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Article ; Online: Marked Eosinophilia in a 27-Year-Old Woman With Recent Onset Ulcerative Colitis.

Herndon, John S / Vitta, Swaroop / Weber, Frederick H

2020 Volume 160, Issue 1, Page(s) 29–30

MeSH term(s)	Adult ; Cholangitis/diagnosis ; Cholangitis/etiology ; Cholangitis/therapy ; Colitis, Ulcerative/complications ; Colitis, Ulcerative/diagnostic imaging ; Colitis, Ulcerative/pathology ; Eosinophilia/diagnosis ; Eosinophilia/etiology ; Eosinophilia/therapy ; Female ; Humans
Language	English
Publishing date	2020-08-21
Publishing country	United States
Document type	Case Reports ; Journal Article
ZDB-ID	80112-4
ISSN	1528-0012 ; 0016-5085
ISSN (online)	1528-0012
ISSN	0016-5085
DOI	10.1053/j.gastro.2020.08.030
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Ui V Zs.44: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MO 572: Show issues

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Article ; Online: A Case of a Pathological Complete Response to Neoadjuvant Nivolumab plus Ipilimumab in Periampullary Adenocarcinoma.

Pothuri, Vikram / Herndon, John / Ballentine, Samuel J / Lim, Kian-Huat / Fields, Ryan C

The oncologist

2021 Volume 26, Issue 9, Page(s) 722–726

Abstract: Herein, we report on a patient with known Lynch syndrome and periampullary adenocarcinoma that exhibited a pathological complete response to neoadjuvant nivolumab plus ipilimumab. Two MSH2 mutations, high microsatellite instability, high tumor mutational ...

Abstract	Herein, we report on a patient with known Lynch syndrome and periampullary adenocarcinoma that exhibited a pathological complete response to neoadjuvant nivolumab plus ipilimumab. Two MSH2 mutations, high microsatellite instability, high tumor mutational burden, and elevated PD-L1 expression were identified by next-generation sequencing and immunohistochemistry. Following FOLFIRINOX (Fluorouracil/Leucovorin/Irinotecan/Oxaliplatin) administration and disease progression, nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) were administered every 3 weeks for four total cycles. The patient responded well with minimal adverse effects and significant improvement in epigastric pain, appetite, and body weight. She then underwent resection consisting of pancreaticoduodenectomy, which demonstrated pathological complete response. Complete genomic profiling of periampullary carcinomas is crucial for optimal treatment selection as true ampullary masses and pancreatic ductal adenocarcinoma have different genetic profiles. This case provides an example of a patient who may have further benefited from first-line nivolumab plus ipilimumab to avoid the reduced efficacy and significant side effects associated with chemotherapy. KEY POINTS: A patient with known Lynch syndrome and ampullary adenocarcinoma harboring two MSH2 mutations, high microsatellite instability (MSI-high), high tumor mutational burden (TMB), and elevated PD-L1 expression achieved pathological complete response with neoadjuvant nivolumab plus ipilimumab. The combination of nivolumab plus ipilimumab may be a better first-line option for patients with ampullary adenocarcinomas harboring deficient mismatch repair, MSI-high, and high TMB. Complete genomic profiling of periampullary adenocarcinomas is crucial for optimal treatment selection as true ampullary masses and pancreatic ductal adenocarcinoma have different genetic profiles. The presence of either MSI-high or high TMB could be an appropriate predictive biomarker for response to nivolumab plus ipilimumab in the context of Lynch syndrome.
MeSH term(s)	Adenocarcinoma/drug therapy ; Adenocarcinoma/genetics ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Female ; Humans ; Ipilimumab/therapeutic use ; Neoadjuvant Therapy ; Nivolumab/therapeutic use ; Pancreatic Neoplasms/drug therapy ; Pancreatic Neoplasms/genetics
Chemical Substances	Ipilimumab ; Nivolumab (31YO63LBSN)
Language	English
Publishing date	2021-05-26
Publishing country	United States
Document type	Case Reports ; Journal Article
ZDB-ID	1409038-7
ISSN	1549-490X ; 1083-7159
ISSN (online)	1549-490X
ISSN	1083-7159
DOI	10.1002/onco.13821
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Zs.A 4845: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 494: Show issues

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Article ; Online: Cancer-associated mutations reveal a novel role for EpCAM as an inhibitor of cathepsin-L and tumor cell invasion.

Sankpal, Narendra V / Brown, Taylor C / Fleming, Timothy P / Herndon, John M / Amaravati, Anusha A / Loynd, Allison N / Gillanders, William E

BMC cancer

2021 Volume 21, Issue 1, Page(s) 541

Abstract: Background: EpCAM (Epithelial cell adhesion molecule) is often dysregulated in epithelial cancers. Prior studies implicate EpCAM in the regulation of oncogenic signaling pathways and epithelial-to-mesenchymal transition. It was recently demonstrated ... ...

Abstract	Background: EpCAM (Epithelial cell adhesion molecule) is often dysregulated in epithelial cancers. Prior studies implicate EpCAM in the regulation of oncogenic signaling pathways and epithelial-to-mesenchymal transition. It was recently demonstrated that EpCAM contains a thyroglobulin type-1 (TY-1) domain. Multiple proteins with TY-1 domains are known to inhibit cathepsin-L (CTSL), a cysteine protease that promotes tumor cell invasion and metastasis. Analysis of human cancer sequencing studies reveals that somatic EpCAM mutations are present in up to 5.1% of tested tumors. Methods: The Catalogue of Somatic Mutations in Cancer (COSMIC) database was queried to tabulate the position and amino acid changes of cancer associated EpCAM mutations. To determine how EpCAM mutations affect cancer biology we studied C66Y, a damaging TY-1 domain mutation identified in liver cancer, as well as 13 other cancer-associated EpCAM mutations. In vitro and in vivo models were used to determine the effect of wild type (WT) and mutant EpCAM on CTSL activity and invasion. Immunoprecipitation and localization studies tested EpCAM and CTSL protein binding and determined compartmental expression patterns of EpCAM mutants. Results: We demonstrate that WT EpCAM, but not C66Y EpCAM, inhibits CTSL activity in vitro, and the TY-1 domain of EpCAM is responsible for this inhibition. WT EpCAM, but not C66Y EpCAM, inhibits tumor cell invasion in vitro and lung metastases in vivo. In an extended panel of human cancer cell lines, EpCAM expression is inversely correlated with CTSL activity. Previous studies have demonstrated that EpCAM germline mutations can prevent EpCAM from being expressed at the cell surface. We demonstrate that C66Y and multiple other EpCAM cancer-associated mutations prevent surface expression of EpCAM. Cancer-associated mutations that prevent EpCAM cell surface expression abrogate the ability of EpCAM to inhibit CTSL activity and tumor cell invasion. Conclusions: These studies reveal a novel role for EpCAM as a CTSL inhibitor, confirm the functional relevance of multiple cancer-associated EpCAM mutations, and suggest a therapeutic vulnerability in cancers harboring EpCAM mutations.
MeSH term(s)	Animals ; Cathepsin L/antagonists & inhibitors ; Cathepsin L/physiology ; Epithelial Cell Adhesion Molecule/genetics ; Epithelial Cell Adhesion Molecule/physiology ; Female ; Humans ; Mice ; Mice, Inbred C57BL ; Mutation ; Neoplasm Invasiveness ; Neoplasms/genetics
Chemical Substances	EPCAM protein, human ; Epithelial Cell Adhesion Molecule ; Cathepsin L (EC 3.4.22.15)
Language	English
Publishing date	2021-05-12
Publishing country	England
Document type	Journal Article
ISSN	1471-2407
ISSN (online)	1471-2407
DOI	10.1186/s12885-021-08239-z
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Article ; Online: Weight loss and weight gain in Parkinson disease.

Ghourchian, Shadi / Gruber-Baldini, Ann L / Shakya, Sunita / Herndon, John / Reich, Stephen G / von Coelln, Rainer / Savitt, Joseph M / Shulman, Lisa M

Parkinsonism & related disorders

2021 Volume 83, Page(s) 31–36

Abstract: Introduction: Parkinson disease (PD) has been associated with both weight loss and gain in different stages of the disease. Our study aimed to determine the prevalence and associations with weight change over two years based on 3% and 5% weight change.!# ...

Abstract	Introduction: Parkinson disease (PD) has been associated with both weight loss and gain in different stages of the disease. Our study aimed to determine the prevalence and associations with weight change over two years based on 3% and 5% weight change. Methods: In this longitudinal analysis, weight at baseline and follow-up was used to classify patients into groups of weight loss, stable, and weight gain. Differences between these groups at baseline and then with change over time were tested. Results: The sample was 668 patients with mean(SD) age 66.1(10) and disease duration 5.3(5.4) years. Using 3% weight change criteria: 32.6% lost, 23.1% gained, and 55.7% had stable weight. Using 5% criteria: 22.6% lost, 15.7% gained, and 61.7% had stable weight. Age was associated with both 3% and 5% change in weight. Other associations with 5% weight change were disease duration, Total and Motor Unified Parkinson's Disease Rating Scale, Older Americans Resource and Services disability, and Hoehn & Yahr staging. The effects of 3% weight loss on Motor UPDRS, IADLs, and depression, and the effects of 5% weight loss on IADLs remained statistically significant when controlling for baseline differences in age, levodopa use, and Total UPDRS. Conclusion: PD patients are more likely to experience 3% than 5% weight change and this lower threshold of weight change was associated with greater disease severity and disability over time. Attention to more subtle weight change may help identify those at greater risk of disability.
MeSH term(s)	Aged ; Cross-Sectional Studies ; Female ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Parkinson Disease/physiopathology ; Retrospective Studies ; Severity of Illness Index ; Weight Gain/physiology ; Weight Loss/physiology
Language	English
Publishing date	2021-01-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1311489-x
ISSN	1873-5126 ; 1353-8020
ISSN (online)	1873-5126
ISSN	1353-8020
DOI	10.1016/j.parkreldis.2020.12.018
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Zs.A 4553: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Fibrosis improvement in patients with HCV treated with direct-acting antivirals.

McPhail, James / Sims, Omar T / Guo, Yuqi / Wooten, David / Herndon, John S / Massoud, Omar I

European journal of gastroenterology & hepatology

2020 Volume 33, Issue 7, Page(s) 996–1000

Abstract: Background and aim: More prospective studies are needed to characterize fibrosis improvement in patients with hepatitis C virus (HCV) who are treated with direct-acting antivirals (DAAs). The aims of this study were to assess changes in elastography ... ...

Abstract	Background and aim: More prospective studies are needed to characterize fibrosis improvement in patients with hepatitis C virus (HCV) who are treated with direct-acting antivirals (DAAs). The aims of this study were to assess changes in elastography scores from baseline to 1-year follow-up in patients with HCV, to identify factors that were independently associated with improvement in fibrosis staging in patients who receive treatment, and to identify factors that were independently associated with no improvement in fibrosis staging among patients who achieved sustained virologic responses (SVR). Methods: Ultrasound elastography and laboratory tests were performed and collected at baseline and at 1-year follow-up for patients who received HCV treatment and for those who did not receive treatment (n = 240). Binomial logistic regression was used to examine factors that were independently associated with improvement in fibrosis staging. Results: In patients who achieved SVR, the mean fibrosis score decreased significantly (-1.3) from 7.4 (2.3) before treatment to 6.1 (2.0) after treatment (P = 0.00). In multivariate analysis of patients who received treatment, higher pre-treatment fibrosis stages [odds ratio (OR) = 13.02, P < 0.00] were positively associated with improvement in fibrosis staging at 1-year follow-up. Higher BMI (OR = 0.93, P < 0.05) was negatively associated with improvement in fibrosis staging. Discussion: This study supports the growing body of literature that suggests fibrosis regression is achievable in a significant number of patients who achieve SVR with all-oral DAA regimens. Equally important, fibrosis regression is more likely to occur in patients with advanced stages of fibrosis and less likely in patients who are obese.
MeSH term(s)	Antiviral Agents/therapeutic use ; Hepacivirus/genetics ; Hepatitis C/drug therapy ; Hepatitis C, Chronic/complications ; Hepatitis C, Chronic/drug therapy ; Humans ; Liver Cirrhosis/diagnostic imaging ; Liver Cirrhosis/drug therapy ; Sustained Virologic Response
Chemical Substances	Antiviral Agents
Language	English
Publishing date	2020-07-08
Publishing country	England
Document type	Journal Article
ZDB-ID	1034239-4
ISSN	1473-5687 ; 0954-691X
ISSN (online)	1473-5687
ISSN	0954-691X
DOI	10.1097/MEG.0000000000001821
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Zs.A 2932: Show issues

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Article ; Online: The MK2/Hsp27 axis is a major survival mechanism for pancreatic ductal adenocarcinoma under genotoxic stress.

Grierson, Patrick M / Dodhiawala, Paarth B / Cheng, Yi / Chen, Timothy Hung-Po / Khawar, Iftikhar Ali / Wei, Qing / Zhang, Daoxiang / Li, Lin / Herndon, John / Monahan, Joseph B / Ruzinova, Marianna B / Lim, Kian-Huat

Science translational medicine

2021 Volume 13, Issue 622, Page(s) eabb5445

Abstract: Combination chemotherapies remain the cornerstone treatment for pancreatic ductal adenocarcinoma (PDAC), but de novo and acquired resistance is common. In this study, we aimed to identify and characterize resistance mechanisms to a FIRINOX chemotherapy ... ...

Abstract	Combination chemotherapies remain the cornerstone treatment for pancreatic ductal adenocarcinoma (PDAC), but de novo and acquired resistance is common. In this study, we aimed to identify and characterize resistance mechanisms to a FIRINOX chemotherapy regimen (a combination of 5-fluorouracil, irinotecan, and oxaliplatin) because it is the most aggressive regimen currently used clinically for patients with PDAC. Using an unbiased reverse-phase protein array, we detected phospho-activation of heat shock protein 27 (Hsp27) as the most up-regulated event after FIRINOX treatment in PDAC cells. Silencing
MeSH term(s)	Adenocarcinoma ; Animals ; Cell Line, Tumor ; DNA Damage ; HSP27 Heat-Shock Proteins/genetics ; HSP27 Heat-Shock Proteins/metabolism ; Humans ; Intracellular Signaling Peptides and Proteins ; Mice ; Pancreatic Neoplasms/drug therapy ; Protein Serine-Threonine Kinases
Chemical Substances	HSP27 Heat-Shock Proteins ; Intracellular Signaling Peptides and Proteins ; MAP-kinase-activated kinase 2 (EC 2.7.1.-) ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2021-12-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.abb5445
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Article ; Online: Correction: Defactinib, Pembrolizumab, and Gemcitabine in Patients with Advanced Treatment Refractory Pancreatic Cancer: a Phase I Dose Escalation and Expansion Study.

Clinical cancer research : an official journal of the American Association for Cancer Research

2023 Volume 29, Issue 22, Page(s) 4698

Language	English
Publishing date	2023-11-14
Publishing country	United States
Document type	Published Erratum
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-23-2993
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Article ; Online: Pollock: fishing for cell states.

Bioinformatics advances

2022 Volume 2, Issue 1, Page(s) vbac028

Abstract: Motivation: The use of single-cell methods is expanding at an ever-increasing rate. While there are established algorithms that address cell classification, they are limited in terms of cross platform compatibility, reliance on the availability of a ... ...

Abstract	Motivation: The use of single-cell methods is expanding at an ever-increasing rate. While there are established algorithms that address cell classification, they are limited in terms of cross platform compatibility, reliance on the availability of a reference dataset and classification interpretability. Here, we introduce Pollock, a suite of algorithms for cell type identification that is compatible with popular single-cell methods and analysis platforms, provides a set of pretrained human cancer reference models, and reports interpretability scores that identify the genes that drive cell type classifications. Results: Pollock performs comparably to existing classification methods, while offering easily deployable pretrained classification models across a wide variety of tissue and data types. Additionally, it demonstrates utility in immune pan-cancer analysis. Availability and implementation: Source code and documentation are available at https://github.com/ding-lab/pollock. Pretrained models and datasets are available for download at https://zenodo.org/record/5895221. Supplementary information: Supplementary data are available at
Language	English
Publishing date	2022-05-13
Publishing country	England
Document type	Journal Article
ISSN	2635-0041
ISSN (online)	2635-0041
DOI	10.1093/bioadv/vbac028
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Article ; Online: Stromal Reprogramming by FAK Inhibition Overcomes Radiation Resistance to Allow for Immune Priming and Response to Checkpoint Blockade.

Cancer discovery

2022 Volume 12, Issue 12, Page(s) 2774–2799

Abstract: The effects of radiotherapy (RT) on tumor immunity in pancreatic ductal adenocarcinoma (PDAC) are not well understood. To better understand if RT can prime antigen-specific T-cell responses, we analyzed human PDAC tissues and mouse models. In both ... ...

Abstract	The effects of radiotherapy (RT) on tumor immunity in pancreatic ductal adenocarcinoma (PDAC) are not well understood. To better understand if RT can prime antigen-specific T-cell responses, we analyzed human PDAC tissues and mouse models. In both settings, there was little evidence of RT-induced T-cell priming. Using in vitro systems, we found that tumor-stromal components, including fibroblasts and collagen, cooperate to blunt RT efficacy and impair RT-induced interferon signaling. Focal adhesion kinase (FAK) inhibition rescued RT efficacy in vitro and in vivo, leading to tumor regression, T-cell priming, and enhanced long-term survival in PDAC mouse models. Based on these data, we initiated a clinical trial of defactinib in combination with stereotactic body RT in patients with PDAC (NCT04331041). Analysis of PDAC tissues from these patients showed stromal reprogramming mirroring our findings in genetically engineered mouse models. Finally, the addition of checkpoint immunotherapy to RT and FAK inhibition in animal models led to complete tumor regression and long-term survival. Significance: Checkpoint immunotherapeutics have not been effective in PDAC, even when combined with RT. One possible explanation is that RT fails to prime T-cell responses in PDAC. Here, we show that FAK inhibition allows RT to prime tumor immunity and unlock responsiveness to checkpoint immunotherapy. This article is highlighted in the In This Issue feature, p. 2711.
MeSH term(s)	Mice ; Animals ; Humans ; Focal Adhesion Protein-Tyrosine Kinases ; Carcinoma, Pancreatic Ductal/drug therapy ; Carcinoma, Pancreatic Ductal/radiotherapy ; Pancreatic Neoplasms/drug therapy ; Pancreatic Neoplasms/radiotherapy ; Immunotherapy ; Tumor Microenvironment ; Cell Line, Tumor ; Pancreatic Neoplasms
Chemical Substances	Focal Adhesion Protein-Tyrosine Kinases (EC 2.7.10.2)
Language	English
Publishing date	2022-09-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2625242-9
ISSN	2159-8290 ; 2159-8274
ISSN (online)	2159-8290
ISSN	2159-8274
DOI	10.1158/2159-8290.CD-22-0192
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Article ; Online: Defactinib, Pembrolizumab, and Gemcitabine in Patients with Advanced Treatment Refractory Pancreatic Cancer: A Phase I Dose Escalation and Expansion Study.

Clinical cancer research : an official journal of the American Association for Cancer Research

2022 Volume 28, Issue 24, Page(s) 5254–5262

Abstract: Purpose: Targeting focal adhesion kinase (FAK) renders checkpoint immunotherapy effective in pancreatic ductal adenocarcinoma (PDAC) mouse model. Defactinib is a highly potent oral FAK inhibitor that has a tolerable safety profile.: Patients and ... ...

Abstract	Purpose: Targeting focal adhesion kinase (FAK) renders checkpoint immunotherapy effective in pancreatic ductal adenocarcinoma (PDAC) mouse model. Defactinib is a highly potent oral FAK inhibitor that has a tolerable safety profile. Patients and methods: We conducted a multicenter, open-label, phase I study with dose escalation and expansion phases. In dose escalation, patients with refractory solid tumors were treated at five escalating dose levels of defactinib and gemcitabine to identify a recommended phase II dose (RP2D). In expansion phase, patients with metastatic PDAC who progressed on frontline treatment (refractory cohort) or had stable disease (SD) after at least 4 months of standard gemcitabine/nab-paclitaxel (maintenance cohort) were treated at RP2D. Pre- and posttreatment tumor biopsies were performed to evaluate tumor immunity. Results: The triple drug combination was well-tolerated, with no dose-limiting toxicities. Among 20 treated patients with refractory PDAC, the disease control rate (DCR) was 80%, with one partial response (PR) and 15 SDs, and the median progression-free survival (PFS) and overall survival (OS) were 3.6 and 7.8 months, respectively. Among 10 evaluable patients in the maintenance cohort, DCR was 70% with one PR and six SDs. Three patients with SD came off study due to treatment- or disease-related complications. The median PFS and OS on study treatment were 5.0 and 8.3 months, respectively. Conclusions: The combination of defactinib, pembrolizumab, and gemcitabine was well-tolerated and safe, had promising preliminary efficacy, and showed biomarker activity in infiltrative T lymphocytes. Efficacy of this strategy may require incorporation of more potent chemotherapy in future studies.
MeSH term(s)	Animals ; Mice ; Gemcitabine ; Deoxycytidine ; Albumins ; Paclitaxel ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Pancreatic Neoplasms/pathology ; Adenocarcinoma/pathology ; Pancreatic Neoplasms
Chemical Substances	Gemcitabine ; defactinib (53O87HA2QU) ; Deoxycytidine (0W860991D6) ; pembrolizumab (DPT0O3T46P) ; Albumins ; Paclitaxel (P88XT4IS4D)
Language	English
Publishing date	2022-10-14
Publishing country	United States
Document type	Clinical Trial, Phase I ; Multicenter Study ; Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-22-0308
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