tbuckley/cabot-search huggingface dataset:
Targeting the immunosuppressive tumor microenvironment: Synergistic effect of low-dose IL12 in combination with dual immune checkpoint inhibition in a preclinical model of ovarian cancer.
Authors: Paul G. Pavicic, Patricia A. Rayman, Hussein Al-Sudani, C. Marcela Diaz-Montero, Haider Mahdi
Journal: Journal of Clinical Oncology (2020)

7 Background: Epithelial ovarian cancer (OC) is the most lethal gynecologic cancer with ~22,000 women diagnosed annually in the US. The impact of immune checkpoint inhibition (ICI) in the treatment of solid tumors has been significant. However, the response rates for OC are low ranging from 11-15%. It is critical to explore strategies to enhance the efficacy of ICI immunotherapy in OC. Targeting immunosuppressive factors and cells within the tumor microenvironment (TME) represents a feasible approach. The use of IL12 is attractive because induces potent antitumor activity by targeting myeloid cells and lymphocytes. However its clinical application has been hindered by its potential systemic toxicity. Here we explore the use of low dose intraperitoneal IL12 to enhance the antitumor activity of dual ICI in OC. Methods: Mice bearing ID8-VEGF tumors implanted intraperitoneally received either anti-PD1 alone or dual ICI treatment of anti-PD1 plus anti-CTLA4 with or without low dose IL12. Ascites accumulation was used as surrogate for tumor progression and determined by assessing weight increase. Blood and ascites were analyzed by flow cytometry for frequency of PMN-MDSC, M-MDSC, and activated T cells. Results: Low dose IL12 alone induced a significant delay in ascites accumulation when compared to untreated controls or mice treated with PD1 monotherapy or dual ICI. Addition of IL12 to dual ICI resulted in significant tumor regression and extended survival benefit compared to dual ICI alone. A synergistic effect of IL12 was not observed when combined with PD1 monotherapy. Antitumor responses associated with a marked decrease in the frequency of M-MDSC in blood and a decrease in both PMN- and M-MDSC in ascites. Decrease in MDSC associated with elevated levels of activated T cells. Conclusions: Low dose IL12 can induce regression of ID8-VEGF tumors. However, durable responses were only observed when IL12 was added to dual ICI. This suggests that IL12 can induce changes in the TME, particularly on MDSC, that can potentiate the antitumor activity of dual ICI. Our findings also suggest a crucial role of CTLA4 blockade perhaps via T reg targeting.
China coronavirus should be on “everybody’s agenda,” says vaccine expert
Authors: Elisabeth Mahase
Journal: BMJ (2020)

China coronavirus should be on "everybody's agenda," says vaccine expert Elisabeth MahaseThe BMJ Novel coronavirus (2019-nCoV) should be on "everybody's agenda," says Seth Berkley, chief executive officer of Gavi, the Vaccine Alliance.He said that, while some responses may be "over-reaching," what is currently known about the virus suggests that it should be treated seriously.
Significance of intratumoral tertiary lymphoid structure (TLS) as predictictive factors of nivolumab therapy after conversion surgery for unresectable gastric cancer: A retrospective study.
Authors: Hiroaki Tanaka, Takuya Mori, Kenjiro Kimura, Kazuya Muguruma, Kosei Hirakawa, Masaichi Ohira
Journal: Journal of Clinical Oncology (2020)

412 Background: Conversion surgery for unresectable advanced gastric cancer has been increasing with the development of chemotherapy. Adjuvant chemotherapy regimens after conversion surgery have not been standardized. The main mechanism of nivolumab is augmentation of antitumor immune response of tumor infiltrating cytotoxic T cells (CTL) to cancer cells, and it has recently been reported that nivolumab therapy before and after chemotherapy is effective in other carcinomas. We previously reported that tertiary lymphoid architecture (TLS) correlates with tumor-infiltrating T cells and is associated with a better prognosis in untreated patients. The purpose of this study was to investigate the relationship between the presence of TLS in the primary tumor and prognosis in patients with gastric cancer who underwent conversion therapy. Methods: We evaluated 52 patients with advanced gastric cancer including 17 patients underwent conversion surgery and 35 patients underwent palliative surgery without prior chemotherapy in our department from 2009 to 2017. The local immune environment and presence of TLS was evaluated by immunohistochemical staining. Results: Intratumoral TLS occurred in 20% of patients with advanced cancer who did not receive chemotherapy before surgery and in 52% of patients who received conversion surgery. And the prognosis of patients with the presence of TLS was better than no TLS. Intratumoral CD8 T-cell infiltration was slightly associated presence of TLS. We had a case in which nivolumab was highly effective and converted to conversion surgery, and a case in which nivolumab was highly effective in patients with recurrence after conversion surgery. TLS was observed in the vicinity of the tumor in these patients. Conclusions: The prognosis was good in the case in which intratumoral TLS was present after conversion surgery. These results suggest that the adjuvant nivolumab therapy may improve the outcome of patients underwent conversion surgery for advanced gastric cancer. These results suggest that peri-tumor TLS is a predictor of nivolumab efficacy in adjuvant therapy after conversion surgery.
Phase II trial of BPM31510-IV plus gemcitabine in advanced pancreatic ductal adenocarcinomas (PDAC).
Authors: Madappa N. Kundranda, David Propper, Paul S. Ritch, James Strauss, Manuel Hidalgo, Roopinder Gillmore, Rangaprasad Sarangarajan, Niven R. Narain, Michael A. Kiebish, Leonardo O Rodrigues, Elder Granger, Ramesh Ramanathan, Angela Tatiana Alistar, Lynne A. Bui, Sant P. Chawla, Anna A. Niewiarowska
Journal: Journal of Clinical Oncology (2020)

723 Background: BPM31510-IV is an Ubidecarenone (CoQ10) drug-lipid conjugate nanodispersion targeting metabolic machinery in cancer, shifting bioenergetics from lactate dependency towards mitochondrial OxPhos to generate ROS and activate apoptosis. An MTD of BPM31510-IV in combination with gemcitabine was established at 110mg/kg in a Phase I clinical trial, which determined the dose for the Phase 2 investigation. Methods: Eligible patients (aged ≥ 18 y) with relapsed/refractory PDAC to standard treatment (ST) and met inclusion/exclusion criteria were recruited. Patients received 110mg/kg IV BPM31510 in combination with gemcitabine in a 144-hour infusion. Tumor response was evaluated at week 10 and then every 8 weeks. Study endpoints assessed were Overall Response Rate (ORR), Overall Survival (OS), Progression-Free Survival (PFS), Time to Progression (TTP), Tumor Response using Adaptive Molecular Responses (multi-omic molecular profiling), changes in CA 19-9 levels and patient reported Quality of Life (QOL) using the validated FACT-HEP PRO. A comprehensive multi-omic profiling for identification of biomarkers for patient stratification was explored. Results: Of the 35 patients enrolled to receive therapy, 18 patients met criteria of an adequately treated cohort (ATC- received BPM31510-IV + gemcitabine for 30 days over 2 cycles and had a RECIST 1.1 evaluation) while remaining (n = 17) had progressive disease (PD). Half of the ATC population (n = 9/18, 50%) achieved best ORR of stable disease (SD); 10/18 (55 %) demonstrated SD as best response at target lesions and 8/18 demonstrated SD at end of Cycle 2. The mTTP was 121 days (70 – 147, 95% CI); PFS 118 days (70 – 131, 95% CI) and OS 218 days (131 – 228, 95% CI), respectively. Overall, BPM31510-IV was well tolerated; the most common AE’s were GI related. Conclusions: The efficacy signal observed in this heavily pretreated population in addition to the toxicity profile warrants further clinical investigation of BPM31510-IV + gemcitabine in advanced PDAC. Clinical trial information: NCT02650804 . [Table: see text]
Performance of a blood-based test for the detection of multiple cancer types.
Authors: Brian M. Wolpin, Donald A. Richards, Allen Lee Cohn, Xiaoji Chen, Joerg Bredno, Kathryn N. Kurtzman, Jessica Yecies, Rita Shaknovich, Nan Zhang, Mohan K. Tummala, David R. Spigel, David Cosgrove, Sharon Wilks, Robert D. Siegel, Eric T. Fung, Arash Jamshidi, Alex Aravanis, Anne-Renee Hartman, Minetta C. Liu, Eric A. Klein
Journal: Journal of Clinical Oncology (2020)

283 Background: Cancers of the esophagus, stomach, pancreas, gallbladder, liver, bile duct, colon and rectum will account for 17% of incident cancer diagnoses and 26% of cancer-related deaths in the US in 2019. We developed a methylation-based cfDNA early multi-cancer detection test that also can predict the tissue of origin (TOO) of these and other cancers types; performance of this test for gastrointestinal (GI) tract cancers is reported here. Methods: The Circulating Cell-free Genome Atlas (CCGA; NCT02889978) study is a prospective, multi-center, observational, case-control study with longitudinal follow-up, enrolling individuals with cancer ( &gt; 20 cancers, all stages, newly diagnosed) and without cancer. Plasma cfDNA was subjected to a cross-validated targeted methylation (TM) sequencing assay. Methylation fragments were combined across targeted genomic regions and assigned a probability of cancer and a predicted TOO. GI cancer classes were upper GI (esophagus/stomach, n = 67), pancreas/gallbladder/extrahepatic bile duct (n = 95), liver/intrahepatic bile duct (n = 29), and colon/rectum (n = 121). Results: Detection across all GI cancers was 82% (95% CI 77-86) at a &gt; 99% pre-set specificity. Overall predicted TOO accuracy was 92% (88-95) among the samples for which TOO was predicted (6/255 had indeterminate predicted TOO). The table shows performance by GI cancer type. Conclusions: Simultaneous detection at high specificity ( &gt; 99%) of multiple cancer types, including GI cancers across stages at high sensitivity (82%), was shown using TM analysis of cfDNA. Accurate (92%) localization of cancers to specific regions of the GI tract was also achieved. Detection of multiple GI cancers from a single noninvasive blood test could be a practical method for detecting GI and other cancers, and may facilitate diagnostic work-ups. Clinical trial information: NCT02889978. [Table: see text]
Phenotype and function of circulating memory T cells in human vitiligo*
Authors: C. Martins, A.‐S. Darrigade, C. Jacquemin, T. Barnetche, A. Taieb, K. Ezzedine, K. Boniface, J. Seneschal
Journal: British Journal of Dermatology (2020)

Vitiligo is a chronic inflammatory skin disorder characterized by the loss of melanocytes. While a T helper cell (Th)1/cytotoxic T cell (Tc)1‐skewed immune response is now well demonstrated in vitiligo, recent data suggest that the T‐cell component could be more complex, involving different combinatorial T‐cell subsets. To analyse the phenotype and function of circulating CD4+ and CD8+ memory T‐cell subsets in patients with stable and active vitiligo, in comparison with patients with psoriasis and healthy controls. This is a monocentric, prospective, descriptive and exploratory study. Multiparametric flow cytometry analyses were performed to evaluate the surface expression of homing and T‐cell‐subset markers together with intracellular cytokine production in peripheral blood mononuclear cells from 60 patients with vitiligo, 25 patients with psoriasis and 28 healthy donors. Vitiligo peripheral blood circulating effector and central memory T cells expressed similar proportions of skin‐homing markers. Decrease in the frequencies of circulating CD4+ and CD8+ Th1/Tc1, Th17/Tc17, and Th1/Th17 or Tc1/Tc17 effector memory T‐cell subsets were observed in patients with vitiligo compared with healthy donors. Similar observations were made in psoriasis. In contrast, vitiligo circulating T cells showed a similar capacity for proinflammatory cytokine production compared with those in psoriasis and healthy controls. The decreased frequencies of circulating Th1/Tc1, Th17/Tc17 and Th1/Th17–Tc1/Tc17 cells suggest a possible migration of these T‐cell subsets into the skin of patients with vitiligo. These could be targeted to prevent flares of the disease. What is already known about this topic? Vitiligo is a chronic inflammatory skin disorder associated with the loss of melanocytes. Vitiligo is characterized by a T helper cell (Th)1/cytotoxic T cell (Tc)1‐skewed immune response in the skin. What does this study add? A thorough analysis of the phenotype and function of circulating memory T cells suggests the migration of Th1/Tc1, Th17/Tc17 and Th1/Th17–Tc1/Tc17 cell subsets in the skin. What is the translational message? A better understanding of the different immune T‐cell subsets involved in vitiligo could lead to better therapeutic options. Linked Comment: Matos. Br J Dermatol 2020; 183:803.
Hepatic CEACAM1 expression indicates donor liver quality and prevents early transplantation injury
Authors: Kojiro Nakamura, Shoichi Kageyama, Fady M. Kaldas, Hirofumi Hirao, Takahiro Ito, Kentaro Kadono, Kenneth J. Dery, Hidenobu Kojima, David W. Gjertson, Rebecca A. Sosa, Maciej Kujawski, Ronald W. Busuttil, Elaine F. Reed, Jerzy W. Kupiec-Weglinski
Journal: Journal of Clinical Investigation (2020)

Although CEACAM1 (CC1) glycoprotein resides at the interface of immune liver injury and metabolic homeostasis, its role in orthotopic liver transplantation (OLT) remains elusive. We aimed to determine whether/how CEACAM1 signaling may affect hepatic ischemia-reperfusion injury (IRI) and OLT outcomes. In the mouse, donor liver CC1 null mutation augmented IRI-OLT (CC1-KO→WT) by enhancing ROS expression and HMGB1 translocation during cold storage, data supported by in vitro studies where hepatic flush from CC1-deficient livers enhanced macrophage activation in bone marrow-derived macrophage cultures. Although hepatic CC1 deficiency augmented cold stress-triggered ASK1/p-p38 upregulation, adjunctive ASK1 inhibition alleviated IRI and improved OLT survival by suppressing p-p38 upregulation, ROS induction, and HMGB1 translocation (CC1-KO→WT), whereas ASK1 silencing (siRNA) promoted cytoprotection in cold-stressed and damage-prone CC1-deficient hepatocyte cultures. Consistent with mouse data, CEACAM1 expression in 60 human donor liver biopsies correlated negatively with activation of the ASK1/p-p38 axis, whereas low CC1 levels associated with increased ROS and HMGB1 translocation, enhanced innate and adaptive immune responses, and inferior early OLT function. Notably, reduced donor liver CEACAM1 expression was identified as one of the independent predictors for early allograft dysfunction (EAD) in human OLT patients. Thus, as a checkpoint regulator of IR stress and sterile inflammation, CEACAM1 may be considered as a denominator of donor hepatic tissue quality, and a target for therapeutic modulation in OLT recipients.
Response to: ‘Do we need the PFAPA syndrome in adults with non-monogenic periodic fevers?’ by Fayand et al
Authors: Marco Gattorno, Michael Hofer, Federica Vanoni, Silvia Federici, Luca Cantarini, Nicolino Ruperto
Journal: Annals of the Rheumatic Diseases (2020)

We really thank Fayand and coworkers for their interest to the new Eurofever/PRINTO classification criteria for periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA)1 and for their interesting exercise to apply the three most recent criteria to their population of adult patients with recurrent fever fulfilling the revised Marshall’s criteria for PFAPA.2

Indeed, in the last few years, three new criteria for PFAPA have been proposed.3–5 Of note, the methodology used for the development of the three set of criteria was rather different, as is for the process of their validation in an independent population.

Cantarini’s criteria were exclusively developed for adult-onset PFAPA patients. Seventy-four adult patients fulfilling the modified Marshall’s criteria were compared with 62 patients with fever of unknown origin (FUO). A multivariate analysis identified the set of variables with the highest accuracy in distinguishing PFAPA from FUO patients.4 The criteria have not been validated in an independent population, so far.

Vanoni’s criteria were created using the standard consensus procedures (Delphi survey and Nominal Group Technique in a Consensus Conference) among 22 paediatric experts in autoinflammation. The new proposed criteria were tested in 80 paediatric PFAPA patients followed in two centres for autoinflammatory diseases (Genoa and Lausanne). For this validation process, the diagnosis of PFAPA was not done on the basis of modified Marshall’s criteria, but on the clinical judgement of the two …
Potential use of lenvatinib for patients with unresectable hepatocellular carcinoma beyond progression of sorafenib treatment: A real-world evidence and in vitro assessment with protein phosphorylation array.
Authors: Yasushi Sato, Tetsu Tomonari, Hironori Tanaka, Takahiro Tanaka, Akihiro Hirao, Koichi Okamoto, Hiroshi Miyamoto, Naoki Muguruma, Harumi Kagiwada, Masashi Kitazawa, Kazuhiko Fukui, Katsuhisa Horimoto, Tetsuji Takayama
Journal: Journal of Clinical Oncology (2020)

485 Background: No information is available on the efficacy and safety of lenvatinib (LEN) as a second/third-line treatment for unresectable hepatocellular carcinoma (HCC) after sorafenib (SOR) therapy. We evaluated the characteristics and the therapeutic efficacy and safety of LEN as a second- and third-line treatment as well as first- treatment for unresectable HCC patients in clinical settings. Moreover, to rationalize these clinical findings in vitro, we assessed the anti-tumor activity of LEN on SOR-resistant cell line and performed a comprehensive phosphorylated protein array analysis associated with 377 signal transduction pathways using SOR-resistant and parental HCC cells. Methods: We retrospectively enrolled 51 unresectable HCC patients. Radiologic responses in 41 patients were evaluated by modified RECIST. Active signal transduction pathways in the cells were identified by protein array analysis, including 1205 proteins. Results: The evaluated patients comprised 25 TKI-naive (first- line), 7 intolerant to SOR (second-line), and 9 patients resistant to regorafenib (third-line). The ORRs were 64% in first-line, 42.8% in second-line, and 22.2% in third-line groups (first-line vs. third-line p&lt; 0.05). The OS in the first-line was significantly longer than that in third-line group ( p&lt; 0.05). Patients with better liver functional reserve (Child score, ALBI grade) exhibited higher ORR and longer OS. LEN was well-tolerated in the second/third-line treatment. The IC50 value of LEN against PLC/PRF5-R2 (30 μM) was significantly higher than that against PLC/PRF5 (6.4 μM). LEN significantly inhibited more signal transduction pathways related to FRS2, a crucial FGFR downstream molecule, in PLC/PRF5 than in PLC/PRF5-R2 cells. Conclusions: Our study indicates that LEN was active and safe in the second/third-line treatment for unresectable HCC. LEN seems more effective for HCC patients with better hepatic reserve function, or before TKI-resistance is acquired because of the partial cross-resistance to SOR.
Preventive effects of gender and metabolic syndrome in 40s on colorectal cancer by colonoscopy.
Authors: Hyun-Soo KIM, Su Young Kim, Jung Kuk Lee
Journal: Journal of Clinical Oncology (2020)

59 Background: This study was aimed at measuring the preventive effect of colonoscopy for CRC development depending on age of index colonoscopy, gender and metabolic syndrome among persons aged 40 to 59 years. Methods: Between January 2005 and December 2006, data for the population aged from 40 to 59 who underwent colonoscopy (CSP cohort) claimed were collected from National Health Insurance Service (NHIS). Non-CSP (N-CSP) subjects were also collected by 1:5 propensity score matching with parameters of age, sex, and metabolic profiles, smoking, alcohol and past history of cancer. After one year of washout period, the risk of developing CRC was estimated by the occurrence of new case from January 2009 to December 2014 using the link of National CRC Registry to NHIS database. Compared with N-CSP cohort, hazard ratios (HRs) were obtained via conditional logistic regression analysis to estimate the risk of CRC in CSP cohort by age groups. Results: A total of 2,339,359 subjects were included (CSP cohort: 395,738 and matched N-CSP cohort: 1,943,621). The HRs for developing CRC by ages of 40-44, 45-49, 50-54, and 55-59 years in a CSP cohort were 0.864 ( P = NS), 0.591 ( P &lt; 0.001), 0.599 ( P &lt; 0.001), and 0.524 ( P &lt; 0.001) in men, and 0.774 ( P = NS), 0.841 ( P = NS), 0.598 ( P &lt; 0.001), and 0.605 ( P &lt; 0.001) in women, respectively. Interestingly, when confined to patients with metabolic syndrome in their 40s, HRs for CRC in the colonoscopy cohort were statistically significantly lowered to 0.372 in early 40’s and 0.386 in men of late 40s, respectively, but not in women of 40s. Conclusions: The CRC prevention effect of colonoscopy is expected from late 40s in men and early 50s in women. Furthermore, in cases with metabolic syndrome, the preventive effect of colonoscopy is expected in men of early forties.
Metachronous colorectal pathology among survivors of young-onset colorectal cancer: Implications for postresection colonoscopic surveillance.
Authors: Oliver Peacock, Yun Yang, Selvi Thirumurthi, Sa Thi Nguyen Nguyen, Phillip Lum, Miguel A. Rodriguez-Bigas, Brian K. Bednarski, Craig Messick, John Michael Skibber, George J. Chang, Eduardo Vilar Sanchez, Y. Nancy You
Journal: Journal of Clinical Oncology (2020)

64 Background: Patients with sporadic young-onset colorectal cancer (CRC) are postulated to have a more biologically active colorectum prone to malignant transformation earlier in life. It is unknown whether there is elevated risk for metachronous colorectal pathology after the index cancer. We aimed to define this risk, to inform their post-resection endoscopic surveillance. Methods: Consecutive CRC patients (aged 18-50, n = 728) were prospectively followed after surgical resection between 2009 and 2017. Patients presenting with hereditary CRC, recurrent disease, or without endoscopy follow-up were excluded. All endoscopy records were subjected to natural language processing and further reviewed. Metachronous colorectal pathology of interest included: high-risk adenoma (≥1cm in size, &gt; 3 in number, or tubulovillious/high-grade dysplasia histology), second CRC, and endoscopically detectable local recurrence. Results: During a 48-month (median) follow-up, 457 patients underwent 1,192 person-years of colonoscopic follow-up. The median age at CRC diagnosis was 44 years. Disease arose from the proximal colon in 9.4%, distal colon in 23.0% and rectum in 67.6%, and was stages I/II in 191 (41.8%), III in 185 (40.4%), and IV in 81 (17.7%). The majority (95.8%) underwent segmental resection, while the remainder had extended resections for synchronous pathology not amendable to preoperative endoscopic clearance. The overall incidence of metachronous pathology was 32 per 1000 person-years: 31 patients developed high-risk adenomas (6.8%), 1 had a second CRC (0.2%), and 7 had luminal recurrences (1.5%). The median time to metachronous pathology was 13.9 (IQR: 11.8-33.1) months, with 21 (53.8%) detected between 12 and 48 months post-resection. Conclusions: For young-onset CRC survivors, the incidence of metachronous colorectal pathology was 32 per 1000 person-years of follow-up. Given the time pattern of detection, adding an interval colonoscopy between the current recommended post-resection surveillance at 12 and 48 months may be beneficial. [Table: see text]
Clinical Characterization of E-Cigarette, or Vaping, Product Use–associated Lung Injury in 36 Patients in Pittsburgh, Pennsylvania
Authors: Richard H. Zou, Perry J. Tiberio, Georgios A. Triantafyllou, Phillip E. Lamberty, Michael J. Lynch, John W. Kreit, Bryan J. McVerry, Mark T. Gladwin, Alison Morris, Jared Chiarchiaro, Meghan E. Fitzpatrick, Jason J. Rose
Journal: American Journal of Respiratory and Critical Care Medicine (2020)