tbuckley/cabot-search huggingface dataset:
STING activation normalizes the intraperitoneal vascular-immune microenvironment and suppresses peritoneal carcinomatosis of colon cancer
Authors: Seung Joon Lee, Hannah Yang, Woo Ram Kim, Yu Seong Lee, Won Suk Lee, So Jung Kong, Hye Jin Lee, Jeong Hun Kim, Jaekyung Cheon, Beodeul Kang, Hong Jae Chon, Chan Kim
Journal: Journal for ImmunoTherapy of Cancer (2021)

Peritoneal carcinomatosis is a fatal clinical presentation of colon cancer, characterized by unresponsiveness to conventional anticancer therapies, including immune checkpoint inhibitors. Here, we elucidated the immune-evasion mechanisms during the peritoneal carcinomatosis of colon cancer and developed a novel immunotherapy by activating the stimulator of interferon genes (STING) pathway. We generated a syngeneic peritoneal carcinomatosis model of colon cancer. Mice were intraperitoneally treated with either STING agonist (MIW815, also known as ADU-S100) or PD-1 blockade or both. The tumor microenvironment was comprehensively analyzed using multiplexed immunofluorescence imaging, flow cytometry, and NanoString immune profiling. Intraperitoneal colon cancer cells induce a massive influx of immunosuppressive M2-like macrophages, upregulate immune checkpoints, and impair effector T cell functions during peritoneal dissemination; these collectively create a highly angiogenic and immunosuppressive milieu that is resistant to anti-PD-1 monotherapy. Intraperitoneal administration of a STING agonist suppressed aberrant angiogenesis, increased pericyte coverage, and normalized tumor vessels, thereby facilitating the infiltration of activated CD8+ T cells into peritoneal tumor nodules. Moreover, STING activation reprogramed tumor-associated macrophages toward the M1 phenotype. STING activation converted immunologically cold peritoneal tumors into T-cell-inflamed tumors in a type-I interferon-dependent manner. Lastly, the STING agonist synergistically cooperated with PD-1 and/or COX2 blockade to further suppress the peritoneal dissemination of colon cancer, resulting in complete eradication of tumor and ascites, and inducing durable antitumor immunity. STING activation can normalize the peritoneal vascular and immune microenvironment, providing a rationale for a novel combination therapeutic strategy for peritoneal carcinomatosis in colon cancer.
It Starts With the Brain
Authors: Michael Wynn
Journal: JAMA (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Comparison of next-generation sequencing and FISH/IHC for molecular classification in glioma.
Authors: Deze Jia, Yi Lu, Xiaomin Li, Tiantian Han, Wanglong Deng, Fanfeng Bu, Guanghua Lu
Journal: Journal of Clinical Oncology (2021)

e14021 Background: The updated 2016 edition of the WHO Classification of CNS tumors indicates that IDH1 R132H, H3 K27M mutations, and co-deletion of 1p19q are strong stratification and prognostic markers glioma. FISH/IHC, as the commonly detected methods, present specific false-negative rates in the actual condition. Methods: In our study, IDH1 R132H status of 158 cases was assessed by IHC and NGS, and H3 K27M statuses of 83 patients were evaluated by IHC and NGS. 22 positive cases of 1p/19q co-deletion, all confirmed by FISH, were assessed by NGS. Results: For IDH1 R132H, 2 cases were IHC negative and were positive as confirmed by NGS. Another 10 patients with weakly IHC positive results were negative in NGS. Combined with histologic hallmarks, 6 cases of these samples could be diagnosed as glioblastoma, IDH wildtype; 1 case with POLE could be diagnosed as giant cell glioblastoma; 3 cases with BRAF V600E mutation, BRAF fusion, and ATRX mutation, respectively, could be diagnosed as pilocytic astrocytoma. Towards H3 K27M, 3 cases with IHC weakly positive were negative in NGS. Among these samples, 2 cases were diagnosed as glioblastoma, IDH wildtype by molecular and histologic hallmarks, and 1 case was medulloblastoma, SHH. Using NGS, IDH1 R132H /H3 K27M statues can be distinctly distinguished in which that is unknown by IHC. The results of NGS and FISH showed a 90.9%(20/22) consistent rate for the 1p19q co-deletion. 1 case was 1p deletion and intact 19q by FISH while 1p19q co-deletion by NGS because of the 19p deletion. 1 case was 1p19q co-deletion by FISH but 1p19q wildtype by NGS, diagnosed as glioblastoma, IDH wildtype with chr7+/10-. Conclusions: In our study, the agreement between NGS results and clinical pathology diagnosis was approximately 100%. NGS may act as the primary technology of molecular classification in glioma in the future.
Efficacy of EGFR-TKIs monotherapy versus TKI plus chemotherapy as first-line treatment in EGFR mutant lung adenocarcinoma with liver metastases.
Authors: Huijuan Wang, Mengmeng Li, Mina Zhang, Zhang guo Wei, Xiangtao Yan, Zhiyong Ma, Ruyue Xing
Journal: Journal of Clinical Oncology (2021)

e21099 Background: Liver metastasis is one of the most reasons for the poor prognosis of patients with advanced lung cancer. Seeking for active and effective treatment measures is very important for these patients. At present, the first-line standard treatment of the advanced NSCLC with EGFR mutation is EGFR-TKIs monotherapy. However, its efficacy is poor in the advanced non-small cell lung cancer with EGFR mutation and liver metastases. The objective of this study is to evaluate the efficacy of EGFR-TKIs plus chemotherapy in patients with EGFR mutation of advanced non-small cell lung cancer with liver metastases. Methods: The clinical data of a total of 384 advanced NSCLC patients with EGFR mutation positive who were admitted to The Affiliated Cancer Hospital of Zhengzhou University/Henan Cancer Hospital from February 2017 to June 2020 were retrospectively analyzed. There were 75 patients with liver metastases. Patients were divided into two groups, and accepted EGFR-TKIs monotherapy or EGFR-TKIs plus chemotherapy, respectively. All patients treatment response were evaluated by the RECIST1.1 Response evaluation criteria in solid tumors.Progression free-survival (PFS) were also analyzed. Results: In the study, 75 patients were finally screened. There were 37 patients in the EGFR-TKIs monotherapy group and 38 patients in the TKI plus chemotherapy group. The median follow-up time was 23.0 months. At the latest follow-up date (2021-01-01), 57 patients had disease progression and 35 patients had died. Comparing with EGFR-TKIs monotherapy,the first-line PFS of EGFR-TKI plus chemotherapy group was longer, and the median PFS was 12.7 months VS 7.4 months (P = 0.018).The ORR of primary lung lesions was no significant difference between these two groups（65.8%VS 51.4% P = 0.204), and DCR (97.4% VS 94.6% P = 0.981) also had no difference between two groups（P &gt; 0.05）. ORR of liver metastases in the EGFR-TKIs plus chemotherapy group was significantly higher than EGFR-TKIs monotherapy group ORR (65.8%VS 40.5%，P = 0.028). Conclusions: In advanced NSCLC patients with EGFR mutation and liver metastases, comparing with EGFR-TKIs monotherapy, taking EGFR-TKIs plus chemotherapy as first-line treatment had longer PFS, and better efficacy on liver lesions.
IMMU-16. TARGETING GLYPICAN 2 (GPC2) ON PEDIATRIC MALIGNANT BRAIN TUMORS WITH MRNA CAR T CELLS
Authors: Jessica Foster, Crystal Griffin, Allison Stern, Cameron Brimley, Samantha Buongervino, Phillip Storm, David Barrett, John Maris, Adam Resnick, Kristopher Bosse
Journal: Neuro-Oncology (2021)

Abstract Glypican 2 (GPC2) is a cell-surface oncoprotein initially identified in neuroblastoma, retinoblastoma, and medulloblastoma as an ideal target for immunotherapy (Cancer Cell, 2017). Here we evaluated GPC2 expression across the spectrum of pediatric brain tumors using RNA sequencing from specimens in the Children’s Brain Tumor Network (CBTN). High GPC2 expression, defined as &amp;gt;10 FPKM, was found in 100% of embryonal tumors with multilayered rosettes (ETMRs) (n=6), 95% of medulloblastomas (n=122), 86% of other embryonal tumors (n=21), 50% of choroid plexus carcinomas (n=4), 42% of high grade gliomas (HGG) (n=117), and 37% of diffuse midline gliomas (DMG) (n=65). Within medulloblastoma subtypes, group 4 tumors had the highest expression, and within the HGG tumor cohort H3.3 G34 mutated gliomas had the highest GPC2 expression. High GPC2 protein expression was validated with medulloblastoma and HGG/DMG primary tumors and cell lines using IHC, Western blot, and flow cytometry. We next developed two potent CAR T cell constructs using the D3 specific scFv directed against GPC2 for testing in brain tumor models. GPC2-directed CAR T cells were tested in vitro against medulloblastoma and HGG cells lines, and in vivo using two patient-derived medulloblastoma xenograft models: Rcmb28 (group 3) and 7316-4509 (group 4). GPC2-directed mRNA CAR T cells induced significant GPC2-specific cell death in medulloblastoma and HGG cellular models with concomitant T cell degranulation compared to CD19-directed mRNA CAR T cells. In vivo, GPC2-directed mRNA CAR T cells delivered locoregionally induced significant tumor regression measured by bioluminescence after 4–6 intratumoral infusions of 4 x 106 CAR T cells (p&amp;lt;0.0001 for Rcmb28, p&amp;lt;0.05 for 7316-4509). No GPC2-directed CAR T cell related toxicity was observed. GPC2 is a highly differentially expressed cell surface protein on multiple malignant pediatric brain tumors that can be targeted safely with local delivery of mRNA CAR T cells.
Somatic uniparental disomy mitigates the most damaging <i>EFL1</i> allele combination in Shwachman-Diamond syndrome
Authors: Sangmoon Lee, Chang Hoon Shin, Jawon Lee, Seong Dong Jeong, Che Ry Hong, Jun-Dae Kim, Ah-Ra Kim, Boryeong Park, Soo Jin Son, Oleksandr Kokhan, Taekyeong Yoo, Jae Sung Ko, Young Bae Sohn, Ok-Hwa Kim, Jung Min Ko, Tae-Joon Cho, Nathan T. Wright, Je Kyung Seong, Suk-Won Jin, Hyoung Jin Kang, Hyeon Ho Kim, Murim Choi
Journal: Blood (2021)
Molecular characteristics of BRAF mutated non-small cell lung cancer and therapeutic outcomes: Multi-institution study.
Authors: Guillermo Martos, Aliyah Pabani, D. Gwyn Bebb, Amanda Williams Gibson, Michelle Liane Dean, Lance Petersen
Journal: Journal of Clinical Oncology (2021)

e21029 Background: BRAF-mutations are uncommon, present in only 2-4% of all new non-small cell lung cancer (NSCLC) diagnoses. BRAF-mutation type has treatment implications, where the most common BRAFV600E shows sensitivity to tyrosine kinase inhibitors (Dabrafenib or Vemurafenib) with additional benefit seen in duel therapy adding MEK-inhibitors (Trametinib or Cobimetinib). Clinical responses have also been observed with immune checkpoint inhibitors in both V600E and non-V600E mutant patients. The optimal management strategy in this patient population is still unknown. Methods: Patients from the province of Alberta, Canada, with a BRAF-mutation and initiating systemic therapy between 2018 and 2020 were identified. Demographic, clinical, treatment and outcome data were extracted from the institutional Glans-Look Lung Cancer Database. Results: 31 patients with a BRAF-mutation were identified: 52% alive, 58% female, 87% ‘ever’ smokers (average: 40 pack-years). 70% ECOG &gt; 2, 58% Stage IV at diagnosis, with the M1b (one extrathoracic metastatic site) being the most common. 87% had an adenocarcinoma histology and 64.5% carried the BRAFV600E mutation. 19% had other concurrent mutations (KRAS, PIK3CA or EGFR-L858R), 52% showed high PD-L1 expression ( &gt; 50%). In addition, concurrent mutations also were associated with high PD-L1 positivity. 55% of the cohort received systemic treatment, with 71% still on treatment at the time of analysis. Conclusions: BRAF mutant NSCLC is associated with high PD-L1 expression and responses to both checkpoint inhibitors and BRAF inhibitor combinations. Treatment with immunotherapy appears to have a superior toxicity profile and prolonged disease control in both BRAF V600E and non-V600E mutant NSCLC and is an effective first-line strategy. Higher overall response rates are observed with BRAF inhibitor combinations in BRAF V600E patients. Further investigation is warranted to further elucidate sequencing strategies among specific subgroups.[Table: see text]
Plasma cells promote osteoclastogenesis and periarticular bone loss in autoimmune arthritis
Authors: Noriko Komatsu, Stephanie Win, Minglu Yan, Nam Cong-Nhat Huynh, Shinichiro Sawa, Masayuki Tsukasaki, Asuka Terashima, Warunee Pluemsakunthai, George Kollias, Tomoki Nakashima, Hiroshi Takayanagi
Journal: Journal of Clinical Investigation (2021)
Contemporary Medical Management of Peripheral Artery Disease
Authors: Marc P. Bonaca, Naomi M. Hamburg, Mark A. Creager
Journal: Circulation Research (2021)

Peripheral artery disease (PAD) is a manifestation of systemic atherosclerosis. Modifiable risk factors including cigarette smoking, dyslipidemia, diabetes, poor diet quality, obesity, and physical inactivity, along with underlying genetic factors contribute to lower extremity atherosclerosis. Patients with PAD often have coexistent coronary or cerebrovascular disease, and increased likelihood of major adverse cardiovascular events, including myocardial infarction, stroke and cardiovascular death. Patients with PAD often have reduced walking capacity and are at risk of acute and chronic critical limb ischemia leading to major adverse limb events, such as peripheral revascularization or amputation. The presence of polyvascular disease identifies the highest risk patient group for major adverse cardiovascular events, and patients with prior critical limb ischemia, prior lower extremity revascularization, or amputation have a heightened risk of major adverse limb events. Medical therapies have demonstrated efficacy in reducing the risk of major adverse cardiovascular events and major adverse limb events, and improving function in patients with PAD by modulating key disease determining pathways including inflammation, vascular dysfunction, and metabolic disturbances. Treatment with guideline-recommended therapies, including smoking cessation, lipid lowering drugs, optimal glucose control, and antithrombotic medications lowers the incidence of major adverse cardiovascular events and major adverse limb events. Exercise training and cilostazol improve walking capacity. The heterogeneity of risk profile in patients with PAD supports a personalized approach, with consideration of treatment intensification in those at high risk of adverse events. This review highlights the medical therapies currently available to improve outcomes in patients with PAD.
Durability of response to immune checkpoint inhibitors (ICI) in metastatic Merkel cell carcinoma (mMCC) after treatment cessation.
Authors: Alison Margaret Weppler, Laetitia Da Meda, Ines Silva, Wen Xu, Giovanni Grignani, Alexander M. Menzies, Matteo S. Carlino, Georgina V. Long, Ina Nordman, Christopher Steer, Megan Lyle, Claudia Trojaniello, Paolo Antonio Ascierto, Celeste Lebbe, Shahneen Kaur Sandhu
Journal: Journal of Clinical Oncology (2021)

9543 Background: mMCC is a rare, aggressive neuroendocrine cancer which often occurs in older patients (pts) with multiple comorbidities. While initial response rates to ICI are high, optimal treatment duration, durability of response after treatment cessation and response to retreatment with ICI is unknown. Methods: mMCC pts from 12 international centres who received at least one dose of ICI and subsequently stopped treatment without progression for a minimum of 12 weeks were studied. Demographics, disease characteristics and treatment course were examined. Results: 40 pts with mMCC were included. Pt characteristics are summarised in Table. Median time on treatment was 13.5 months (range 1 to 35). Median time to best response was 4.5 months (range 1 to 17) and median time receiving treatment after best response was 8 months (range 0 to 29). 25 pts (63%) stopped primarily due to being in a complete or partial response (CR or PR), 9 (23%) due to toxicity and 6 (15%) due to other reasons, primarily pt choice or comorbidities. At time of discontinuation, 30 pts (75%) were in a CR, 8 (20%) in a PR and 2 pts (5%) had stable disease (SD). After a median follow up of 12 months from discontinuation, 14 pts (35%) have progressed (PD); 5 (36%) at a previous site, 5 (36%) at a new site and 4 (29%) at both. PD occurred after a median of 5.5 months (range 4 to 29) off treatment. 4 pts (29%) had a CNS recurrence, none of whom previously had CNS involvement. Pts in CR at time of discontinuation were less likely to progress (CR: 26% PD vs non-CR: 67% PD, p=0.044), but still had a considerable rate of PD (CR: 26%, PR: 57%, SD: 100%). Those who progressed had numerically less cycles of ICI prior to treatment cessation (17 vs 32, p&gt;0.05). Baseline disease factors, time to best response and duration of treatment after best response were not associated with PD. ICI was restarted in 8 of 14 pts (57%) with PD, with response rate to retreatment of 75% (4 CR, 2 PR, 1 SD, 1 PD – pt with leptomeningeal disease). Median time to best response at retreatment was 3 months (range 2 to 7), with all responses ongoing after a median of 10 months back on treatment. 3 pts had an isolated site of PD successfully treated with radiation therapy and remain in remission off ICI. Conclusions: ICI responses in mMCC do not appear as durable off treatment as in other cancers, including in patients who achieve a CR. Ongoing treatment should be considered, though initial data on response to retreatment is promising.[Table: see text]
Atezolizumab in first-line treatment of metastatic nonsquamous non-small cell lung cancer in the real-world setting.
Authors: Javier De Castro, Begoña Campos Balea, Diego Perez Parente, Letizia Polito, Marcus Lawrance, Pedro Ruiz Gracia, Leah Adler, Marta Marina Arroyo, Mark A. Socinski
Journal: Journal of Clinical Oncology (2021)

e21112 Background: The phase III IMpower150 study showed efficacy benefits with atezolizumab in combination with bevacizumab, carboplatin and paclitaxel (ABCP; arm B) as first-line (1L) treatment for patients (pts) with metastatic non-squamous (nsq) NSCLC. The FDA approved this regimen for these pts (with no EGFR or ALK mutations [WT]) on December 2018. However, to date there is limited evidence on its use in real life. This study aimed to explore the use of ABCP in the real-world setting and to describe the characteristics of early adopters (those who received ABCP in 1L). Methods: Data were extracted from the Flatiron Health database (US population). Pts with advanced stage IIIB/IV nsq NSCLC at diagnosis receiving ABCP regimen in any line were eligible for the study. Finally, early adopters were selected. Results: A total of 67 pts received the ABCP regimen in 1L. Baseline characteristics for these pts and comparisons with the IMpower150 population are summarized in Table. Real-world (rw) response in the WT group ( n = 49; 6 pts were excluded due to EGFR mutations and 12 because minimum follow-up was not reached) was similar to that of the IMpower150 series (rwRR: 55.1% [40.2-69.3] vs. 63.5% [58.2-68.5]), despite the WT population being older with a higher proportion of ECOG PS = 1. In patients who would have met the IMpower150 inclusion criteria ( n = 24), rwRR was 70.8% (48.9-87.4). Conclusions: The ABCP regimen has been adopted in the real-world setting. In terms of efficacy, response rates and current PFS data were in line with trial results, despite the population being unselected and having a worse clinical profile. Longer follow-up is required for rwOS data. vs. arm B IMpower150 results.[Table: see text]
Effect of a geriatric management unit on the outcomes of hospitalized older adults with cancer in Mexico.
Authors: Gretell Henriquez Santos, Andrea de la O Murillo, Enrique Soto Perez De Celis
Journal: Journal of Clinical Oncology (2021)

12039 Background: Geriatric assessments and interventions improve the outcomes of hospitalized older adults with cancer, but their implementation in developing countries is limited. We studied the effect of a specialized geriatrician-led inpatient geriatric management unit compared with a conventional internal medicine ward on the outcomes of hospitalized Mexican older adults with cancer. Methods: This retrospective study included patients aged ≥65 with solid tumors who had a cancer-related hospitalization at a public academic center in Mexico City between March 2015 and October 2018. Patients hospitalized in the geriatric management unit (cases) were paired in a 1:2 fashion with those in internal medicine wards (controls). Pairing was done by age (+/- 5 years), tumor type, and admission date (+/- 3 months). We studied the effect of being hospitalized in the geriatric management unit on length of stay (LOS), incidence of delirium, hospital-acquired complications, and in-hospital mortality. Multivariate logistic regression models for each outcome were created using variables which were significant on univariate analysis. Results: 300 patients (100 cases, 200 controls, median age 75) were included. The most common tumors were gastrointestinal (GI) (53%) and genitourinary (25%). Both groups were comparable regarding baseline comorbidities (Charlson index 8.5 vs. 7.7, p = 0.99) and illness severity at admission (NEWS2 score 2.6 vs. 2.3, p = 0.82). No difference in median LOS was found between cases and controls (9.1 vs. 9.5 days, p = 0.34). Diagnosis of a GI tumor (OR 3.4, 95% CI 1.3-5.5), hospital-acquired complications (OR 4.9, 95% CI 2.5-7.3), and delirium (OR 5.5, 95% CI 2.3-8.7) were associated with longer LOS. 14% of patients in both groups had delirium. Hospitalization in the geriatric management unit reduced the risk of delirium (OR 0.35, 95% CI 0.1-0.9), while a higher Charlson index (OR 1.2, 95% CI 1.0-1.4), NEWS2 score (OR 1.2, 95% CI 1.1-1.4), and hospital-acquired complications (OR 7.3, 95% CI 2.9-18.5) increased it. 34% of patients developed hospital-acquired complications. Diagnosis of a GI tumor (OR 1.9, 95% CI 1.1-3.3) and higher NEWS2 score (OR 1.2, 95% CI 1.1-1.4) increased the risk of hospital-acquired complications. No differences in in-hospital mortality were seen between cases and controls (12% vs. 10%, p = 0.59). A higher NEWS2 score at admission (OR 1.4, 95% CI 1.2-1.7) and delirium (OR 10.7, 95% CI 3.2-36.3) increased the risk of death. Conclusions: Among older Mexican adults hospitalized for a cancer-related diagnosis, receiving care in a geriatric management unit led to a significant decrease in the risk of delirium. No improvements were seen in LOS, complications, or in-hospital mortality, which were associated with tumor and patient-related characteristics. Geriatric co-management can lead to improved geriatric outcomes in developing countries with limited resources.