tbuckley/cabot-search huggingface dataset:
Mechanism study of nanoparticulate CpG-ODN (K3-SPG) for anti-tumor activity.
Authors: Yuji Kitahata, Koji Kobiyama, Masahiro Katsuda, Motoki Miyazawa, Hiroki Yamaue, Ken J Ishii
Journal: Journal of Clinical Oncology (2016)

e14572 Background: Unmethylated CpG motif containing oligodeoxynucleotide (CpG ODN) is promising immunotherapeutic agent for cancer, but suffered from its limited potency partly due to the delivery method to the tumor microenvironment. CpG ODN stimulates innate immune signaling via TLR9, and has been expected as potent anti-cancer drug. However the effectiveness is varied among reports. Methods: Here we generated a nanoparticulate CpG-ODN (K3) wrapped by the nonagonistic Dectin-1 ligand b-glucan schizophyllan (SPG), K3-SPG. We used a nano-particulate K3-SPG through intravenous administration. Results: To test potent of K3-SPG for anti-cancer drag, we administered K3 and K3-SPG intratumorally (i.t.) or intravenously (i.v.), and found that i.t. injection of K3 and K3-SPG suppressed tumor (B16-F10 (melanoma), MC38 (colon cancer), EG7 (thymoma)) growth significantly, while the systemic administration of K3 did not but K3-SPG could suppress tumor growth as well as i.t. injection. Knockout mice studies revealed that the effect was depended on Th1 driving cytokines. Imaging system revealed that systemically administered K3-SPG was present within tumor-microenvironment, this result indicated that circulating K3-SPG reached into the tumor microenvironment and induced potent anti-tumor effects without any additional tumor antigen in various mouse tumor models. Conclusions: Our results also suggest that systemically administration of K3-SPG can be a re-evaluating potent immunotherapy for approachable cancers.
TCT-296 Cardiac surgery compared to antibiotics only in patients developing infective endocarditis after transcatheter aortic valve replacement
Authors: Norman Mangner, Sergey Leontyev, Felix Woitek, Philipp Kiefer, Stephan Haussig, Meinhard Mende, Florian Schlotter, Georg Stachel, Jennifer Adam, Martin Misfeld, Holger Thiele, Michael Borger, David Holzhey, Axel Linke
Journal: Journal of the American College of Cardiology (2018)
Mapping PD-1 inhibitors’ side effects using patient-reported outcomes (PRO) generated by a digital patient-powered network (PPN).
Authors: Daniel A. Vorobiof, Irad Deutsch, Eliran Malki, Maytal Bivas-Benita
Journal: Journal of Clinical Oncology (2018)

e15087 Background: Checkpoint inhibitors such as programmed cell death receptor 1 (PD-1) antibodies have significantly improved the prognosis in several malignancies. While treatment with the PD-1 targeting antibodies, pembrolizumab and nivolumab, has substantial clinical benefit, it is associated with a spectrum of adverse events (AE) different from most chemotherapy drugs. Most evidence on AE from anti PD-1 drugs was collected in clinical trials and now there is a need for insights on the treatment patterns and AE in daily practice. Belong PPN is a social network for cancer patients and caregivers, providing them with access to patients, healthcare professionals and disease management tools. In this study, we used PRO to explore the immunotherapy treatment patterns among Belong’s users and evaluated the associated AE. Methods: Patients treated with either pembrolizumab or nivolumab were identified in the Belong PPN. Data included patient-generated treatment data and medical records provided voluntarily and anonymously. Validation of data was done by algorithms and manually by the research team to assure accuracy. Results: Treatment with PD-1 inhibitors was validated and confirmed for 51 patients, showing 57% used pembrolizumab and 43% nivolumab. PD-1 treatment was detected in patients diagnosed with 7 different malignancies, mainly lung cancer (68%), melanoma (16%) and colorectal cancer (6%). Patients reported 23 different side effects covering clinically documented gastrointestinal, dermatologic, pulmonary and other toxicities. The three most frequent AE were fatigue/tiredness (23%), nausea (8%) and diarrhea (8%). Comparing the two drugs distinctly showed fatigue/tiredness as a hallmark side effect of pembrolizumab, which was even more prominent among lung cancer patients (35% of its reported AE). Conclusions: Data from the Belong PPN successfully captured the spectrum of PD-1 inhibitors’ reported AE. Analyzing PRO of post approval treatments could provide deeper understanding of treatment patterns, expose limiting AE that bear implications on cost of treatment, improve management recommendations and provide a comprehensive outlook of patients’ outcomes.
Cancer survivorship, financial wellbeing and food insecurity in the U.S.
Authors: Zhiyuan Zheng, Ahmedin Jemal, Xuesong Han, Amy J. Davidoff, Matthew P. Banegas, Jingxuan Zhao, K Robin Yabroff
Journal: Journal of Clinical Oncology (2018)

10075 Background: Cancer is associated with increased out-of-pocket spending for medical care and limitations in the ability to work, frequently lasting many years after diagnosis. Few studies have addressed other non-medical financial consequences of cancer. This study examines general financial wellbeing and food insecurity for cancer survivors. Methods: Using the National Health Interview Survey (2013-2016), we identified cancer survivors (18-64: n = 4340; 65+: n = 6014) and those without a cancer history (18-64: n = 99,958; 65+: n = 27,642). Financial wellbeing measures included worry about standard of living, monthly bills, housing costs, and credit card payments. Financial food insecurity measures included food running out, food not lasting, and eating unbalanced meals. Additionally, skipping meals, eating less, hungry, losing weight, and not eating for an entire day were examined among those who reported any food insecurity. Predicted margins were generated to examine the burden associated with a cancer history, controlling for demographic characteristics, health insurance, income, and comorbidities, stratified by age (non-elderly: 18-64; elderly: 65+). Results: In the non-elderly population, cancer survivors consistently reported higher worry about standard of living (45% vs 41%), monthly bills (35% vs 31%), housing costs (28% vs 25%), and credit card payments (14% vs 13%) than those without a cancer history. Moreover, a cancer history was associated with increased food insecurity, i.e. food running out (18% vs 15%), food not lasting (16% vs 13%), and eating unbalanced meals (13% vs 11%). Among those with food insecurity, a cancer history was associated higher likelihood of skipping meals (41% vs 36%), eating less (42% vs 38%), and not eating for an entire day (22% vs 18%, all p < .05). In the elderly population, cancer survivors (n = 6014) are comparable to those without a cancer history, with 28% reported any financial wellbeing and 10% reported any food insecurity. Conclusions: Non-elderly cancer survivors experience poor financial wellbeing and food insecurity, which go beyond medical financial hardships. Future efforts should assess the relationships between various aspects of adverse financial consequences due to cancer.
A phase II RCT of high-dose vitamin D supplementation for androgen deprivation therapy (ADT)-induced bone loss among older prostate cancer (PCa) patients.
Authors: Luke Joseph Peppone, Karen Michelle Mustian, Anita Roselyn Peoples, Sarah L. Kerns, Jennifer E Reschke, Calvin Cole, Michelle Christine Janelsins, Matthew Asare, Charles Stewart Kamen, Eva Culakova, Hong Zhang, Chunkit Fung, Po-Ju Lin, Supriya Gupta Mohile
Journal: Journal of Clinical Oncology (2017)

10113 Background: ADT is the most commonly used systemic therapy for treating locally advanced and metastatic PCa. ADT use causes hypogonadism, which can result in accelerated bone loss and fragility fractures. Vitamin D (VITD) may protect against bone loss; however it remains unclear if the recommended daily allowance (RDA) of VITD is sufficient to reduce bone loss or whether higher doses are needed. The aim of this phase II RCT was to collect preliminary data on the effect of high-dose VITD on bone mineral density (BMD) in ADT-treated PCa patients compared to the RDA of VITD. Methods: Older PCa patients (≥60 years old) with VITD insufficiency ( &lt; 32 ng/ml), within 6 months of starting ADT and with 6 more planned months of ADT were randomized 1:1 to high-dose VITD (hVITD; 600 IU/daily plus 50,000 IU/weekly) or RDA of VITD (rVITD; 600 IU/daily plus placebo weekly) for 24 weeks. All subjects received 100% of the RDA for calcium (1,000 mg/day). BMD was assessed at the total hip (TH) and lumbar spine (LS) via DXA at pre- and post-intervention. ANCOVA was used to test the change in BMD between groups. Results: 59 PCa patients were accrued (85% white; mean age = 67.6). Serum analyses confirmed high compliance in both groups (25-OH VITD change: hVITD = +32.0 ng/ml vs rVITD = +4.3 ng/ml; p &lt; 0.01). The safety of hVITD was similar to rVITD (Grade I hypercalcemia: hVITD: n = 1 vs rVITD: n = 0). Bone loss was significantly reduced for the hVITD group compared to rVITD group for total hip (TH BMD% change: hVITD = −1.5% vs rVITD = −4.1%; p = 0.02), with a trend for the femoral neck (BMD% change: hVITD = −1.7% vs rVITD = −4.3%; p = 0.06) and trochanter (BMD% change: hVITD = −1.0% vs rVITD = −2.8%; p = 0.10). There was no difference between groups for LS bone loss (LS BMD% change: hVITD = −0.8% vs rVITD = −0.6%; p = 0.75). Conclusions: High-dose VITD supplementation produced significantly greater reductions in hip BMD loss among older PCa patients receiving ADT compared to rVITD. Clinically, higher doses of VITD may be necessary to effectively prevent ADT-induced bone loss. A definitive phase III RCT is needed to confirm these findings. Funding: NCI R21CA175793, K07CA168911 &amp; UG1CA189961. Bio-Tech Pharmacal Inc. supplied all agents. Clinical trial information: NCT02064946.
Immune related adverse events (irAE) with platinum chemotherapy (CT) with durvalumab (D) ± tremelimumab (T): CCTG IND226.
Authors: Nathalie Daaboul, Isabelle Gauthier, Dongsheng Tu, Pamela Brown-Walker, Xiaoqun Sun, Desiree Hao, Rosalyn A. Juergens, Penelope Ann Bradbury, Mihaela Mates, Mustapha Ali Tehfe, Christian K. Kollmannsberger, Peter Michael Ellis, Andrew George Robinson, Paul Wheatley-Price, Scott Andrew Laurie, Lesley Seymour
Journal: Journal of Clinical Oncology (2017)

3058 Background: CT is immunomodulatory and requires corticosteroids (CS) premedication. We hypothesized that the incidence of irAE may be lower when D ± T is given with CT or CS. Methods: Patients (pts) receive CT (pemetrexed, nabpaclitaxel, etoposide or gemcitabine + cisplatin or carboplatin; usual 4-6 cycles) with D ± T, followed by D ± T alone (1 year total); pts with ≥ g2 (selected) or ≥ g3 irAE discontinued D ± T. Cycles were coded as CT + D ± T or D ± T; pts could contribute to both. CS: high (dexamethasone &gt; 10mg/day for 5 days) or low CS. irAE were D ± T related gastrointestinal (GI), skin, endocrine, neurologic, hypersensitivity, pneumonitis (PN) or other immune (nephritis (GN), pancreatitis, hepatitis). Biochemistry (BIO; all causality): creatinine, transaminases/bilirubin (LFTS) and amylase/lipase was summarised. Results: In this ongoing study, 118 pts received 723 cycles. Pts had good performance status (PS 0-1), 78 had thoracic malignancies and 84 no prior CT. 44 pts continue on D ± T alone; 32 pts continue on CT + D ± T while 76 pts discontinued D ± T primarily due to disease progression; 15 discontinued for ≥ g2 irAE [PN (3), hepatitis (1), GN (2), adrenal (1), myocarditis (1), GI (3), thrombocytopenia (1), hyperthyroidism (1), encephalitis (1), pt decision (1)]. 67 pts had high CS cycles while 78 pts had low. 50% pts had irAE and 10% had ≥ g3 irAE, most commonly skin and GI. GI (15 vs 11%), skin (26 vs 20%) and PN (3 vs 0%) were reported in more pts during CT + D ± T cycles (non significant (NS)) ; hypothyroidism was more common with D ± T alone (18 vs 10%; p = NS). IrAE rates and severity were similar between high (67 pts) or low CS (78 pts) except for GI (19 vs 10%; p = NS). BIO were more common during CT + D ± T (74% of pts vs 48% p = 0.003); rates in high CS were similar to low CS. LFTs (ALT/AST - 41% vs 16%; 38% vs 9%; p = 0.005) and amylase/lipase (18 vs 9%; 19 vs 14%; p = NS) were more common in pts with CT + D ± T cycles vs pts with D ± T alone cycles. Conclusions: There is no evidence that CT or CS abrogates irAE in this exploratory analysis. GI, skin, pneumonitis, LFTS and amylase/lipase were more common during CT + D ± T suggesting additive/multifactorial causes; hypothyroidism is more common in D ± T cycles, which may reflect time on treatment. Clinical trial information: NCT02537418.
Gene expression profiling of single circulating tumor cells in ovarian cancer: Establishment of a multi-marker gene panel.
Authors: Tanja N. Fehm, Christina Blassl, Jan Dominik Kuhlmann, Alessandra Webers, Pauline Wimberger, Hans Neubauer
Journal: Journal of Clinical Oncology (2016)

e17085 Background: Circulating tumor cells (CTCs) in the blood of ovarian cancer patients (OCP) are associated with decreased overall survival, whereby CTCs with epithelial-mesenchymal-transition (EMT) or stem-like traits are supposed to be involved in metastatic progression and recurrence. Investigating the transcriptional profiles of CTCs might help to identify therapy resistant tumor cells and to overcome treatment failure. We established a multi-marker PCR for the molecular characterization of single CTCs, detecting epithelial (EpCAM, Muc1, CK5/7), EMT (N-cad, vim, Snai1/2, CD117, CD146, CD49f) and stem cell (CD44, ALDH1A1, Nanog, SOX2, Notch1/4, Oct4, Lin28) associated transcripts. Methods: Primer specificity and PCR-performance was successfully validated on OvCar3 genomic DNA and cDNA. Assay sensitivity was evaluated by spiking experiments and immunomagnetic tumor cell enrichment (AdnaTest OvarianCancerSelect), resulting in a 100% concordance for the epithelial markers EpCAM and Muc-1 to the AdnaTest OvarianCancerDetect. By processing blood from OCP, high assay sensitivity could be verified. In blood of healthy donors no signals for epithelial markers were detected, for EMT and stem cell markers, however, signals were obtained mainly originating from leukocytes which calls for single cell analysis. Results: By using Ovcar3 cells we successfully established a workflow enabling the characterization of single CTCs. It comprises CTC enrichment, single cell isolation via micromanipulation, reverse transcription and multiplex-PCR analysis. Finally, 15 single CTCs from 3 OCP were analyzed and found to be positive for stem cell and EMT markers. Albeit, inter-cellular and intra/inter-patient heterogeneity and co-expression of epithelial, mesenchymal and stem cell transcripts on the same CTC was observed. Conclusions: We have established a robust workflow to perform sensitive single cell panel gene expression analysis without the need of pre-amplification steps. Our data point towards a heterogeneous expression of stem cell and EMT associated transcripts in ovarian cancer CTCs and might help to identify therapy resistant CTCs to predict treatment response.
Treatment beyond progression with nivolumab (nivo) in patients (pts) with advanced renal cell carcinoma (aRCC) in the phase III CheckMate 025 study.
Authors: Bernard J. Escudier, Robert J. Motzer, Padmanee Sharma, John Wagstaff, Elizabeth R. Plimack, Hans J. Hammers, Frede Donskov, Howard Gurney, Jeffrey Alan Sosman, Pawel Zalewski, Ulrika Harmenberg, David F. McDermott, Toni K. Choueiri, Martin Eduardo Richardet, Yoshihiko Tomita, Alain Ravaud, Justin Doan, Huanyu Zhao, Helene Hardy, Saby George
Journal: Journal of Clinical Oncology (2016)

4509 Background: Immunotherapy response patterns differ from traditional therapies, and pts may benefit from treatment after initial RECIST progression (CCR 2009;15:7412–20). We investigated pts treated beyond progression (TBP) with nivo in study CheckMate 025—nivo vs everolimus (eve) in previously treated pts with aRCC (NCT01668784). Methods: Treatment beyond progression was allowed in pts who had investigator-assessed clinical benefit and tolerated study drug. Pts TBP continued to receive nivo ≥4 wk after first RECIST version 1.1–defined progression to account for any delayed scan results; pts not TBP (NTBP) discontinued treatment after first progression. Pts without progression were excluded from this analysis. Results: Of 406 nivo pts treated, 38% were TBP; 36% were NTBP (of 397 eve pts treated, 17% were TBP; 36% were NTBP—current analysis for nivo only). Baseline characteristics were generally similar except for higher Karnofsky performance status (KPS) ≥90 with TBP vs NTBP (72% vs 62%) and less bulky tumor burden (18% vs 26%). Median overall duration of treatment (DOT) was 8.8 (TBP) and 2.3 mo (NTBP). From randomization to progression, objective response rate was 20% and 14%; median time to response was 1.9 and 3.7 mo; duration of response was 5.6 and 7.0 mo for TBP and NTBP pts, respectively. Treatment-related adverse events occurred in 71% of pts TBP and 70% of pts NTBP before first progression. Characteristics at first progression are shown (Table). Median DOT after first progression was 3.4 mo. Of 140 pts TBP with tumor measurements before and after progression, 14% had ≥30% tumor burden reduction from first progression. Median overall survival was 28.1 (TBP) vs 15.0 mo (NTBP); P<0.001.Conclusions: Treatment beyond progression with nivo can be associated with tumor shrinkage after progression. Evaluating disease characteristics at first progression may facilitate decision making to continue nivo treatment beyond progression. Clinical trial information: NCT01668784.Characteristics at first progression, % TBP NTBP New lesions 41 44 Increase in target lesions 55 43 Site of new lesions 5 14 Bone 5 8 Liver KPS ≥90 73 48 Small (<13 cm) to bulky (≥13 cm) tumor burden change 7 13 Quality of life FKSI-DRS, median 31 27
Trial in progress: Multicenter observational study to evaluate the relationship between gut bacterial flora and their therapeutic or adverse effects in advanced non-small cell lung cancer patients treated with nivolumab.
Authors: Takashi Yokoi, Ryo Itotani, Maiko Niki, Hiroshige Yoshioka, Katsuya Hirano, Suguru Yamamoto, Hideki Ishikawa, Takashi Kijima, Masataka Hirabayashi, Motonari Fukui
Journal: Journal of Clinical Oncology (2018)

TPS9114 Background: Nivolumab is one of the standard therapies for pretreated advanced non-small cell lung cancer (NSCLC). A correlation between PD-L1 expression on tumor cells and antitumor effects of nivolumab has been shown especially in non-squamous NSCLC. However, PD-L1 expression is an insufficient biomarker because of the weak correlation. It is therefore important to explore better biomarkers. In recent years, the antitumor effects of immune checkpoint inhibitors have been shown to depend on distinct Bacteroides species in preclinical mouse models. This multicenter observational study was planned to evaluate the relationship between gut bacterial flora and their therapeutic or adverse effects on advanced NSCLC patients treated with nivolumab. Methods: We prospectively collect microbiome samples from patients with NSCLC who will be treated with nivolumab. Gut (fecal) microbiome samples are collected at treatment initiation and after four doses of nivolumab. We will analyze the trend of gut microbiome differences The key inclusion criteria are histologically or cytologically proven NSCLC, pretreated NSCLC without any immune checkpoint inhibitor, ECOG PS 0-2, one or more measurable lesions, and written informed consent. The key exclusion criteria are previous or active interstitial pneumonia, autoimmune disease, exposure to corticosteroids or antibiotics, and previous or active inflammatory bowel disease. Clinical trial information: UMIN000026375.
Lowering hospital walls to achieve health equity
Authors: Anna Matheson, Chris Bourke, Alison Verhoeven, M Imran Khan, Denis Nkunda, Zaib Dahar, Lis Ellison-Loschmann
Journal: BMJ (2018)

Builiding HealtHy CoMMunitiesLowering hospital walls to achieve health equity Hospitals have a pivotal role in reducing health inequities for indigenous people and other marginalised groups, argue Anna Matheson and colleagues form health systems to achieve better health for all on 21 July
Multimodal treatment in operable stage III non-small cell lung cancer using the new TNM staging classification version 8: Long term results of a pooled analysis of three SAKK trials.
Authors: Martin Frueh, Daniel C. Betticher, Roger Stupp, Alexandros Xyrafas, Solange Peters, Hans-Beat Ris, Adrian Ochsenbein, Ralph Alexander Schmid, Rolf A. Stahel, Walter Weder, Matthias Guckenberger, Sacha Rothschild, Didier Lardinois, Nicolas Mach, Michael Thomas Mark, Oliver Gautschi, Sandra Thierstein, Christine Biaggi Rudolf, Miklos Pless
Journal: Journal of Clinical Oncology (2018)

8531 Background: The impact of the 8th edition of the TNM staging system on the optimal treatment choice and the best treatment strategy for stage III non-small cell lung cancer (NSCLC) is unclear. We applied the 8th version of the TNM classification to a pooled analysis of stage III NSCLC trials in order to test its validity and assess long term outcomes and prognostic factors. Methods: Individual patient data of 368 patients from three very similarly designed trials (SAKK 16/96, SAKK 16/00 and SAKK 16/01) were pooled. Patients with operable stage III NSCLC received preoperative radiotherapy following three cycles of induction cisplatin/docetaxel (tri-modal) or neoadjuvant cisplatin/docetaxel alone (bi-modal). Factors associated with improved 5-year overall survival (OS) were evaluated using a logistic regression model. Results: When applying the 8th TNM staging version*, 162 patients moved from stage IIIA to IIIB* and 5-and 10-year OS rates were 41% and 29% for stage IIIA and 35% and 27% for stage IIIB*. When using the 6th version 5- and 10-year OS rates were 38% and 28% for stage IIIA and 36% and 24% for stage IIIB. Factors associated with improved 5-year OS were age, R0 resection and pCR (p = 0.043, p < 0.001 and p = 0.009). There was no difference in the bi- vs. tri-modal group with regards to OS (median: 28 months [95% CI: 21-39 months] vs. 37 months [95% CI: 24-51 months], p = 0.9), event-free survival (median: 12 months [95% CI: 9-15 months] vs. 13 months [95% CI: 10-22 months], p = 0.71), local recurrence rate (48% vs 44%, p = 0.61), and pathologic complete remissions (pCR) rate (15% vs. 16% p = 0.75). R0 resection rates were lower in the bi-modal group (69% vs. 87%, p < 0.001). Conclusions: Similarly favourable long term outcomes were observed when the 8th vs. 6th TNM classification was applied. With the exception of the excluded patients with T4* due to multiple lesions in different lobes, multimodality treatment decisions in operable stage III NSCLC can be based on the 8th TNM version in upcoming trials. Tri-modal therapy resulted in higher R0 resection rates but did not improve OS. Younger age, R0 resection and pCR were associated with improved 5-year survival.