbuckley/cabot-search huggingface dataset:
Topoisomerase II, carbonyl reductase I, and chemosensitivity for amrubicin in the treatment of patients with small-cell lung cancer
Authors: T. Seto, T. Yamanaka, N. Masuda, K. Eguchi, Y. Takiguchi, H. Okamoto, T. Ogura, A. Yokoyama, Y. Ichinose, K. Watanabe
Journal: Journal of Clinical Oncology (2009)

8104 Background: Amrubicin (AMR) has been suggested to provide a new effective therapeutic option for small-cell lung cancer (SCLC). It is a totally synthetic 9-aminoanthracyclin and converted by carbonyl reductase I (CBR-I) to its active form, amrubicinol, that has higher potent activity than the parent drug and inhibits purified human topoisomerase II (topo-II). We previously reported the promising result of a prospective phase II trial for AMR monotherapy in patients with second-line SCLC (Thoracic Oncology Research Group Study 0301). Using blood samples at enrollment in this trial, the clinical significance of topo-II and CBR-I expression levels on antitumor effect as well as toxicity has been examined. Methods: Total RNA was extracted from the blood with an RNeasy Mini Kit (Qiagen Inc.) and DNase treatment was performed using the RNase-Free DNase Set (Qiagen Inc.). RT-PCR analysis was performed using TaqMan technology. Quantification of target cDNA (Top-II alpha, CBR-I and beta-actin gene) was conducted using an ABI PRISM 7700 Sequence Detection System (Applied Biosystems Inc.). Quantification was performed using the relative standard curve method. Results: The trial registered a total of 60 patients, of which 40 blood samples were available. Nineteen patients achieved a CR or PR to AMR according to the RECIST assessment and 21 did not. Patients with tumor response had a significantly lower Topo-II level than those without (p=0.0465, Wilcoxon test), although there was no association between tumor response and the level of CBR-I (p=0.3229, Wilcoxon test). We did not find any significant association between the levels of the two enzymes and toxicity. Conclusions: Topo-II may be a potential predictor of response in the treatment of AMR for second-line SCLC. Further investigations in larger patient materials are warranted. No significant financial relationships to disclose.
OC-079 Role of metal vs plastic stents for endoscopic ultrasound guided drainage of peri-pancreatic fluid collections: a systematic review and meta-analysis
Authors: J Ramesh, R Saunders, S Cicconi, R Sutton, JP Neoptolemos, C Halloran
Journal: Gut (2017)

Introduction  The use of fully covered metal stents (FCSEMS) and specifically designed lumen apposing metal stents (LAMS) for transmural drainage of peri-pancreatic fluid collections has become widespread. A systematic review published in 20151 did not support the routine use of metal stents for drainage of pancreatic fluid collections. However, recent studies have shown conflicting data; therefore a systematic review and meta-analysis was performed.  Method  We conducted a Pubmed search for English language original comparative studies between plastic and metal stents from January 2014 to January 2017. The random effects model was used to calculate pooled risk ratios (RR) with 95% confidence intervals (CI). Outcomes analysed were clinical success, defined as near complete or complete resolution of the pseudocyst on imaging, adverse events and requirement of further intervention.  Results  The search identified 183 studies, 6 studies2-7 with 592 (284 metal, 308 plastic) patients met inclusion criteria and were included in the meta-analysis. Clinical success was achieved in 96.1% vs 87.5%, in the metal and plastic groups respectively, RR 1.08 [95% CI 1.01–1.15], I2=38.1%. The rate of adverse events was 10.7% for metal stents vs 26.6% for plastic, RR 0.43 [95% CI 0.21–0.88], I2=53.5%. Further intervention was required in 18.2% of patients in the metal stent group vs 27.3% RR 0.61 [95% CI 0.22–1.71], I2= 73.6%.  Conclusion  Metal stent usage for drainage of peripancreatic fluid collections improves clinical outcomes and reduces adverse events.  References  . Bang J, et al. Dig Endosc2015;27(4):486–98.  . Lee B, et al. Endoscopy2014;46(12):1078–84.  . Mukai S, et al. Endoscopy2015;47(1):47–55.  . Bang J, et al. Dig Endosc2017;29(1):83–90.  . Bapaye A, et al. Dig Endosc2017;29(1):104–110.  . Ang T, et al. Endosc Ultrasound2016;(5): 320–7.  . Sharaiha R, et al. Gastrointest Endosc2015;82(5):822–7.  Disclosure of Interest  None Declared
Trial to extend breast cancer screening won’t resume randomisation after pandemic
Authors: Elisabeth Mahase
Journal: BMJ (2020)

A major UK breast cancer screening trial that was set up to determine whether extending the age bracket to include women aged 47-49 and 71-73 would reduce mortality will not restart randomisation after the covid-19 pandemic.

The trial randomised women aged 47-49 and 71-73 in England so that half would receive a screening invitation outside the normal age bracket (50-70 years). The trial was halted alongside other screening services to allow the NHS to cope with covid-19, but the researchers have announced that randomisation will not resume.

However, they said that follow-up by electronic linkage to routine government records will continue “throughout the 2020s and beyond.”

The announcement was welcomed by those who had criticised the trial for a lack of explicit and fully informed consent …
Widespread Metastatic Gastric Signet-Ring Cell Carcinoma Shown by 68Ga-FAPI PET/CT
Authors: Chunlei Fan, Wei Guo, Guoqiang Su, Bo Chen, Haojun Chen
Journal: Clinical Nuclear Medicine (2020)

Abstract The present study compared 68 Ga-FAPI and 18 F-FDG PET/CT in a patient with GSRCC (gastric signet-ring cell carcinoma). In this case, 68 Ga-FAPI PET/CT shows much higher tumor-to-background contrast of primary tumor and reveals more metastatic lesions than 18 F-FDG PET/CT. This case demonstrates that 68 Ga-FAPI PET/CT outperforms 18 F-FDG in identifying both primary and metastatic lesions in GSRCC.
Ultra Deep Whole Exome Sequencing of Classical Hodgkin Lymphoma (cHL) Reveals Novel Recurrent Somatic Mutations
Authors: Felicia Gomez, Kilannin Krysiak, Cody Ramirez, Eric J. Duncavage, Zachary Skidmore, Grace Triska, Lee Trani, Nancy L. Bartlett, Amanda F. Cashen, Neha Mehta-Shah, Brad S Kahl, Friederike Kreisel, Malachi Griffith, Todd A. Fehniger, Obi Griffith
Journal: Blood (2017)
Early evidence of tolerability and clinical activity from a phase I study of TRC105 (anti-CD105 antibody) in patients with advanced refractory cancer
Authors: L. Rosen, M. S. Gordon, H. I. Hurwitz, M. K. Wong, B. J. Adams, D. Alvarez, B. K. Seon, B. R. Leigh, C. P. Theuer
Journal: Journal of Clinical Oncology (2009)

3518 Background: CD105 (endoglin) is an angiogenic membrane protein that is over-expressed on proliferating vasculature in solid tumors and up-regulated following anti-VEGF therapy. TRC105 is a human/murine chimeric IgG1 anti-CD105 monoclonal antibody that inhibits angiogenesis and tumor growth via endothelial cell growth inhibition, ADCC, and apoptosis. Methods: The safety and PK of TRC105 were evaluated in patients with refractory cancer. Subjects were to have adequate organ function and no CNS or central thoracic tumors. TRC105 was escalated in cohorts of 3–6 patients to a maximum feasible dose of 1.0 mg/kg i.v. every 2 weeks. Results: 19 ECOG PS 0–1 patients received TRC105 at doses between 0.01–1.0 mg/kg, including 11 men and 8 women aged 37 to 79 years (median 59). One patient experienced dose-limiting toxicity (DLT) at 0.1 mg/kg of grade 4 gastric ulcer bleeding on Day 4 which resolved spontaneously. No other grade 3 or 4 adverse events were reported. Possibly related grade 1–2 adverse events were rare including fatigue, anemia, proteinuria, dysgeusia, diarrhea, flushing, hyperuricemia and intermittent postcoital vaginal bleeding. One patient with castrate-refractory prostate cancer remains on study after 13 months of TRC105 at 0.01 mg/kg with a complete PSA response and bone scan normalization. In addition, 6-month stable disease was seen in a patient with ovarian cancer (CA125 decrease of 16%). Best response also included stable disease (n = 3) and progression (n = 14). Serum TRC105 concentrations expected to saturate CD105 binding sites (&gt; 0.2 ug/mL) were achieved at a dose of 0.3 mg/kg, and concentrations &gt; 10 ug/mL were achieved at 1.0 mg/kg. HAMA became detectable in 1 patient after 3 months of TRC105 therapy. Conclusions: TRC105 is tolerated at doses with evidence of clinical activity. Additional monotherapy and combination studies are planned. [Table: see text]
Tough magnesium phosphate-based 3D-printed implants induce bone regeneration in an equine defect model
Authors: Nasim Golafshan, Elke Vorndran, Stefan Zaharievski, Harold Brommer, Firoz Babu Kadumudi, Alireza Dolatshahi-Pirouz, Uwe Gbureck, René van Weeren, Miguel Castilho, Jos Malda
Journal: Biomaterials (2020)

One of the important challenges in bone tissue engineering is the development of biodegradable bone substitutes with appropriate mechanical and biological properties for the treatment of larger defects and those with complex shapes. Recently, magnesium phosphate (MgP) doped with biologically active ions like strontium (Sr2+) have shown to significantly enhance bone formation when compared with the standard calcium phosphate-based ceramics. However, such materials can hardly be shaped into large and complex geometries and more importantly lack the adequate mechanical properties for the treatment of load-bearing bone defects. In this study, we have fabricated bone implants through extrusion assisted three-dimensional (3D) printing of MgP ceramics modified with Sr2+ ions (MgPSr) and a medical-grade polycaprolactone (PCL) polymer phase. MgPSr with 30 wt% PCL (MgPSr-PCL30) allowed the printability of relevant size structures (>780 mm3) at room temperature with an interconnected macroporosity of approximately 40%. The printing resulted in implants with a compressive strength of 4.3 MPa, which were able to support up to 50 cycles of loading without plastic deformation. Notably, MgPSr-PCL30 scaffolds were able to promote in vitro bone formation in medium without the supplementation with osteo-inducing components. In addition, long-term in vivo performance of the 3D printed scaffolds was investigated in an equine tuber coxae model over 6 months. The micro-CT and histological analysis showed that implantation of MgPSr-PCL30 induced bone regeneration, while no bone formation was observed in the empty defects. Overall, the novel polymer-modified MgP ceramic material and extrusion-based 3D printing process presented here greatly improved the shape ability and load-bearing properties of MgP-based ceramics with simultaneous induction of new bone formation.
Phase I/II trial of CCI 779 and bevacizumab in advanced renal cell carcinoma (RCC): Safety and activity in RTKI refractory RCC patients
Authors: J. R. Merchan, H. C. Pitot, R. Qin, G. Liu, T. R. Fitch, J. Picus, W. J. Maples, C. Erlichman
Journal: Journal of Clinical Oncology (2009)

5039 Background: Combined mTOR and VEGF blockade is a potentially promising and rational strategy for the treatment of advanced RCC. We previously reported the phase I safety and efficacy results of CCI 779 (C) +bevacizumab (B) n RTKI naïve stage IV RCC patients (pts) (J Clin Oncol. 2007;25[18S Suppl]:5034). We now report the interim results of the phase 2 study of C+B in RTKI refractory RCC patients. Methods: Design: Open label, phase I/II study of C+B in advanced RCC pts. Patients with measurable stage IV RCC with a component of clear/conventional cell type, performance status 0–2 and good organ function were eligible. Up to two prior treatment regimens were allowed (at least one prior RTKI). Phase II dose was C = 25 mg IV weekly and B = 10 mg/kg every 2 weeks repeated in 4 week cycles. The primary objective of the phase II portion was to assess the proportion of patients who were progression-free 6 months after study entry. Secondary objectives were assessment of response rates and toxicity. Accrual goal = 40 pts. Results: Thirty-five pts have been enrolled into the phase 2 portion to date with 4 pts ineligible. Twenty-five pts are evaluable for response assessment and 29 pts are evaluable for toxicity. Baseline characteristics (N: 35): M/F: 28/7; Number of met. sites: 1/2/3+: 15/9/11; prior nephrectomy: 31; Number of prior therapies: 1 = 29; 2 = 2. Most common (&gt;5%) Gr 3–4 AEs (N = 29) included fatigue (6), hypercholesterolemia (2), hypertriglyceridemia (2), anorexia (2), rash (2), and anemia (2). Responses were: PR/SD/PD = 4 (16%)/18 (72%)/3 (12%). Median number of cycles administered was 4. Six month progression free rates will mature by may 2009. Conclusions: C+B combination at the recommended phase 2 doses is feasible and well tolerated. Clinical benefit rates (PR/SD) in RTKI refractory RCC patients (88%) are encouraging. Data on 6 month progression-free rates are expected to mature in 4/09. Updated data on safety, response rates, and 6-month progression free rates will be presented on all evaluable patients. Correlative studies on available plasma, serum and tumor samples for angiogenic and molecular biomarkers are underway. Supported by N01-CM62205, R21 CA 119545–02, and Commonwealth Foundation. [Table: see text]
Metabolism and transport pathways of the blood stable camptothecin AR-67 (7-t-butyldimethylsilyl-10-hydroxycamptothecin)
Authors: M. Milewska, J. Horn, N. Monks, J. A. Moscow, S. M. Arnold, M. Leggas
Journal: Journal of Clinical Oncology (2009)

2553 Background: AR-67 is a 3 rd generation camptothecin analog with superior stability of its active lactone form (&gt;85%). This stability has been credited in part to the -R 10 hydroxyl group (-OH); a group also present on the two clinically approved analogs, topotecan and irinotecan. As with SN-38, the active metabolite of irinotecan, the -OH of AR-67 may be a site for glucuronidation by a UDP glucuronosyltransferase. Moreover, many camptothecins are substrates for the efflux transporter BCRP (ABCG2) and the anionic carboxylate may be a substrate for the liver uptake transporter OATP1B1 (SLCO1B1). Pharmacogenetic studies have established that significant portions of the population have polymorphisms in these genes, which lead to altered pharmacokinetics and toxicity profiles of their substrates. This report describes in-vitro metabolism and transport studies with AR-67 as well as identification of metabolites in plasma and urine from patients enrolled in a phase I study. Methods: AR-67 and its metabolites were detected using chromatography methods with fluorescence or MS/MS detection. In vitro metabolism studies were done with UGT and CYP450 enzyme isoforms expressed in Sf9 cells. In vivo AR-67 metabolic products were identified in clinical plasma and urine specimens. Collection of clinical specimens has been described (control #09-AB-30336-ASCOAM). AR-67 uptake and efflux studies were performed in cells transfected with ABCG2 or SLCO1B1. Results: AR-67 glucuronidation was demonstrated to occur in vitro, primarily by UGT1A8. AR-67 was also found to be a substrate of CYP3A4 and CYP3A5. Only limited glucuronide and oxidation metabolite peaks were observed in patient samples at the highest concentrations. Diminished accumulation of AR-67 lactone was observed in BCRP expressing Saos-2 cells and significant uptake of AR-67 carboxylate was observed in OATP1B1 expressing cells. Conclusions: Unlike SN-38, AR-67 was not found to be a major substrate of UGT1A1, but was rapidly processed by UGT1A8, an isoform that is highly expressed in the GI tract. These data may explain the absence of diarrhea during this phase I study. The pharmacologic significance of ABCG2 and SLCO1B1 polymorphisms should be explored further in the context of population studies. [Table: see text]
An immune evasion mechanism with IgG4 playing an essential role in cancer and implication for immunotherapy
Authors: Hui Wang, Qian Xu, Chanyuan Zhao, Ziqi Zhu, Xiaoqing Zhu, Junjie Zhou, Shuming Zhang, Tiqun Yang, Biying Zhang, Jun Li, Meiling Yan, Renming Liu, Changchun Ma, Yan Quan, Yongqu Zhang, Weifeng Zhang, Yiqun Geng, Chuangzhen Chen, Shaobin Chen, Ditian Liu, Yuping Chen, Dongping Tian, Min Su, Xueling Chen, Jiang Gu
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Recent impressive advances in cancer immunotherapy have been largely derived from cellular immunity. The role of humoral immunity in carcinogenesis has been less understood. Based on our previous observations we hypothesize that an immunoglobulin subtype IgG4 plays an essential role in cancer immune evasion. Methods The distribution, abundance, actions, properties and possible mechanisms of IgG4 were investigated with human cancer samples and animal tumor models with an extensive array of techniques both in vitro and in vivo. Results In a cohort of patients with esophageal cancer we found that IgG4-containing B lymphocytes and IgG4 concentration were significantly increased in cancer tissue and IgG4 concentrations increased in serum of patients with cancer. Both were positively related to increased cancer malignancy and poor prognoses, that is, more IgG4 appeared to associate with more aggressive cancer growth. We further found that IgG4, regardless of its antigen specificity, inhibited the classic immune reactions of antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis and complement-dependent cytotoxicity against cancer cells in vitro, and these effects were obtained through its Fc fragment reacting to the Fc fragments of cancer-specific IgG1 that has been bound to cancer antigens. We also found that IgG4 competed with IgG1 in reacting to Fc receptors of immune effector cells. Therefore, locally increased IgG4 in cancer microenvironment should inhibit antibody-mediated anticancer responses and help cancer to evade local immune attack and indirectly promote cancer growth. This hypothesis was verified in three different immune potent mouse models. We found that local application of IgG4 significantly accelerated growth of inoculated breast and colorectal cancers and carcinogen-induced skin papilloma. We also tested the antibody drug for cancer immunotherapy nivolumab, which was IgG4 in nature with a stabilizing S228P mutation, and found that it significantly promoted cancer growth in mice. This may provide an explanation to the newly appeared hyperprogressive disease sometimes associated with cancer immunotherapy. Conclusion There appears to be a previously unrecognized immune evasion mechanism with IgG4 playing an essential role in cancer microenvironment with implications in cancer diagnosis and immunotherapy.
Impact of age and comorbidities on treatment effect, tolerance, and toxicity in metastatic colorectal cancer (mCRC) patients treated on CALGB 80203
Authors: J. A. Meyerhardt, N. Jackson McCleary, D. Niedzwiecki, D. Hollis, A. Venook, R. Mayer, R. Goldberg
Journal: Journal of Clinical Oncology (2009)

4038 Background: Little is known regarding the interaction of comorbid conditions (CC) and age when treating pts for mCRC. We sought to determine the impact of CC and age (&lt;70 and ≥70 yrs) on survival and toxicity in these pts. Methods: We utilized a cohort of 238 pts with mCRC enrolled in CALGB 80203, a curtailed, multicenter 2x2 phase III trial of fluorouracil/leucovorin + oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) ± cetuximab. Endpoints were overall survival (OS; time to death), progression-free survival (PFS; time to recurrence or death), and grade 3/4 toxicity. Pts completed a self-administered questionnaire on diet and lifestyle that included a modified Charlson's comorbidity survey. Cox models were adjusted for treatment (rx) arm, gender, and prior rx. Results: In CALGB 80203, 77% were &lt; 70 and 23% ≥70. Thirty-five percent of pts had at least one CC (34% &lt; 70 yrs; 41% ≥ 70 yrs). At least one grade 3/4 toxicity was experienced by 87% of pts ≥70 v 66% &lt;70 (p=0.002), primarily hematologic (56% v 31%, p=0.003). Amongst 238 pts, 94% and 84% experienced a PFS event and OS event, respectively. No pts are censored prior to 3 yrs. Median follow-up was 23 mos. The adjusted hazard ratio (HR) for ≥70 v &lt;70 of PFS was 1.0 (0.7–1.4) and of OS was 1.1 (0.8–1.6). Similarly, there were no significant differences in HR for PFS and OS by # CC. The table demonstrates no evidence of interaction between CC and age. Conclusions: While the early closure of CALGB 80203 presents sample size limitations for subset analyses, we did not observe an impact on PFS or OS by age and/or CC. Older pts did experience more toxicity from rx. Further studies with larger datasets are warranted. [Table: see text] [Table: see text]
Human immune disorder associated with homozygous hypomorphic mutation affecting MALT1B splice variant
Authors: Necil Kutukculer, Thomas Seeholzer, Thomas J. O’Neill, Carina Graß, Ayca Aykut, Neslihan Edeer Karaca, Asude Durmaz, Ozgur Cogulu, Guzide Aksu, Torben Gehring, Andreas Gewies, Daniel Krappmann
Journal: Journal of Allergy and Clinical Immunology (2020)
An Edematous and Ulcerative Eruption With Nasolabial Sparing in an Older Woman
Authors: Ashley M. DiLorenzo, Helena B. Pasieka, Michael A. Cardis
Journal: JAMA Dermatology (2020)

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