tbuckley/cabot-search huggingface dataset:
Tolerability and safety of a replication-competent adenovirus-mediated double suicide gene therapy (Ad5-yCD/mutTK(SR39)rep-ADP) with chemotherapy in locally advanced pancreatic cancer: Phase 1 trial.
Authors: Jong-Chan Lee, Dong Woo Shin, Se Yeol Yang, Min Jae Kim, Jae Hyup Jung, Jingu Kang, Jaihwan Kim, Jin-Hyeok Hwang
Journal: Journal of Clinical Oncology (2019)

e15761 Background: Up to 35% of pancreatic cancers are considered ‘locally advanced’ (LAPC) at the time of diagnosis. Replication-competent adenovirus-mediated double suicide gene therapy (Ad5-yCD/mutTK(SR39)rep-ADP) showed an anti-cancer effect in prostatic cancer patients in previous studies. We aimed to investigate tolerability and safety of Ad5-yCD/mutTK(SR39)rep-ADP in combination with gemcitabine in patients with LAPC. Methods: In this single-center, open label, dose-escalation phase I trial, we recruited adult patients (≥18 years) with newly diagnosed LAPC. Patients with histologically confirmed pancreatic ductal adenocarcinoma with good performance were enrolled. We injected Ad5-yCD/mutTK(SR39)rep-ADP into pancreatic mass with EUS-FNB needle in combination with oral 5-fluorocytosine 500mg qd, oral valgancyclovir 450mg qd, and standard gemcitabine (1000mg/m 2 , day 1-8-15 infusion every 4 weeks). In the three-stage dose-escalation scheme with traditional 3+3 design, the dose of Ad5-yCD/mutTK(SR39)rep-ADP in each cohort was 1x10 11 , 2x10 11 , and 1x10 12 vp/mL, respectively. Every patient has been evaluated adenovirus-induced toxicity in 8 weeks and tumor response in 12 weeks. The primary aim is to establish the maximum tolerated dose (MTD) of Ad5-yCD/mutTK(SR39)rep-ADP, as assessed by dose-limiting toxicities (DLT). Results: From 2016 to 2018, we enrolled 11 patients and analyzed nine patients for the final cohort. Two were dropped out by withdrawal of consents. In the first evaluation period (8 weeks), any of patients did not experience dose-related serious adverse event. Only one patients of in 3 rd cohort experienced transient grade II fever. In the second evaluation period (12 weeks), two patients showed partial response (PR) and seven showed stable disease (SD). Adenovirus DNA fragments disappeared in median 50 days (range 20 – 139). After the gemcitabine periods, five patients received 2 nd -line chemotherapy with FOLFIRINOX, and overall survival was median 14.9 months (range 8.9 – 21.9). Conclusions: In this phase I trial, Ad5-yCD/mutTK(SR39)rep-ADP has been well-tolerated without dose-related severe adverse events, and no MTD reached in locally advanced pancreatic cancer. Phase II clinical trial is needed for evaluating clinical efficacy. Clinical trial information: NCT02894944.
Pulmonary immunization: deposition site is of minor relevance for influenza vaccination but deep lung deposition is crucial for hepatitis B vaccination
Authors: Jasmine Tomar, Wouter F. Tonnis, Harshad P. Patil, Anne H. de boer, Paul Hagedoorn, Rita Vanbever, Henderik W. Frijlink, Wouter L.J. Hinrichs
Journal: Acta Pharmaceutica Sinica B (2019)

Vaccination via the pulmonary route could be an attractive alternative to parenteral administration. Research towards the best site of antigen deposition within the lungs to induce optimal immune responses has conflicting results which might be dependent on the type of vaccine and/or its physical state. Therefore, in this study, we explored whether deep lung deposition is crucial for two different vaccines, i.e., influenza and hepatitis B vaccine. In view of this, influenza subunit vaccine and hepatitis B surface antigen were labeled with a fluorescent dye and then spray-dried. Imaging data showed that after pulmonary administration to mice the powders were deposited in the trachea/central airways when a commercially available insufflator was used while deep lung deposition was achieved when an in-house built aerosol generator was used. Immunogenicity studies revealed that comparable immune responses were induced upon trachea/central airways or deep lung targeting of dry influenza vaccine formulations. However, for hepatitis B vaccine, no immune responses were induced by trachea/central airways deposition whereas they were considerable after deep lung deposition. Thus, we conclude that deep lung targeting is not a critical parameter for the efficacy of pulmonary administered influenza vaccine whereas for hepatitis B vaccine it is.
Oncologic outcomes and morbidity following heated intraperitoneal chemotherapy at cytoreductive surgery for primary epithelial ovarian cancer: A systematic review and meta-analysis.
Authors: Genevieve Bouchard-Fortier, Maria Christine Cusimano, Rouhi Fazelzad, Lin Lu, Taymaa May, Antoine Bouchard-Fortier, Sarah Ferguson
Journal: Journal of Clinical Oncology (2019)

e17093 Background: Heated intraperitoneal chemotherapy (HIPEC) following cytoreductive surgery in the treatment of primary epithelial ovarian cancer (EOC) after neoadjuvant chemotherapy was associated with a significant 12 months improved overall survival (OS) in a well-designed randomized controlled trial. Nonetheless, there remains uncertainty about the benefit and safety of HIPEC in ovarian cancer. The aim of this review was to assess efficacy and safety of HIPEC in primary EOC. Methods: We conducted a systematic search in Medline, Embase, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews, from inception to February 22 nd 2018 for observational and randomized studies of patients with primary EOC undergoing HIPEC at cytoreductive surgery with no language restrictions . We assessed risk of bias with the Institute of Health Economics Quality Appraisal Checklist for single-arm studies, and Newcastle-Ottawa Quality Scale for double-arm studies. We determined the pooled proportion of 30-day grade 3-4 morbidity, reoperation, and postoperative death. Results: Thirty-five articles including 1937 patients with primary EOC met inclusion criteria. Timing of HIPEC and type of chemotherapy regimens were not consistent between studies. There was significant variation in the reported OS of patients treated with HIPEC at cytoreductive surgery for primary EOC (3-year OS:48-77%; 5-year OS:17-72%). Thirteen articles were including in a meta-analysis to determine to the safety of HIPEC. The pooled proportions for 30-day Grade 3-4 morbidity, 30-day reoperation, and 30-day postoperative death were 33.0% (95% CI 23.0-45.0), 9.0% (95% CI 5.0-17.0) and 3.0% (95% CI 1.0-5.0) respectively. Conclusions: The use of HIPEC in primary EOC is associated with significant morbidity. There is significant heterogeneity in current literature. Higher quality, large prospective randomized control trials are needed to further support the benefit of HIPEC at cytoreductive surgery in the first-line treatment of primary EOC.
Prevalence of pathogenic germline variants in DNA repair by race, age, and ethnicity in men with prostate cancer.
Authors: Alexandria Mara, Jason Zhu, Yuan Wu, Tom Callis, Shan Yang, Edward D. Esplin, Robert L. Nussbaum, Tian Zhang, Megan Ann McNamara, Michael Roger Harrison, Daniel J. George, Kathleen A. Cooney, Andrew J. Armstrong
Journal: Journal of Clinical Oncology (2019)

5062 Background: Patients with advanced prostate cancer (PC) frequently harbor pathogenic or likely pathogenic (P/LP) germline variants (GVs) in mismatch repair (MMR) and homologous repair (HR) enzymes which have clinical and treatment implications. However, whether the prevalence of such GVs differ by race, ethnicity, family history, or age is unknown in men with PC. Methods: This is a retrospective analysis of germline DNA from men with PC in the United States, tested by Invitae. Baseline characteristics including self-identified race, ethnicity, family history (FH), and age were recorded. Race and ethnicity were analyzed by 3 cohorts: non-Ashkenazi Caucasian Americans (CA), non-Ashkenazi African Americans (AA), and Ashkenazi Jewish Americans (AJ). Chi-square testing was performed to identify significant differences across these categories between the three cohorts, with respect to combined and individual pathogenic MMR (MSH2/6, MLH1, PMS2, and MUTYH) and HR genes (BRCA1/2, ATM, CHEK2, RAD51D, and PALB2). Results: 3057 men were included in the final analysis: 2248 (74%) men were CA, 229 (7%) were AA, and 210 (7%) were AJ. Of these, 2665 (87%) men had a FH of PC and 463 (15%) had a P/LP GV. In addition, 1068 (35%) were found to have a variant of uncertain significance, and 35 (1.6%) had the HOXB13 G84E variant. There were no significant differences in the overall prevalence of MMR (CA 1.5% vs AA 0.9% vs AJ 1.4%, p = 0.89) or HR genes (CA 7.8% vs AA 7.9% vs AJ 10.5%, p = 0.37) by race/ethnicity. With respect to individual genes, AJ had a higher prevalence of pathogenic BRCA1 alterations (AJ 3.3% vs CA 0.8% vs AA 1.7%, p = 0.0034) and CHEK2 alterations (AJ 4.3% vs CA 2.8% vs AA 0.4%, p = 0.02). There were no significant differences in the prevalence of individual or specific classes of GVs between those with or without a self-reported FH of prostate or breast/ovarian cancers. There was also no association between prevalence of HR genes and age at germline testing (p = 0.40). Conclusions: This national study found that the overall prevalence of pathogenic GVs in MMR and HR genes do not differ by race, ethnicity, or age at the time of testing, and suggests that all men with advanced prostate cancer should be offered germline testing.
Circulating tumor DNA molecular profiling in rare cancer patients from the MASTER KEY Project.
Authors: Hitomi Sumiyoshi Okuma, Kan Yonemori, Takuji Seo, Emi Noguchi, Keiko Wakakuwa, Ken Kato, Hitoshi Ichikawa, Takashi Kohno, Akihiro Hirakawa, Aya Kuchiba, Taro Shibata, Tamie Sukigara, Kenichi Nakamura, Hiroyuki Mano, Toshirou Nishida, Yasuhiro Fujiwara
Journal: Journal of Clinical Oncology (2019)

e14532 Background: In April 2017, MASTER KEY Project, composed of a prospective registry study part and a multiple clinical trials part, was established to promote treatment development for rare cancers, which is lacking standard or investigational therapeutic options. Circulating tumor DNA (ctDNA) analysis by next-generation sequencing (NGS) has provided new insight into personalized medicine in a more accessible, non-invasive manner; however, most reports are focused on common cancers. We report genetic alterations detected by ctDNA NGS analysis in rare solid cancers. Methods: Prospectively consented patients (pts), also enrolled in MASTER KEY registry study, had ctDNA NGS testing at a CLIA-certified lab (Guardant360) for point mutations, indels, copy number amplifications, fusions, and microsatellite instability. Alterations were assessed for incidence according to cancer type, functional impact, therapeutic implications, and comparison with tissue NGS. Main inclusion criteria: 1) age ≥16, 2) histological diagnosis of rare cancer (annual incidence less than 6 cases per 100,000 population), cancer of unknown primary (CUP), or rare tissue subtypes of common cancers, 3) active metastatic / unresectable cancer, 4) a written consent. Results: From Nov. 2018 to Jan 2019, 50 pts had Guardant360 testing. Diseases included: soft tissue sarcoma (28), ovarian carc. (7), CUP (4), salivary gland tumor (3), thyroid carc. (2), GIST (1), adrenal cortical carc. (1), rare subtype of GI tract (1), malignant mesothelioma (1), nephroblastoma (1), NET (1), NUT carc. (1). All Japanese, male/female = 14/36, median age 61, ECOG performance status 0/1/2/3 = 30/19/0/1. 76% of pts (38/50) had ≥1 alteration detected, with median number of 2 alterations (range: 0-9), with VAF(0.1-60.3%); 87%(33/38) of those pts had a variant most likely pathogenic; 61% (20/33) of those pts had a variant potential for clinical action. Mean TAT was 10.3 days. 19 pts had tissue NGS testing and in 3 pts, alterations were detected by ctDNA NGS but not by tissue NGS. Updated results of 100 patients will be presented at the conference. Conclusions: Most rare cancer patients with advanced disease had a detectable genomic alteration by Guardant360. Clinical trial information: UMIN000034394.
A nationwide study for patterns of immune thrombocytopenia treatment in patients with chronic lymphocytic leukemia.
Authors: Suheil Albert Atallah-Yunes, Faris Haddadin, Anis Kadado, Jackson Clark, Audrey Anne Ready, Syed S. Ali
Journal: Journal of Clinical Oncology (2019)

e18193 Background: Steroids and Intravenous immunoglobulin (IVIG) are considered as the first line of therapy in immune thrombocytopenia (ITP) when treatment is indicated. Approximately 5% of patients with untreated CLL and 25-30% of patients with previously treated CLL have thrombocytopenia. There is limited data about ITP treatment patterns and therapeutic responses in patients with CLL. Methods: This is a retrospective cohort study using the 2016 National Inpatient Sample of adults ( &gt; 18 years) hospitalized for ITP as the admitting diagnosis and CLL as a secondary diagnosis based on ICD-10 codes. Primary outcomes were rate of administration of IVIG, splenectomy, platelet transfusion and packed red blood cell transfusion during same admission. Length of hospitalization was a secondary outcome. Multivariate linear regression was used to adjust for cofounders of age, gender, race and Charlson comorbidity Index. STATA 15 was used for analysis. Results: 14,490 patients were admitted for ITP (56% females, mean age 46), of which 255 had CLL (95 females, mean age was 72.4). On multivariate linear regression there was a significant increase in the use of IVIG among ITP patients with CLL (OR: 2.11; 95%-CI 1.05-4.23, P = 0.03). While there was no difference in terms of splenectomy rate ( OR: 0.35, 95% CI 0.05 to 2.52, p = 0.28 ) or rate of platelet transfusion (Odds ratio 1.15, 95% CI 0.63 to 2.08, p = 0.65) and packed red blood cell transfusion (Odds ratio 1.03, 95% CI 0.44 to 2.39, p = 0.94) between patients who have ITP with CLL and patients admitted with ITP without CLL. No statistical difference was found in hospitalization length. Conclusions: Patients hospitalized for ITP with CLL were more likely to require IVIGs. This could be explained by several theories including the need for a more rapid increase in platelet count as thrombocytopenia may be more severe due to bone marrow infiltration by CLL, immune dysfunction and/or treatment induced thrombocytopenia. Additionally, CLL patients can have hypogammaglobinemia making them more likely to get IVIG as a treatment of choice for ITP and as an immune replacement. Also ITP patients with CLL may have less response to steroids, as was noted in a previous study. Fear of atypical infections due to steroids in CLL patients may result in increased IVIG use. Further research of the microenvironment of ITP in CLL patients might explain the difference in treatment pattern and therapeutic response in this population.
Cerebro- and renoprotective activities through platelet-derived biomaterials against cerebrorenal syndrome in rat model
Authors: Hon-Kan Yip, Kuan-Hung Chen, Navneet Kumar Dubey, Cheuk-Kwan Sun, Yue-Hua Deng, Chun-Wei Su, Wen-Cheng Lo, Hsin-Chung Cheng, Win-Ping Deng
Journal: Biomaterials (2019)
Correlation of response to stereotactic radiotherapy and immunotherapy with toxicity and predictions by differences in Treg population.
Authors: Simone Reinwald, Gishan Ratnayake, Di Yu, Rachel Ward, Robin Smith, Andrew Haydon, Menno Van Zelm, Sashendra Senthi
Journal: Journal of Clinical Oncology (2019)

e14039 Background: Combining stereotactic ablative radiotherapy (SABR) and anti-PD1 therapy may result in synergism but the response and toxicity rates has not been established. Biomarkers to predict clinical outcomes in this setting could improve patient selection, informed consent and cost-effectiveness. Here, we report exploratory analyses from Phase I clinical trial. Methods: Metastatic melanoma patients with at least two metastases received SABR to a single metastatic site and standard dose immunotherapy with anti-PD1 and/or anti-CTLA4 therapy. Peripheral blood mononuclear cells (PBMC) were collected prior to each immunotherapy cycle and analysed with 17-color flow cytometry to quantify CD4+ and CD8+ T cell subsets as potential biomarkers for response and toxicity. RECIST v1.1 at six months dichotomized responders (stable disease or any response) from non-responders (progressive disease). The presence of CTCAE v4 defined grade 3 or higher toxicity within six months dichotomized those with and without significant toxicity. Mann-Whitney tests were used to assess differences in biomarkers between response and toxicity groups. The Phi Coefficient (pr) was used to correlate these groups. Results: Sixteen of 25 patients had bloods available for testing. There were 11 responders (5 non-responders) and three with significant toxicity (13 without). At 12 months all responders were still alive, while all non-responders had died. Response significantly correlated with developing toxicity (pr = 0.869, p = 0.027). Prior to treatment, responders had a significantly higher percentage of total regulatory T cells (Tregs; CD4+CD25+CD127-) compared to non-responders (p = 0.011). After SABR and four cycles of immunotherapy, Treg frequencies had significantly changed (p = 0.046), with decreases in most responders and increase in all non-responders. Other CD4+ and CD8+ did not correlate with response or toxicity. Conclusions: Patients developing significant toxicities appear more likely to respond, reinforcing the importance of aggressively managing toxicities rather than ceasing treatment. Patients with higher pre-treatment Treg population and decreasing levels with treatment were significantly more likely to respond to SABR and immunotherapy. Clinical trial information: ACTRN12616001064493.
Correlation of histopathologic regression with progression free survival (PFS) in patients (pts) with RAS wildtype metastatic colorectal cancer (mCRC) under fluorouracil/folinic acid, irinotecan, and oxaliplatin (FOLFOXIRI) plus panitumumab (pmab) or FOLFOXIRI alone: Subgroup analysis of VOLFI (AIO-KRK-0109).
Authors: Stefanie Noepel-Duennebacke, Hendrik Juette, Celine Lugnier, Michael Geissler, Uwe Marc Martens, Volker Heinemann, Swantje Held, Renate Klaassen-Mielke, Dominik Paul Modest, Anke C. Reinacher-Schick, Thomas Seufferlein, Andrea Tannapfel
Journal: Journal of Clinical Oncology (2019)

e15024 Background: We recently demonstrated improved objective response rate in untreated all-RAS wildtype mCRC with the addition of the anti-EGFR-antibody pmab to FOLFOXIRI. In this subgroup analysis we focused on histopathological response as a predictive marker for PFS. Additionally we analyzed chemotherapy induced steatosis hepatitis (CASH) in both treatment arms. Methods: Tissue samples from pts. achieving secondary resection of liver metastases in VOLFI were analyzed. We defined a cut-off for very good histopathological response at 20% of residual tumor cells in proportion to the total tumor area. For CASH sinusoidal obstructive syndrome, ballooning, steatosis, cholestasis, fibrosis and inflammation were determined. PFS was estimated using LIFETEST procedure. Results: Tissue of 14/19 resected pts. was evaluable (pmab-FOLFOXIRI/FOLFOXIRI: 11/3). All showed partial remission by RECIST. Median age was 56 yrs. (32–67), male/female: 7/7. All primary tumors were located in the left colon. Molecular analysis detected 1 BRAF (V600E) mutation and 1 MSI-H tumor. Median treatment duration until resection in this cohort: pmab-FOLFOXIRI 7 cycles (3-12)/FOLFOXIRI 9.5 cycles (7-11).7 pts. achieved very good histopathological response with vital tumor cells ≤20% (pmab-FOLFOXIRI/FOLFOXIRI 5/2) and 7 pts. showed vital tumor cells &gt;20% (pmab-FOLFOXIRI/FOLFOXIRI 6/1). The cut-off correlated with an improved PFS in the group ≤20 vs &gt;20% (median PFS 12.40; confidence interval (CI) 6.43-51.22 vs PFS 9.88; CI 6.17-15.26 months). The severity of CASH was not increased by the addition of pmab. Conclusions: In this preliminary analysis of VOLFI histopathological response seems to correlate with a better PFS after secondary resection of liver metastases. There was no relevant difference in CASH between pmab-FOLFOXIRI vs. FOLFOXIRI alone. The trial is registered with ClinicalTrials.gov, NCT01328171. Clinical trial information: AIO-KRK-0109.
PRODIGE 53-UCGI 30 (SULTAN): A randomized phase II study comparing treatment intensification with hepatic arterial infusion chemotherapy plus systemic chemotherapy to systemic chemotherapy alone in patients with liver-only colorectal metastases considered still non resectable after at least two months of systemic induction chemotherapy.
Authors: Valerie Boige, Jean-Pierre Pignon, Mathilde Wagner, Eric Dupont Bierre, Samuel Le Sourd, Franck Audemar, Ayhan Ulusakarya, Veronique Guerin-Meyer, Veronica Pezzella, Maximiliano Gelli, Diane Goere, Julien Taieb
Journal: Journal of Clinical Oncology (2019)

TPS3619 Background: In the first-line setting, current combination chemotherapy (CT) achieve high objective response rates (ORR) ranging from 40% to 80% and leads to complete resection rate (CRR) of colorectal cancer liver metastasis (CRCLM) in 25% to 50% of patients with initially non-resectable CRLM. However, when patients with CRLM are still not amenable to resection after induction CT, ORRs (~5-30%) and CRRs ( &lt; 10%) obtained with second-line systemic CT are much lower. Combining hepatic arterial infusion (HAI) and systemic (SYS) CT for unresectable CRLM lead to high ORR and the potential of cure in the second-line and further setting. Methods: This multicenter randomized phase II trial conducted in 20 centers in France plans to include 140 patients with CRLM still not amenable to a curative intent-treatment after at least two months of first-line induction SYS CT whatever the tumor response. Patients are randomized (1:1) between intensified biweekly regimen combining HAI oxaliplatin (100 mg/m²) and SYS FOLFIRI (leucovorin 400 mg/m², irinotecan 180 mg/m², and 5-FU 2.4 g/m²over 48 h) plus cetuximab 500 mg/m² or bevacizumab 5 mg/kg (according to RAS status and prior response/tolerance to SYS induction CT) or SYS CT alone according to current guidelines. The primary endpoint is to evaluate and compare the curative-intent (R0-R1) resection (and/or ablation) rate (CRR) of CRLM in both arms. A gain of 20% in CRR is expected (30% in the experimental arm vs. 10% in the control arm; α 5% [two-sided]; β 20%). Stratification factors at randomization are prior adjuvant or SYS induction oxaliplatin-based CT, tumor response to SYS induction CT, and center. Secondary endpoints include progression-free (overall, hepatic and extrahepatic) and overall survival, ORR, relative change in the sum of longest diameters of RECIST target lesions (DoR) and feasibility/tolerability. Since study start, 3 patients have been enrolled to date (planned accrual period: 3 years). Clinical trial information: NCT03164655.