tbuckley/cabot-search huggingface dataset:
Characterization and clinical outcomes of mismatch repair deficient (dMMR) small bowel adenocarcinoma (SBA).
Authors: Alicia Latham, Diane Lauren Reidy, Neil Howard Segal, Rona Yaeger, Karuna Ganesh, Louise Catherine Connell, Nancy E. Kemeny, Jinru Shia, Jaclyn Frances Hechtman, Preethi Srinivasan, Zalak Patel, Kaitlyn Tkachuk, Michael F. Berger, Leonard B. Saltz, Andrea Cercek, Zsofia Kinga Stadler
Journal: Journal of Clinical Oncology (2019)

1511 Background: SBA is a rare cancer known to be associated with Lynch syndrome (LS). The prevalence, tumor characteristics, and clinical course of SBAs in the setting of LS is not well understood. We sought to characterize SBA according to mismatch repair and germline mutation status, comparing clinical outcomes. Methods: A retrospective review of SBAs at a single institution identified 74 SBAs that were assessed for dMMR either via immunohistochemical staining (IHC) or microsatellite instability status (MSI) using NGS. Germline DNA was analyzed for mutations in LS-associated mismatch repair genes ( MLH1, MSH2, MSH6, PMS2, EPCAM) and when available, clinical records were reviewed. Results: Of 74 individuals with SBA, 28.4% (21/74) of tumors exhibited dMMR and/or high-frequency MSI (MSI-H). The overall prevalence of LS in SBA was 9.5% (7/74), with all LS patients having dMMR/MSI-H tumors. 33.3% (7/21) of dMMR/MSI-H SBA patients had LS. The distribution of germline mutations among LS patients was 57.1% (4/7) in MLH1, 28.6% (2/7) in MSH2, and 14.3% (1/7) in PMS2. One patient with an dMMR/MSI-H tumor was found to have a high-penetrance APC mutation, diagnostic of familial adenomatous polyposis (FAP). In the 38 patients with available clinical follow-up, median age of onset was similar in the dMMR/MSI-H vs the pMMR/MSS group (62 vs 57, p = 0.8). The prevalence of synchronous/metachronous cancers was 5.9% (1/17) in the pMMR/MSS group and 38% (8/21) in the dMMR/MSI-H group (p = 0.02), with 62.5% (5/8) of these in LS (p = 0.001; synchronous/metachronous in LS (5/7) vs. non-LS (4/31)). In the pMMR/MSS group, 58.8% (10/17) of patients presented with metastatic disease at diagnosis, compared to 19% (4/21) in the dMMR/MSI-H group (p = 0.01). In dMMR/MSI-H SBA patients with early-stage disease, 11.8% (2/17) recurred, compared to 71.4% (5/7) in the pMMR/MSS group (p = 0.009). Conclusions: This preliminary evaluation suggests that SBA exhibiting dMMR/MSI-H status is more closely associated with early-stage disease and lower recurrence rates, similar to prior observations in colon cancer. LS was found in 9.5% of all SBA and in 33.3% of dMMR/MSI-H tumors, suggesting that germline assessment for LS in SBA is warranted.
Targeting of CD317 by the immunotoxin HM1.24-ETA’ to allow immunotherapy in glioblastoma patients.
Authors: Dorothee Gramatzki, Emese Szabo, Martin Gramatzki, Matthias Peipp, Michael Weller
Journal: Journal of Clinical Oncology (2019)

e13560 Background: Glioblastoma is the most common primary malignant brain tumor with a poor prognosis. CD317 (HM1.24) is a transmembrane protein and may exist in differently spliced variants. It is highly expressed on plasma cells in multiple myeloma, as well as in certain solid tumor types. While several antibody drug conjugates are already in clinical practice, small immunotoxins with a different intracellular mode of action are only established in hairy cell leukemia. The immunotoxin HM1.24-ETA’ protein is a CD317 single chain Fv (scFv) antibody fused to a truncated version of Pseudomonas aeruginosa exotoxin A (ETA’). Methods: In vivo CD317 mRNA expression in human glioma of different grades and survival probabilities of glioblastoma patients based on CD317 mRNA expression were analyzed using the database of the Cancer Genome Atlas network (TCGA). CD317 protein expression was analyzed by immunohistochemistry in a human tissue microarray (TMA). In vitro CD317 mRNA expression was assessed by RT-PCR and CD317 protein levels by flow cytometry in several human glioblastoma cell lines. A cytotoxicity assay after treatment with HM1.24-ETA’ immunotoxin was performed in human glioblastoma cell lines. Results: Data on mRNA expression from the TCGA database demonstrated, that CD317 was upregulated in human glioblastomas compared to lower grade gliomas. In the group of glioblastoma patients increased CD317 mRNA expression was associated with decreased probability of survival ( p&lt; 0.001). CD317 protein levels correlated directly with the tumor grade of astrocytic gliomas in the TMA. CD317 was expressed heterogeneously on mRNA and protein levels in the tested cell-lines in vitro. HM1.24-ETA’ induced cytotoxicity in CD317-positive glioblastoma cells in a concentration-dependent manner. Animal experiments currently performed suggest activity in glioblastoma xenografted mice. Conclusions: These data highlight CD317 as an interesting target antigen and HM1.24-ETA’ immunotoxin as a strategy for immunotherapy of glioblastoma patients.
Randomized phase III trial comparing pegylated liposomal doxorubicin (PLD) 50 mg/m<sup>2</sup> and 40 mg/m<sup>2</sup> in patients with platinum-resistant Müllerian carcinoma (JGOG3018).
Authors: Akira Yabuno, Tsutomu Tabata, Hirofumi Michimae, Tetsuro Oishi, Miwa Nonaka, Masashi Takano, Toru Hirata, Keiichi Fujiwara, Toru Sugiyama
Journal: Journal of Clinical Oncology (2019)

5550 Background: The standard dose of single-agent pegylated liposomal doxorubicin (PLD) is 50 mg/m 2 every 4 weeks, but 40 mg/m 2 has recently been used in clinical practice, though there is no evidence available to support its use. Methods: A Phase III, randomized, multicenter, non-inferiority study comparing progression-free survival (PFS) of patients with platinum-resistant Mullerian carcinoma (epithelial ovarian, fallopian tube, or primary peritoneal carcinoma) treated with an experimental arm (40 mg/m 2 PLD) versus a standard arm (50 mg/m 2 PLD) until 10 courses, disease progression, or unacceptable toxicity was conducted. Eligible patients had ≤ 2 prior lines. Stratification was by performance status (PS) and PFS of prior chemotherapy (&lt;3 months versus ≥3 months). The primary endpoint was PFS, and secondary endpoints were overall survival (OS), toxicity profile, clinical response, and tolerability. The target total number of patients was 412. Results: The trial was closed due to accrual futility as patient recruitment was slow , with 272 patients randomized to the experimental arm (n=137) and the standard arm (n=135). The final analysis was performed with 234 deaths and 269 events for PFS. Median patient age was 62 years; 58% of patients had a treatment-free interval less than 3 months, and 81% of patients had PS 0. In the experimental versus standard arm, median PFS was 4.0 months versus 4.0 months (HR 1.065, 95.8%CI: 0.830-1.366), and median OS was 14.0 months versus 14.0 months (HR 1.078, 95%CI: 0.831-1.397). Adverse events ≥Grade 2 including oral cavity mucositis were more frequent in the standard arm than in the experimental arm (26.7% vs. 13.5%, respectively; p=0.0089), but there was no difference in ≥Grade 2 hand-foot-skin reactions (19.8% vs. 15.0%, respectively; p=0.333). Conclusions: The non-inferiority of PFS with the reduced dosing schedule was not confirmed because the trial was closed prematurely, but PFS and OS were similar. These results suggest a reduction of the standard dose of PLD because of the low rate of oral mucositis in patients with platinum-resistant ovarian cancer treated with the lower dose regimen. Clinical trial information: UMIN000003130.
Real-life data: Women with recurrent platinum-sensitive ovarian cancer and BCARGEM treatment.
Authors: Frederique C. van der Scheun, Cheryl P. Bruijnen, Petronella Witteveen, Britt B.M. Suelmann
Journal: Journal of Clinical Oncology (2019)

5566 Background: Ovarian cancer is still the most mortal gynaecological cancer in the world. Even after achieving a good clinical response after initial treatment, the cancer will relapse in 80% of the patients. Treatments that improves progression-free survival (PFS) are necessary. In 2012, the OCEANS trial showed an improved PFS (12.4 months) for patients with platinum-sensitive recurrent ovarian, primary peritoneal, or fallopian cancer (ROC) treated with carboplatin, gemcitabine plus the monoclonal antibody bevacuzimab followed by maintenance therapy of bevacuzimab (BV) till progression (BCARGEM). Based on this trial, bevacizumab was incorporated in the second line treatment protocol of various European countries for patients with platinum-sensitive ROC. However, there is no real life information yet available on the effectivity and tolerance of this one randomized clinical trial (RCT) in clinical practise. Therefore, the aim of this study was to assess what the real time efficacy and tolerance of treatment with BCARGEM was in patients with platinum-sensitive ROC. Methods: All patients with platinum-sensitive ROC and treated with BCARGEM in the UMC Utrecht Cancer Center were retrospectively selected for analysis. All data such as baseline information, assessments and adverse events during cycles were obtained from medical records. The primary outcome was PFS; secondary outcomes were relative dose intensity (RDI), adverse events (AE) leading to dose modifications, and overall survival (OS). Results: Overall, the median PFS of the 39 patients with platinum-sensitive ROC and treated with BCARGEM was 9.4 months (95% CI 4.6 - 14.2). The median OS was 20.9 months (95% CI 15.0-26.7). The average RDI for BCARGEM was 67%. None of the patients reached a RDI of 100%. In most patients (69%) neutropenia grade ≥ 3 led to dose modifications or discontinuance of BCARGEM. After treatment with BCARGEM, 34 patients started treatment with BV till progression. The median number of cycles of BV was 5. In 26 of the cases the BV was ended due to progression. Conclusions: In our retrospective study, the PFS of real life patients treated with BCARGEM is lower compared to the study patients in the OCEANS trial; 9.4 versus 12.4 months. In addition, the RDI of BCARGEM is very low reflecting the many AEs leading to dose modifications or discontinuation. Therefore, this study underlines the fact that results of RCTs with strict in- and exclusion criteria do not represent actual outcomes in clinical care, because the selected study patient does not match the patient we face in real time.
Design and accrual of S1417CD: Development of a prospective financial impact assessment tool in patients with metastatic colorectal cancer (mCRC).
Authors: Veena Shankaran, Joseph M. Unger, Amy K. Darke, Jennifer Marie Suga, James Lloyd Wade, Peter Kourlas, Sreenivasa R Chandana, Mark Allen O'Rourke, Suma Satti, Diane Liggett, Dawn L. Hershman, Scott David Ramsey
Journal: Journal of Clinical Oncology (2019)

TPS6652 Background: Few studies have assessed the financial impact of cancer diagnosis (dx) in diverse patients (pts) and caregivers (cgs) using objective and standard financial measures. S1417CD, led by the SWOG Cancer Research Network, is the first prospective cohort study assessing financial outcomes to be conducted in the NCI Community Oncology Research Program (NCORP). We present our experience with design and accrual. Methods: Pts age ≥ 18 within 120 days of mCRC dx were considered eligible and asked to identify a caregiver (cg) who could participate concurrently. The primary endpoint is incidence of treatment-related financial hardship, defined as ≥ 1 of the following: debt accrual, selling/refinancing home, ≥ 20% income decline, or borrowing money. Measures include 1) pt and cg surveys (baseline (BL), 3, 6, 9 and 12 months (mo)) assessing out-of-pocket spending, financial impacts, cg burden, and quality of life and 2) pt credit reports (BL, 6, and 12 mo). Linkage to records from TransUnion, a national credit agency, required pt social security number (SSN) and processes for batched credit report transfer via secure web portal. The accrual goal was n = 374 pts in 3 years. The study activated on Apr 1, 2016 and closed on Feb 1, 2019 after reaching its accrual goal. A total of 380 pts (median age 59.7 years) and 155 cgs enrolled (41% cg participation). Enrollment steadily increased during the study period; 56% enrolled in the last 12 mo. Credit data were not obtainable for 76 (20%) pts due to early death, lack of credit, or inability to match records. S1417CD, the first cooperative group led study assessing financial outcomes in the community setting, completed enrollment faster than anticipated. Required SSN collection was not a barrier to enrollment, which improved as sites became familiar with data security measures. Robust accrual to S1417CD demonstrates pts’ and cgs’ desire to improve understanding of financial toxicity and its solutions. Follow-up will conclude in 12 mo with results to follow. SWOG plans to launch a randomized study (S1912) assessing the impact of financial navigation on household finances, using credit data for primary endpoint assessment. Clinical Trials Registry Identifier NCI-2015-01885. Clinical trial information: NCT02728804.
Non-opioid analgesics: New opportunities in early rehabilitation of patients with gynecological cancer.
Authors: Sergey V. Tumanyan, Oleg I. Kit, Elena M. Frantsiyants, Tatiana I. Moiseenko, Oksana V. Oros, Elizaveta Yu. Sugak
Journal: Journal of Clinical Oncology (2019)

e17129 Background: An important principle of analgesia is its effect on each component of the pain formation. The purpose of the study was to improve analgesia in the perioperative period in patients with gynecological cancer. Methods: This prospective randomized study of the quality and effectiveness of various analgesics included 97 patients aged 22-67 years receiving surgery for gynecological cancer. The patients were divided into two groups. Group 1 (n = 47): patient-controlled analgesia with trimeperidine and nonsteroidal anti-inflammatory drugs (NSAIDs); group 2 (n = 50): preemptive analgesia based on lidocaine, magnesium sulphate, nefopam and NSAIDs. Results and pain syndrome were assessed by levels of glucose, cortisol, insulin, lactate, C-reactive protein (CRP), Kerdo autonomic index, visual analogue scale (VAS), levels of personal and reactive anxiety and depression. Results: Analgesic effect of trimeperidine was obtained in 83.3% (p &lt; 0.05). However, the effect was less pronounced, compared to non-opioid analgesics, and did not reduce the psychosomatic component of pain after surgical treatment. In group 2, non-opioid analgesia limited the increase of cortisol, glucose, insulin, CRP and lactate (p &lt; 0.05) providing effective pain relief in the perioperative period. Non-opioid analgesics promoted an optimal analgesic effect, did not cause residual sedation, anxiety, depressive effects and cognitive impairments, which showed their obvious advantage over opioids. Opioid-sparing effect was 96.3% (p &lt; 0.05). Reducing the consumption of narcotic analgesics without worsening the quality of postoperative analgesia and the patient's well-being is an important advantage which allows minimizing the negative effects of opioids, facilitating the early rehabilitation of patients. Conclusions: Non-opioid analgesics can significantly limit endocrine and metabolic changes without worsening the quality of analgesia in the perioperative period.
A living systematic review of immune checkpoint inhibitors in cancer patients: A novel platform for evidence synthesis in oncology.
Authors: Irbaz Bin Riaz, Rabbia Siddiqi, Saad Malik, Elizabeth Jane Cathcart-Rake, Ognjen Gajic, Victor Montori, Zhen Wang, Vitaly Herasevich, Ronald S. Go, S. Vincent Rajkumar, M. Hassan Murad
Journal: Journal of Clinical Oncology (2019)

6596 Background: Several previous systematic reviews and meta-analyses have attempted to summarize toxicity of Immune checkpoint inhibitors (ICIs). However, very soon after each one of these reviews has been published, it became outdated. ICIs are currently used in 14 different cancers and data is rapidly evolving from new clinical trials. A living Systematic review, which is defined as a systematic review that is continually updated to incorporate relevant new evidence as it becomes available, is necessary in this situations. Therefore, we performed an updated systematic review and a meta-analysis which will serve as a foundation of a living Systematic review. Methods: MEDLINE, EMBASE and Cochrane were searched to identify phase 2 and 3 RCTs of PD-1/PD-L1 ICIs. Included studies compared either immunotherapy alone or combination with existing standard of care treatment and reported data for AE’s of interest. DerSimonian-Laird random effects Meta-Analysis was performed to derive pooled odds Ratio (OR) estimates for AE’s of interest. An infrastructure of a living systematic review is being developed and it includes monthly literature searches, cumulative meta-analysis and an online reporting platform. Results: We screened 6746 studies and 31 phase 3 and 2 phase 2 RCTs (n = 21,421) were included in the analysis. 22 RCTs used PD-1/PD-L1 ICIs as a single agent and 11 as a combination therapy. Selected toxicity estimates are summarized in a table. Conclusions: The meta-analysis updates previously published toxicity estimates and provides additional information about the risk of toxicities in single versus combination regimens. We have initiated the first living systematic review in oncology that will be continuously updated, incorporating relevant new evidence as it becomes available, and will provide accurate and up to date toxicity estimates to support clinical decision making. [Table: see text]
Efficacy and safety of talazoparib (TALA) or physician's choice of therapy (PCT) in United States patients (pts) with HER2- germline BRCA1/2-mutated (gBRCAm) locally advanced/metastatic breast cancer (LA/MBC) in the EMBRACA study.
Authors: Sami Diab, Hope S. Rugo, Lida A. Mina, Shannon Puhalla, Reshma L. Mahtani, Norah Lynn Henry, Neelima Denduluri, Denise A. Yardley, Yao Wang, Lillian Shahied Arruda, Iulia Cristina Tudor, Eric Roland Gauthier, Akos Gabor Czibere, Jennifer Keating Litton, Sara A. Hurvitz
Journal: Journal of Clinical Oncology (2019)

1044 Background: TALA is a poly(ADP-ribose) polymerase (PARP) inhibitor approved in the US for HER2- g BRCAm LA/MBC. Approval was based on results from the Phase 3 EMBRACA trial comparing efficacy/safety of TALA (1 mg/d) to PCT (capecitabine, eribulin, gemcitabine, vinorelbine) in HER2- g BRCAm LA/MBC pts. This analysis describes outcomes in US pts included in the pivotal study. Methods: Clinical findings from US pts enrolled in EMBRACA were analyzed. Pt characteristics, progression-free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR), and safety/adverse events (AEs) were among the parameters assessed. Results: Of 431 randomized pts, 156 pts (36%) were from the US (TALA: 99; PCT: 57). Pt characteristics were balanced, although a higher percentage in the TALA arm had more poor prognostic features (eg, triple-negative breast cancer, disease-free interval &lt; 12 mo, and more disease sites). TALA improved PFS, ORR, CBR, and duration of response (DOR) vs PCT (Table). 22% of pts in the TALA arm had a continued objective response at month 12 vs 0 pts in the PCT arm. The most common AEs in the TALA arm included anemia, neutropenia, thrombocytopenia, fatigue, nausea, alopecia, and headache; hematologic grade 3/4 AEs occurred more often than nonhematologic AEs. Conclusions: In US pts with HER2- g BRCAm LA/MBC, TALA demonstrated significant improvements in outcomes vs PCT with a manageable safety profile. Clinical trial information: NCT01945775. [Table: see text]
Stratified monotherapy approach according to MGMT methylation status in elderly patients with glioblastoma.
Authors: Mitsuaki Shirahata, Junichi Adachi, Keiichi Kobayashi, Fumiyuki Yamasaki, Kaoru Tamura, Tomonari Suzuki, Kazuhiko Mishima, Motoo Nagane, Koichi Ichimura, Ryo Nishikawa
Journal: Journal of Clinical Oncology (2019)

2050 Background: The elderly patients with glioblastoma have an extremely poor prognosis. As they often have some degree of age-related vulnerability, it is especially important to minimize a risk of treatment-related adverse events by optimizing treatment intensity for this population. We conducted phaseⅡ clinical trial to investigate the efficacy of stratified monotherapy approach according to O6-methylguanine-DNA methyltransferase (MGMT) methylation status in elderly patients with glioblastoma. Methods: Patients aged 70 years or older with Karnofsky performance status (KPS) of at least 60 were eligible for this study. MGMT methylation status was quantitatively assessed by pyrosequencing based on the average methylation ratio of 16 CpG sites in the MGMT gene promoter. The patients with highly methylated MGMT promoter defined as an average methylation ratio with 30% or higher were treated with temozolomide (TMZ) monotherapy (standard 5/28 regimen), while the others with low or intermediate levels of MGMT promoter methylation were treated with radiation therapy (40Gy/15fr) alone. Results: Between April 2013 and December 2017, 70 patients were enrolled in this study. Median age was 78 years (70-91) and median KPS was 60 (60-100). Of 70 patients, 19 patients with highly methylated MGMT promoter received TMZ monotherapy, while the remaining 51 patients were treated with radiation therapy. Median progression-free survival (PFS) and median overall survival (OS) were 7.5 and 17.4 months in the TMZ group, respectively. Median PFS and median OS were 4.6 and 10.4 months in the radiotherapy group, respectively. Conclusions: For elderly glioblastoma patients with highly methylated MGMT promoter, TMZ monotherapy could be a treatment option. Clinical trial information: UMIN000012172.