Publications by authors named "Robert Anders"

214 Publications

Nuclear PTEN and p53 suppress stress-induced liver cancer through distinct mechanisms.

Biochem Biophys Res Commun 2021 Mar 2;549:83-90. Epub 2021 Mar 2.

Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. Electronic address:

PTEN and p53 are highly mutated in many cancers. These two tumor suppressors have critical functions in the nucleus, such as DNA repair, cell cycle progression, and genome maintenance. However, the in vivo functional relationship of nuclear PTEN and p53 is unknown. Here, we analyzed the liver of mice in which nuclear PTEN and p53 are individually or simultaneously depleted. We found that nuclear PTEN loss greatly upregulates p53 expression upon oxidative stress, while the loss of p53 potentiates stress-induced accumulation of PTEN in the nucleus. Next, we examined oxidative stress-induced DNA damage in hepatocytes, and found that nuclear PTEN loss aggravated the damage while p53 loss did not. Notably, mice lacking nuclear PTEN had increased hepatocellular carcinoma under oxidative stress, while mice lacking p53 in hepatocytes had accelerated hepatocellular carcinoma and intrahepatic cholangiocarcinoma. The formation of cholangiocarcinoma appears to involve the transformation of hepatocytes into cholangiocarcinoma. Simultaneous loss of nuclear PTEN and p53 exacerbated both types of liver cancers. These data suggest that nuclear PTEN and p53 suppress liver cancers through distinct mechanisms.
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http://dx.doi.org/10.1016/j.bbrc.2021.02.093DOI Listing
March 2021

Bacterial-driven inflammation and mutant BRAF expression combine to promote murine colon tumorigenesis that is sensitive to immune checkpoint therapy.

Cancer Discov 2021 Feb 25. Epub 2021 Feb 25.

Medicine, Johns Hopkins University

Colorectal cancer (CRC) is multi-faceted with subtypes defined by genetic, histological, and immunologic features which are potentially influenced by inflammation, mutagens, and/or microbiota. CRCs with activating mutations in BRAF are associated with distinct clinical characteristics though the pathogenesis is not well understood. The Wnt-driven multiple intestinal neoplasia (MinApc[triangle]716/+) enterotoxigenic Bacteroides fragilis (ETBF) murine model is characterized by IL-17-dependent, distal colon adenomas. Herein, we report that addition of the BRAFV600E mutation to this model results in emergence of a distinct locus of mid-colon tumors. In ETBF-colonized BRAFV600ELgr5CreMin (BLM) mice, tumors have similarities to human BRAFV600E tumors, including histology, CpG island DNA hypermethylation, and immune signatures. In comparison to Min ETBF tumors, BLM ETBF tumors are infiltrated by CD8+ T cells, express interferon-gamma signatures, and are sensitive to anti-PDL1 treatment. These results provide direct evidence for critical roles of host genetic and microbiota interactions in CRC pathogenesis and sensitivity to immunotherapy.
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http://dx.doi.org/10.1158/2159-8290.CD-20-0770DOI Listing
February 2021

COVID-19 experience in mainland China: Nursing lessons for the United States of America.

Nurs Forum 2021 Feb 3. Epub 2021 Feb 3.

School of Nursing, The Hong Kong Polytechnic University, Hung Hom, Hong Kong.

COVID-19 emerged in Wuhan, China, and began its worldwide journey. As the severity of the virus became known, the Chinese National Government mobilized resources, and their centralized management was critical to the containment of the epidemic. Healthcare agencies and providers were overwhelmed with patients, many of whom were critically ill and died. Nurses adapted to the work using personal protective equipment, but its initial scarcity contributed to stressful working conditions. Nurses in the United States can take several lessons from the experiences of their Chinese nurse colleagues, including the benefit of centralized management of the epidemic, the need for specialized treatment facilities, and the importance of a national stockpile of critical equipment and supplies. A fully funded United States Department of Health and Human Services Office of Pandemics and Emerging Threats is necessary. A nursing department within the office and a national mobilization plan to send nurses to support local efforts during a pandemic or other threat are likewise essential. Continuous training for nurses, especially caring for patients with infectious diseases in intensive care units, stress management, and how to comfort the dying, are also useful lessons.
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http://dx.doi.org/10.1111/nuf.12546DOI Listing
February 2021

A feasibility study of combined epigenetic and vaccine therapy in advanced colorectal cancer with pharmacodynamic endpoint.

Clin Epigenetics 2021 Feb 2;13(1):25. Epub 2021 Feb 2.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, 1650 Orleans Street, Office 4M10, Baltimore, MD, 21287, USA.

Epigenetic therapies may modulate the tumor microenvironment. We evaluated the safety and optimal sequence of combination DNA methyltransferase inhibitor guadecitabine with a granulocyte macrophage-colony-stimulating-factor (GM-CSF) secreting colon cancer (CRC) vaccine (GVAX) using a primary endpoint of change in CD45RO + T cells. 18 patients with advanced CRC enrolled, 11 underwent paired biopsies and were evaluable for the primary endpoint. No significant increase in CD45RO + cells was noted. Grade 3-4 toxicities were expected and manageable. Guadecitabine + GVAX was tolerable but demonstrated no significant immunologic activity in CRC. We report a novel trial design to efficiently evaluate investigational therapies with a primary pharmacodynamic endpoint.Trial registry Clinicaltrials.gov: NCT01966289. Registered 21 October, 2013.
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http://dx.doi.org/10.1186/s13148-021-01014-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856736PMC
February 2021

Vaccine-Induced Intratumoral Lymphoid Aggregates Correlate with Survival Following Treatment with a Neoadjuvant and Adjuvant Vaccine in Patients with Resectable Pancreatic Adenocarcinoma.

Clin Cancer Res 2021 Mar 4;27(5):1278-1286. Epub 2020 Dec 4.

Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Purpose: Immunotherapy is currently ineffective for nearly all pancreatic ductal adenocarcinomas (PDAC), largely due to its tumor microenvironment (TME) that lacks antigen-experienced T effector cells (Teff). Vaccine-based immunotherapies are known to activate antigen-specific Teffs in the peripheral blood. To evaluate the effect of vaccine therapy on the PDAC TME, we designed a neoadjuvant and adjuvant clinical trial of an irradiated, GM-CSF-secreting, allogeneic PDAC vaccine (GVAX).

Patients And Methods: Eighty-seven eligible patients with resectable PDAC were randomly assigned (1:1:1) to receive GVAX alone or in combination with two forms of low-dose cyclophosphamide. Resected tumors following neoadjuvant immunotherapy were assessed for the formation of tertiary lymphoid aggregates (TLA) in response to treatment. The clinical endpoints are disease-free survival (DFS) and overall survival (OS).

Results: The neoadjuvant treatment with GVAX either alone or with two forms of low-dose cyclophosphamide is safe and feasible without adversely increasing the surgical complication rate. Patients in Arm A who received neoadjuvant and adjuvant GVAX alone had a trend toward longer median OS (35.0 months) than that (24.8 months) in the historical controls who received adjuvant GVAX alone. However, Arm C, who received low-dose oral cyclophosphamide in addition to GVAX, had a significantly shorter DFS than Arm A. When comparing patients with OS > 24 months to those with OS < 15 months, longer OS was found to be associated with higher density of intratumoral TLA.

Conclusions: It is safe and feasible to use a neoadjuvant immunotherapy approach for PDACs to evaluate early biologic responses. In-depth analysis of TLAs is warranted in future neoadjuvant immunotherapy clinical trials.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925374PMC
March 2021

Integrated immunological analysis of a successful conversion of locally advanced hepatocellular carcinoma to resectability with neoadjuvant therapy.

J Immunother Cancer 2020 11;8(2)

Department of Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer death worldwide with a minority of patients being diagnosed early enough for curative-intent interventions. We report the first use of preoperative cabozantinib plus nivolumab to successfully downstage what presented as unresectable HCC as part of an ongoing phase 1b study. Preoperative treatment with cabozantinib and nivolumab led to >99% reduction in alpha-fetoprotein, -37.3% radiographic reduction by RECIST 1.1 and a near complete pathologic response (80% to 100% necrosis). An integrated immunological analysis was performed on the post-treatment surgical tumor sample and matched pre-treatment and post-treatment peripheral blood samples with high-dimensional imaging and cytometry techniques. Bayesian non-negative matrix factorization (CoGAPS, Coordinated Gene Activity in Pattern Sets) and self-organizing map (FlowSOM) algorithms were used to distinguish changes in functional markers across cellular neighborhoods in the single cell data sets. Brisk immunological infiltration into the tumor microenvironment was observed in non-random, organized cellular neighborhoods. Systemically, combination therapy led to marked promotion of effector cytotoxic T cells and effector memory helper T cells. Natural killer cells also increased with therapy. The patient remains without disease recurrence and with a normal alpha-fetoprotein approximately 2 years from presentation. Our study provides proof-of-concept that borderline resectable or locally advanced HCC warrants consideration of downstaging with effective neoadjuvant systemic therapy for subsequent curative resection.
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http://dx.doi.org/10.1136/jitc-2020-000932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682468PMC
November 2020

Challenges of the current precision medicine approach for pancreatic cancer: A single institution experience between 2013 and 2017.

Cancer Lett 2021 Jan 28;497:221-228. Epub 2020 Oct 28.

The Pancreatic Cancer "Precision Medicine" Program, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA. Electronic address:

Recent research on genomic profiling of pancreatic ductal adenocarcinoma (PDAC) has identified many potentially actionable alterations. However, the feasibility of using genomic profiling to guide routine clinical decision making for PDAC patients remains unclear. We retrospectively reviewed PDAC patients between October 2013 and December 2017, who underwent treatment at the Johns Hopkins Hospital and had clinical tumor next-generation sequencing (NGS) through commercial resources. Ninety-two patients with 93 tumors tested were included. Forty-eight (52%) patients had potentially curative surgeries. The median time from the tissue available to the NGS testing ordered was 229 days (interquartile range 62-415). A total of three (3%) patients had matched targeted therapies based on genomic profiling results. Genomic profiling guided personalized treatment for PDAC patients is feasible, but the percentage of patients who receive targeted therapy is low. The main challenges are ordering NGS testing early in the clinical course of the disease and the limited evidence of using a targeted approach in these patients. A real-time department level genomic testing ordering system in combination with an evidence-based flagging system for potentially actionable alterations could help address these shortcomings.
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http://dx.doi.org/10.1016/j.canlet.2020.10.039DOI Listing
January 2021

What can we learn from U.S. military nursing and COVID-19?

Authors:
Robert L Anders

Nurs Inq 2020 10;27(4):e12384

University of Texas at El Paso, El Paso, TX, USA.

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http://dx.doi.org/10.1111/nin.12384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645919PMC
October 2020

The Loss of Nuclear PTEN Increases Tumorigenesis in a Preclinical Mouse Model for Hepatocellular Carcinoma.

iScience 2020 Oct 10;23(10):101548. Epub 2020 Sep 10.

Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

The gene is highly mutated in many cancers, including hepatocellular carcinoma. The PTEN protein is located at different subcellular regions-PTEN at the plasma membrane suppresses PI3-kinase signaling in cell growth, whereas PTEN in the nucleus maintains genome integrity. Here, using nuclear PTEN-deficient mice, we analyzed the role of PTEN in the nucleus in hepatocellular carcinoma that is induced by carcinogen and oxidative stress-producing hepatotoxin. Upon oxidative stress, PTEN was accumulated in the nucleus of the liver, and this accumulation promoted repair of DNA damage in wild-type mice. In contrast, nuclear PTEN-deficient mice had increased DNA damage and accelerated hepatocellular carcinoma formation. Both basal and oxidative stress-induced localization of PTEN in the nucleus require ubiquitination of lysine 13 in PTEN. Taken together, these data suggest the critical role of nuclear PTEN in the protection from DNA damage and tumorigenesis .
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http://dx.doi.org/10.1016/j.isci.2020.101548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516300PMC
October 2020

Engaging nurses in health policy in the era of COVID-19.

Authors:
Robert L Anders

Nurs Forum 2021 Jan 6;56(1):89-94. Epub 2020 Oct 6.

School of Nursing, University of Texas, El Paso, Texas, USA.

Nurses have a unique place in redesigning the future of healthcare, particularly after experiencing health policy failures with the coronavirus disease 2019 pandemic. Nurses consistently outperform other professions to enjoy a decades-long reputation as the most trusted profession. Nevertheless, the nursing voice is missing at a public level; representation in governments and boardrooms negligible. While nurses carry out health policy, rarely are they involved informing policy. While substantial dialog on health system reform, regulatory changes, care coordination, and health information technology occurs, nursing's presence is absent. The barriers are many: a lack of political sophistication, family, and work demands limiting time, and a lack of confidence. Using the Yoder-Wise Framework for Planned Policy Change, opportunities for engagement at each step in the process are made clear. Workplace opportunities provide entry-level representation and exposure to the machinations of governance. Nursing professional associations provide similar opportunities. For many nurses, social media, while not without its risks, offers a familiar and accessible platform by which to engage patients, the public, and policymakers in planned, strategic steps to create policy change and improve healthcare for patients.
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http://dx.doi.org/10.1111/nuf.12514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675349PMC
January 2021

Bariatric Arterial Embolization with Calibrated Radiopaque Microspheres and an Antireflux Catheter Suppresses Weight Gain and Appetite-Stimulating Hormones in Swine.

J Vasc Interv Radiol 2020 Sep 14;31(9):1483-1491. Epub 2020 Aug 14.

Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Purpose: To examine safety and efficacy of bariatric arterial embolization (BAE) with x-ray-visible embolic microspheres (XEMs) and an antireflux catheter in swine.

Material And Methods: BAE with selective infusion of XEMs (n = 6) or saline (n = 4, control) into gastric fundal arteries was performed under x-ray guidance. Weight and plasma hormone levels were measured at baseline and weekly for 4 weeks after embolization. Cone-beam CT images were acquired immediately after embolization and weekly for 4 weeks. Hormone-expressing cells in the stomach were assessed by immunohistochemical staining.

Results: BAE pigs lost weight 1 week after embolization followed by significantly impaired weight gain relative to control animals (14.3% vs 20.9% at 4 weeks, P = .03). Plasma ghrelin levels were significantly lower in BAE pigs than in control animals (1,221.6 pg/mL vs 1,706.2 pg/mL at 4 weeks, P < .01). XEMs were visible on x-ray and cone-beam CT during embolization, and radiopacity persisted over 4 weeks (165.5 HU at week 1 vs 158.5 HU at week 4, P = .9). Superficial mucosal ulcerations were noted in 1 of 6 BAE animals. Ghrelin-expressing cell counts were significantly lower in the gastric fundus (17.7 vs 36.8, P < .00001) and antrum (24.2 vs 46.3, P < .0001) of BAE pigs compared with control animals. Gastrin-expressing cell counts were markedly reduced in BAE pigs relative to control animals (98.5 vs 127.0, P < .02). Trichrome staining demonstrated significantly more fibrosis in BAE animals compared with control animals (13.8% vs 8.7%, P < .0001).

Conclusions: XEMs enabled direct visualization of embolic material during and after embolization. BAE with XEMs and antireflux microcatheters was safe and effective.
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http://dx.doi.org/10.1016/j.jvir.2020.04.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483389PMC
September 2020

Lesson learned from China regarding use of personal protective equipment.

Am J Infect Control 2020 12 11;48(12):1462-1465. Epub 2020 Aug 11.

Department of Plastic Surgery, Fujian Medical University Union Hospital, Fujian Medical University, Fuzhou, China.

Background: In Wuhan, China, in December 2019, the novel coronavirus was detected. The virus causing COVID-19 was related to a coronavirus named severe acute respiratory syndrome coronavirus (SARS-CoV). The virus caused an epidemic in China and was quickly contained in 2003. Although coming from the same family of viruses and sharing certain transmissibility factors, the local health institutions in China had no experience with this new virus, subsequently named SARS-CoV-2.

Methods: Based on their prior experience with the 2003 SARS epidemic, health authorities in China recognized the need for personal protective equipment (PPE). Existing PPE and protocols were limited and reflected early experience with SARS; however, as additional PPE supplies became available, designated COVID-19 hospitals in Hubei Province adopted the World Health Organization guidelines for Ebola to create a protocol specific for treating patients with COVID-19.

Results: This article describes the PPE and protocol for its safe and effective deployment and the implementation of designated hospital units for COVID-19 patients. To date, only 2 nurses working in China who contracted SARS-CoV-2 have died from COVID-19 in the early period of the epidemic (February 11 and 14, 2020).

Conclusions: The lessons learned by health care workers in China are shared in the hope of preventing future occupational exposure.
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http://dx.doi.org/10.1016/j.ajic.2020.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417913PMC
December 2020

A Phase II Study of Allogeneic GM-CSF-Transfected Pancreatic Tumor Vaccine (GVAX) with Ipilimumab as Maintenance Treatment for Metastatic Pancreatic Cancer.

Clin Cancer Res 2020 Oct 26;26(19):5129-5139. Epub 2020 Jun 26.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, The Skip Viragh Center for Pancreas Cancer Clinical Research and Patient Care, and The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins University School of Medicine, Baltimore, Maryland.

Purpose: This phase II study tested granulocyte-macrophage colony-stimulating factor (GM-CSF)-allogeneic pancreatic tumor cells (GVAX) and ipilimumab in metastatic pancreatic ductal adenocarcinoma (PDA) in the maintenance setting.

Patients And Methods: Patients with PDA who were treated with front-line chemotherapy consisting of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) in the metastatic setting and had ongoing response or stable disease after 8-12 doses were eligible. Patients were randomized 1:1 to treatment with GVAX and ipilimumab given every 3 weeks for four doses then every 8 weeks (Arm A) or to FOLFIRINOX continuation (Arm B). The primary objective was to compare overall survival (OS) between the two arms.

Results: Eighty-two patients were included in the final analysis (Arm A: 40; Arm B: 42). The study was stopped for futility after interim analysis. Median OS was 9.38 months [95% confidence interval (CI), 5.0-12.2] for Arm A and 14.7 months (95% CI, 11.6-20.0) for Arm B (HR, 1.75; = 0.019). Using immune-related response criteria, two partial responses (5.7%) were observed in Arm A and four (13.8%) in Arm B. GVAX + ipilimumab promoted T-cell differentiation into effector memory phenotypes both in the periphery and in the tumor microenvironment and increased M1 macrophages in the tumor.

Conclusions: GVAX and ipilimumab maintenance therapy did not improve OS over continuation of chemotherapy and resulted in a numerically inferior survival in metastatic PDA. However, clinical responses and biological effects on immune cells were observed. Further study of novel combinations in the maintenance treatment of metastatic PDA is feasible.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541669PMC
October 2020

Inhibition of miR-21 Regulates Mutant KRAS Effector Pathways and Intercepts Pancreatic Ductal Adenocarcinoma Development.

Cancer Prev Res (Phila) 2020 07 14;13(7):569-582. Epub 2020 May 14.

Department of Oncology, Skip Viragh Center for Pancreas Cancer, Bloomberg Kimmel Institute for Cancer Immunotherapy, and the Sidney Kimmel Cancer Center at Johns Hopkins University School of Medicine, Baltimore, Maryland.

Almost all pancreatic ductal adenocarcinomas (PDA) develop following KRAS activation, which triggers epithelial transformation and recruitment of desmoplastic stroma through additional transcriptional and epigenetic regulation, but only a few of these regulatory mechanisms have been described. We profiled dysregulated miRNAs starting with the earliest premalignant pancreatic intraepithelial neoplasias (PanIN) in genetically engineered mutated KRAS and P53 (KPC) mice programmed to recapitulate human PDA tumorigenesis. We identified miR-21 and miR-224 as cell-specific and compartment-specific regulators in PanINs and PDA. miR-21 is overexpressed in tumor epithelial cells of premalignant ducts, while miR-224 is overexpressed in cancer-associated fibroblasts in PDA stroma. Inhibition of miR-21 reverted protumorigenic functionalities to baseline levels. Overexpression of miR-224 induced activated phenotypes in normal fibroblasts. miR-21 inhibition improved survival in established PDA. Importantly, early systemic miR-21 inhibition completely intercepted premalignant progression. Finally, an evaluation of miR-21 expression in the PDA cohort of The Cancer Genome Atlas identified a correlation between tumor epithelial cell content and miR-21 expression in human tumors providing further rationale for conducting human studies. Thus, miR-21 may be useful for early PanIN detection, and for intercepting developing premalignant pancreatic lesions and other KRAS-driven premalignancies.
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http://dx.doi.org/10.1158/1940-6207.CAPR-20-0053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372516PMC
July 2020

The Immunosuppressive Niche of Soft-Tissue Sarcomas is Sustained by Tumor-Associated Macrophages and Characterized by Intratumoral Tertiary Lymphoid Structures.

Clin Cancer Res 2020 Aug 24;26(15):4018-4030. Epub 2020 Apr 24.

Departement of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD.

Purpose: Clinical trials with immune checkpoint inhibition in sarcomas have demonstrated minimal response. Here, we interrogated the tumor microenvironment (TME) of two contrasting soft-tissue sarcomas (STS), rhabdomyosarcomas and undifferentiated pleomorphic sarcomas (UPS), with differing genetic underpinnings and responses to immune checkpoint inhibition to understand the mechanisms that lead to response.

Experimental Design: Utilizing fresh and formalin-fixed, paraffin-embedded tissue from patients diagnosed with UPS and rhabdomyosarcomas, we dissected the TME by using IHC, flow cytometry, and comparative transcriptomic studies.

Results: Our results demonstrated both STS subtypes to be dominated by tumor-associated macrophages and infiltrated with immune cells that localized near the tumor vasculature. Both subtypes had similar T-cell densities, however, their distribution diverged. UPS specimens demonstrated diffuse intratumoral infiltration of T cells, while rhabdomyosarcomas samples revealed intratumoral T cells that clustered with B cells near perivascular beds, forming tertiary lymphoid structures (TLS). T cells in UPS specimens were comprised of abundant CD8 T cells exhibiting high PD-1 expression, which might represent the tumor reactive repertoire. In rhabdomyosarcomas, T cells were limited to TLS, but expressed immune checkpoints and immunomodulatory molecules which, if appropriately targeted, could help unleash T cells into the rest of the tumor tissue.

Conclusions: Our work in STS revealed an immunosuppressive TME dominated by myeloid cells, which may be overcome with activation of T cells that traffic into the tumor. In rhabdomyosarcomas, targeting T cells found within TLS may be key to achieve antitumor response.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3416DOI Listing
August 2020

Who speaks for nursing? COVID-19 highlighting gaps in leadership.

J Clin Nurs 2020 08 27;29(15-16):2751-2752. Epub 2020 May 27.

Dean and Professor, School of Nursing, Johns Hopkins University, Baltimore, USA.

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http://dx.doi.org/10.1111/jocn.15305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264653PMC
August 2020

Evaluation of Cyclophosphamide/GVAX Pancreas Followed by Listeria-Mesothelin (CRS-207) with or without Nivolumab in Patients with Pancreatic Cancer.

Clin Cancer Res 2020 Jul 9;26(14):3578-3588. Epub 2020 Apr 9.

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.

Purpose: Two studies in previously treated metastatic pancreatic cancer have been completed combining GVAX pancreas vaccine (GM-CSF-secreting allogeneic pancreatic tumor cells) with cyclophosphamide (Cy) and CRS-207 (live, attenuated -expressing mesothelin). In the current study, we compared Cy/GVAX followed by CRS-207 with (Arm A) or without nivolumab (Arm B).

Patients And Methods: Patients with pancreatic adenocarcinoma who received one prior therapy for metastatic disease and RECIST measurable disease were randomized 1:1 to receive treatment on Arm A or Arm B. The primary objective was to compare overall survival (OS) between the arms. Additional objectives included assessment of progression-free survival, safety, tumor responses, CA19-9 responses, and immunologic correlates.

Results: Ninety-three patients were treated (Arm A, 51; Arm B, 42). The median OS in Arms A and B were 5.9 [95% confidence interval (CI), 4.7-8.6] and 6.1 (95% CI, 3.5-7.0) months, respectively, with an HR of 0.86 (95% CI, 0.55-1.34). Objective responses were seen in 3 patients using immune-related response criteria (4%, 2/51, Arm A; 2%, 1/42, Arm B). The grade ≥3 related adverse event rate, whereas higher in Arm A (35.3% vs. 11.9%) was manageable. Changes in the microenvironment, including increase in CD8 T cells and a decrease in CD68 myeloid cells, were observed in long-term survivors in Arm A only.

Conclusions: Although the study did not meet its primary endpoint of improvement in OS of Arm A over Arm B, the OS was comparable with standard therapy. Objective responses and immunologic changes in the tumor microenvironment were evident.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727397PMC
July 2020

Regenerative hepatic pseudotumor: a new pseudotumor of the liver.

Hum Pathol 2020 05 25;99:43-52. Epub 2020 Mar 25.

Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, USA, 55905.

Cases of new pseudotumors of the liver were collected from multiple medical centers. Four resection and 4 biopsy specimens were collected, including 4 women and 4 men at an average age of 48 ± 15 years (range: 28-73 years). The lesions were visible on imaging but were either ill-defined or had indeterminate features for characterization. They ranged in size from 2 to 9 cm and were multiple in five cases. The resection specimens showed lesions that had vague borders but were visible in juxtaposition to the normal liver on gross examination. Histologically, the lesions also had ill-defined borders and were composed of benign reactive liver parenchyma. Central vein thrombi were seen in 5 cases, and portal vein thrombi, in 2 cases. These vascular changes were associated reactive parenchymal changes including sinusoidal dilation, patchy bile ductular proliferation, and portal vein abnormalities. All lesions lacked the histological findings of hepatic adenomas, focal nodular hyperplasia, or other known tumors and pseudotumors of the liver. In summary, this study provides a detailed description of a new pseudotumor of the liver: a reactive, hyperplastic mass-like lesion that forms in association with localized vascular thrombi, for which we propose the term regenerative hepatic pseudotumor. This lesion can closely mimic other benign or malignant hepatic tumors on imaging and histology.
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http://dx.doi.org/10.1016/j.humpath.2020.03.010DOI Listing
May 2020

Role of baseline volumetric functional MRI in predicting histopathologic grade and patients' survival in hepatocellular carcinoma.

Eur Radiol 2020 Jul 6;30(7):3748-3758. Epub 2020 Mar 6.

Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital, Baltimore, MD, USA.

Objectives: We aimed to evaluate the role of volumetric ADC (vADC) and volumetric venous enhancement (vVE) in predicting the grade of tumor differentiation in hepatocellular carcinoma (HCC).

Methods: The study population included 136 HCC patients (188 lesions) who had baseline MR imaging and histopathological report. Measurements of vVE and vADC were performed on baseline MRI. Tumors were histologically classified into low-grade and high-grade groups. The parameters between the two groups were compared using Mann-Whitney U and chi-square tests for continuous and categorical parameters, respectively. Area under receiver operating characteristic (AUROC) was calculated to investigate the accuracy of vADC and vVE. Logistic regression and multivariable Cox regression were used to unveil the potential parameters associated with high-grade HCC and patient's survival, respectively.

Results: Lesions with higher vADC values and a higher absolute vADC skewness were more likely to be high grade on histopathology assessment (p = 0.001 and p = 0.0291, respectively). Also, vVE showed a trend to be higher in low-grade lesions (p = 0.079). Adjusted multivariable model including vADC, vVE, and vADC skewness could strongly predict HCC degree of differentiation (AUROC = 83%). Additionally, a higher Child-Pugh score (HR = 2.39 [p = 0.02] for score 2 and HR = 3.47 [p = 0.001] for score 3), vADC skewness (HR = 1.52, p = 0.02; per increments in skewness), and tumor volume (HR = 1.1, p = 0.001; per 100 cm increments) showed the highest association with patients' survival.

Conclusions: vADC and vVE have the potential to accurately predict HCC differentiation. Additionally, some imaging features in combination with patients' clinical characteristics can predict patient survival.

Key Points: • Volumetric functional MRI metrics can be considered as non-invasive measures for determining tumor histopathology in HCC. • Estimating patient survival based on clinical and imaging parameters can be used for modifying management approach and preventing unnecessary adverse events.
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http://dx.doi.org/10.1007/s00330-020-06742-8DOI Listing
July 2020

A phase 2 study of GVAX colon vaccine with cyclophosphamide and pembrolizumab in patients with mismatch repair proficient advanced colorectal cancer.

Cancer Med 2020 02 26;9(4):1485-1494. Epub 2019 Dec 26.

Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Mismatch repair proficient (MMRp) colorectal cancer (CRC) has been refractory to single-agent programmed cell death protein 1 (PD1) inhibitor therapy. Colon GVAX is an allogeneic, whole-cell, granulocyte-macrophage colony-stimulating factor -secreting cellular immunotherapy that induces T-cell immunity against tumor-associated antigens and has previously been studied in combination with low-dose cyclophosphamide (Cy) to inhibit regulatory T cells.

Methods: We conducted a single-arm study of GVAX/Cy in combination with the PD1 inhibitor pembrolizumab in patients with advanced MMRp CRC. Patients received pembrolizumab plus Cy on day 1, GVAX on day 2, of a 21-day cycle. The primary endpoint was the objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary objectives included safety, overall survival, progression-free survival, changes in carcinoembryonic antigen (CEA) levels, and immune-related correlates.

Results: Seventeen patients were enrolled. There were no objective responses, and the disease control rate was 18% by RECIST 1.1. The median progression-free survival was 82 days (95% confidence interval [CI], 48-97 days) and the median overall survival was 213 days (95% CI 179-441 days). Biochemical responses (≥30% decline in CEA) were observed in 7/17 (41%) of patients. Grade ≥ 3 treatment-related adverse events were observed in two patients (hemolytic anemia and corneal transplant rejection). Paired pre- and on-treatment biopsy specimens showed increases in programmed death-ligand 1 expression and tumor necrosis in a subset of patients.

Conclusions: GVAX/Cy plus pembrolizumab failed to meet its primary objective in MMRp CRC. Biochemical responses were observed in a subset of patients and have not previously been observed with pembrolizumab monotherapy in MMRp CRC, indicating that GVAX may modulate the antitumor immune response.
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http://dx.doi.org/10.1002/cam4.2763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013064PMC
February 2020

Phase 2 study of vismodegib, a hedgehog inhibitor, combined with gemcitabine and nab-paclitaxel in patients with untreated metastatic pancreatic adenocarcinoma.

Br J Cancer 2020 02 20;122(4):498-505. Epub 2019 Dec 20.

Department of Medical Oncology, Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, MD, USA.

Background: The Hedgehog (Hh) signalling pathway is overexpressed in pancreatic ductal adenocarcinoma (PDA). Preclinical studies have shown that Hh inhibitors reduce pancreatic cancer stem cells (pCSC), stroma and Hh signalling.

Methods: Patients with previously untreated metastatic PDA were treated with gemcitabine and nab-paclitaxel. Vismodegib was added starting on the second cycle. The primary endpoint was progression-free survival (PFS) as compared with historical controls. Tumour biopsies to assess pCSC, stroma and Hh signalling were obtained before treatment and after cycle 1 (gemcitabine and nab-paclitaxel) or after cycle 2 (gemcitabine and nab-paclitaxel plus vismodegib).

Results: Seventy-one patients were enrolled. Median PFS and overall survival (OS) were 5.42 months (95% confidence interval [CI]: 4.37-6.97) and 9.79 months (95% CI: 7.85-10.97), respectively. Of the 67 patients evaluable for response, 27 (40%) had a response: 26 (38.8%) partial responses and 1 complete response. In the tumour samples, there were no significant changes in ALDH + pCSC following treatment.

Conclusions: Adding vismodegib to chemotherapy did not improve efficacy as compared with historical rates observed with chemotherapy alone in patients with newly diagnosed metastatic pancreatic cancer. This study does not support the further evaluation of Hh inhibitors in this patient population.

Trial Registration: ClinicalTrials.gov Identifier: NCT01088815.
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http://dx.doi.org/10.1038/s41416-019-0683-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029016PMC
February 2020

The number of microspheres in Y90 radioembolization directly affects normal tissue radiation exposure.

Eur J Nucl Med Mol Imaging 2020 04 18;47(4):816-827. Epub 2019 Nov 18.

Department of Radiology, Division of Vascular and Interventional Radiology, The Johns Hopkins Hospital, Baltimore, MD, USA.

Purpose: In Y90 radioembolization, the number of microspheres infused varies by more than a factor of 20 over the shelf-life of the glass radioembolization device. We investigated the effect of the number of Y90 microspheres on normal liver tissue.

Method: Healthy pigs received lobar radioembolization with glass Y90 microspheres at 4, 8, 12, and 16 days post-calibration, representing a > 20× range in the number of microspheres deposited per milliliter in tissue. Animals were survived for 1-month post-treatment and the livers were explanted and scanned on a micro CT system to fully characterize the microscopic distribution of individual microspheres. A complete 3D microdosimetric evaluation of each liver was performed with a spatially correlated analysis of histopathologic effect.

Results: Through whole-lobe microscopic identification of each microsphere, a consistent number of microspheres per sphere cluster was found at 4, 8, and 12 days postcalibration, despite an 8-fold increase in total microspheres infused from days 4 to 12. The additional microspheres instead resulted in more clusters formed and, therefore, a more homogeneous microscopic absorbed dose. The increased absorbed-dose homogeneity resulted in a greater volume fraction of the liver receiving a potentially toxic absorbed dose based on radiobiologic models. Histopathologic findings in the animals support a possible increase in normal liver toxicity in later treatments with more spheres (i.e., ≥ day 12) compared to early treatments with less spheres (i.e., ≤ day 8).

Conclusion: The microdosimetric evidence presented supports a recommendation of caution when treating large volumes (e.g., right lobe) using glass Y microspheres at more than 8 days post-calibration, i.e., after "2nd week" Monday. The favorable normal tissue microscopic distribution and associated low toxicity of first week therapies may encourage opportunities for dose escalation with glass microspheres and could also be considered for patients with decreased hepatic reserve.
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http://dx.doi.org/10.1007/s00259-019-04588-xDOI Listing
April 2020

Pan-Tumor Pathologic Scoring of Response to PD-(L)1 Blockade.

Clin Cancer Res 2020 02 31;26(3):545-551. Epub 2019 Oct 31.

Department of Dermatology at Johns Hopkins University School of Medicine, Baltimore, Maryland.

Purpose: Pathologic response assessment of tumor specimens from patients receiving systemic treatment provides an early indication of therapeutic efficacy and predicts long-term survival. Grading systems for pathologic response were first developed for chemotherapy in select tumor types. Immunotherapeutic agents have a mechanism of action distinct from chemotherapy and are being used across a broad array of tumor types. A standardized, universal scoring system for pathologic response that encompasses features characteristic for immunotherapy and spans tumor types is needed.

Experimental Design: Hematoxylin and eosin-stained slides from neoadjuvant surgical resections and on-treatment biopsies were assessed for features of immune-related pathologic response (irPR). A total of 258 specimens from patients with 11 tumor types as part of ongoing clinical trials for anti-PD-(L)1 were evaluated. An additional 98 specimens from patients receiving anti-PD-(L)1 in combination with other treatments were also reviewed, including those from three additional tumor types.

Results: Common irPR features (immune activation, cell death, tissue repair, and regression bed) were present in all tumor types reviewed, including melanoma, non-small cell lung, head and neck squamous cell, Merkel cell, and renal cell carcinoma, among others. Features were consistent across primary tumors, lymph nodes, and distant metastases. Specimens from patients treated with anti-PD-(L)1 in combination with another agent also exhibited irPR features.

Conclusions: irPR features are consistent across tumor types and treatment settings. Standardized, pan-tumor irPR criteria (irPRC) are defined and associated specimen-handling considerations are described. Future, prospective studies are merited to validate irPRC in larger datasets and to associate pathologic features with long-term patient outcomes.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002263PMC
February 2020

Detection of Novel Fusion Transcript VTI1A-CFAP46 in Hepatocellular Carcinoma.

Gastrointest Tumors 2019 Aug 10;6(1-2):11-27. Epub 2019 Apr 10.

Division of Gastroenterology and Hepatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Background: Hepatocellular carcinoma (HCC) is now the second-highest cause of cancer death worldwide. Recent studies have discovered a wide range of somatic mutations in HCC. These mutations involve various vital signaling pathways such as: Wnt/-Catenin, p53, telome-rase reverse transcriptase (TERT), chromatin remodeling, RAS/MAPK signaling, and oxidative stress. However, fusion transcripts have not been broadly explored in HCC.

Methods: To identify novel fusion transcripts in HCC, in the first phase of our study, we performed targeted RNA sequencing (in HCC and paired non-HCC tissues) on 6 patients with a diagnosis of HCC undergoing liver transplantation.

Results: As a result of these studies, we discovered the novel fusion transcript, VTI1A-CFAP46. In the second phase of our study, we measured the expression of wild-type VTI1A in 21 HCC specimens, which showed that 10 of 21 exhibited upregulation of wild-type VTI1A in their tumors. VTI1A (Vesicle Transport via Interaction with t-SNARE homolog 1A) is a member of the Soluble N-ethylmaleimide-Sensitive Factor (NSF) attachment protein receptor (SNARE) gene family, which is essential for membrane trafficking and function in endocytosis, autophagy, and Golgi transport. Notably, it is known that autophagy is involved in HCC.

Conclusions: The link between novel fusion transcript VTI1A-CFAP46 and autophagy as a potential therapeutic target in HCC patients deserves further investigation. Moreover, this study shows that fusion transcripts are worthy of additional exploration in HCC.
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http://dx.doi.org/10.1159/000496795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738276PMC
August 2019

Noninvasive Detection of Microsatellite Instability and High Tumor Mutation Burden in Cancer Patients Treated with PD-1 Blockade.

Clin Cancer Res 2019 12 10;25(23):7024-7034. Epub 2019 Sep 10.

Personal Genome Diagnostics, Baltimore, Maryland.

Purpose: Microsatellite instability (MSI) and high tumor mutation burden (TMB-High) are promising pan-tumor biomarkers used to select patients for treatment with immune checkpoint blockade; however, real-time sequencing of unresectable or metastatic solid tumors is often challenging. We report a noninvasive approach for detection of MSI and TMB-High in the circulation of patients.

Experimental Design: We developed an approach that utilized a hybrid-capture-based 98-kb pan-cancer gene panel, including targeted microsatellite regions. A multifactorial error correction method and a novel peak-finding algorithm were established to identify rare MSI frameshift alleles in cell-free DNA (cfDNA).

Results: Through analysis of cfDNA derived from a combination of healthy donors and patients with metastatic cancer, the error correction and peak-finding approaches produced a specificity of >99% ( = 163) and sensitivities of 78% ( = 23) and 67% ( = 15), respectively, for MSI and TMB-High. For patients treated with PD-1 blockade, we demonstrated that MSI and TMB-High in pretreatment plasma predicted progression-free survival (hazard ratios: 0.21 and 0.23, = 0.001 and 0.003, respectively). In addition, we analyzed cfDNA from longitudinally collected plasma samples obtained during therapy to identify patients who achieved durable response to PD-1 blockade.

Conclusions: These analyses demonstrate the feasibility of noninvasive pan-cancer screening and monitoring of patients who exhibit MSI or TMB-High and have a high likelihood of responding to immune checkpoint blockade..
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892397PMC
December 2019

Immunopathologic Stratification of Colorectal Cancer for Checkpoint Blockade Immunotherapy.

Cancer Immunol Res 2019 10 22;7(10):1574-1579. Epub 2019 Aug 22.

Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland.

Mismatch-repair deficiency in solid tumors predicts their response to PD-1 blockade. Based on this principle, pembrolizumab is approved as standard of care for patients with unresectable or metastatic microsatellite instability-high (MSI-H) cancer. Despite this success, a large majority of metastatic colorectal cancer patients are not MSI-H and do not benefit from checkpoint blockade treatment. Predictive biomarkers to develop personalized medicines and guide clinical trials are needed for these patients. We, therefore, asked whether immunohistologic stratification of metastatic colorectal cancer based on primary tumor PD-L1 expression associated with the presence or absence of extracellular mucin defines a subset of metastatic colorectal cancer patients who exhibit a preexisting antitumor immune response and who could potentially benefit from the checkpoint blockade. To address this, we studied 26 advanced metastatic colorectal cancer patients treated with pembrolizumab (NCT01876511). To stratify patients, incorporation of histopathologic characteristics (percentage of extracellular mucin) and PD-L1 expression at the invasive front were used to generate a composite score, the CPM (composite PD-L1 and mucin) score, which discriminated patients who exhibited clinical benefit (complete, partial, or stable disease) from those patients with progressive disease. When validated in larger cohorts, the CPM score in combination with MSI testing may guide immunotherapy interventions for colorectal cancer patient treatment.
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http://dx.doi.org/10.1158/2326-6066.CIR-18-0927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774859PMC
October 2019

Abundant Expression of Lysyl Oxidase-like 2 Protein in Intrahepatic Bile Ducts of Infants With Biliary Atresia.

J Pediatr Gastroenterol Nutr 2019 09;69(3):344-350

Department of Pediatrics.

Introduction: Biliary atresia (BA) is characterized by rapidly progressive inflammation and fibrosis of the biliary tract, which usually progresses despite surgical intervention (Kasai hepatoportoenterostomy). Lysyl oxidase-like (LOXL2) is an extracellular matrix enzyme that catalyzes the cross-linking of fibrillar collagen and elastin and is thought to play a crucial role in tissue fibrosis; anti-LOXL2 drugs have been shown to be antifibrotic in animals.

Objective: The aim of the study was to investigate the presence of LOXL2 in BA livers and hepatic and extrahepatic control tissues.

Methods: Liver wedge biopsies from infants with BA (n = 20) were obtained at Kasai, and were compared with non-BA livers (n = 20). Liver fibrosis was scored using the Ishak scale, and immunohistochemistry was performed using a commercially available polyclonal anti-LOXL2 antibody. The expression of LOXL2 was scored for intensity and for distribution of bile duct staining by a pathologist blinded to the diagnosis. Staining of LOXL2 in pediatric control tissue, muscle (n = 5), heart (n = 5), and bone (n = 10) was performed.

Results: Tissue from patients with BA abundantly expressed LOXL2 (intensity score 2.0 vs 1.4 [P ≤ 0.001]) for non-BA and distribution of bile duct-staining score of 3.0 versus 2.8 (P = 0.001) for non-BA. Fibrosis score of all BA samples was 4.2 versus 3.1 for non-BA. Nonhepatic pediatric tissue displayed minimal to no LOXL2 staining.

Conclusions: There is significant overexpression of LOXL2 in BA hepatic tissue with minimal expression in extrahepatic tissue. The over expression noted in human hepatic tissue at Kasai suggests the rationale for further investigation of anti-LOXL2 therapeutics in BA.
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http://dx.doi.org/10.1097/MPG.0000000000002414DOI Listing
September 2019

Targeting Mechanoresponsive Proteins in Pancreatic Cancer: 4-Hydroxyacetophenone Blocks Dissemination and Invasion by Activating MYH14.

Cancer Res 2019 09 29;79(18):4665-4678. Epub 2019 Jul 29.

Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Metastasis is complex, involving multiple genetic, epigenetic, biochemical, and physical changes in the cancer cell and its microenvironment. Cells with metastatic potential are often characterized by altered cellular contractility and deformability, lending them the flexibility to disseminate and navigate through different microenvironments. We demonstrate that mechanoresponsiveness is a hallmark of pancreatic cancer cells. Key mechanoresponsive proteins, those that accumulate in response to mechanical stress, specifically nonmuscle myosin IIA (MYH9) and IIC (MYH14), α-actinin 4, and filamin B, were highly expressed in pancreatic cancer as compared with healthy ductal epithelia. Their less responsive sister paralogs-myosin IIB (MYH10), α-actinin 1, and filamin A-had lower expression differential or disappeared with cancer progression. We demonstrate that proteins whose cellular contributions are often overlooked because of their low abundance can have profound impact on cell architecture, behavior, and mechanics. Here, the low abundant protein MYH14 promoted metastatic behavior and could be exploited with 4-hydroxyacetophenone (4-HAP), which increased MYH14 assembly, stiffening cells. As a result, 4-HAP decreased dissemination, induced cortical actin belts in spheroids, and slowed retrograde actin flow. 4-HAP also reduced liver metastases in human pancreatic cancer-bearing nude mice. Thus, increasing MYH14 assembly overwhelms the ability of cells to polarize and invade, suggesting targeting the mechanoresponsive proteins of the actin cytoskeleton as a new strategy to improve the survival of patients with pancreatic cancer. SIGNIFICANCE: This study demonstrates that mechanoresponsive proteins become upregulated with pancreatic cancer progression and that this system of proteins can be pharmacologically targeted to inhibit the metastatic potential of pancreatic cancer cells.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-3131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744980PMC
September 2019

Comparison of Biomarker Modalities for Predicting Response to PD-1/PD-L1 Checkpoint Blockade: A Systematic Review and Meta-analysis.

JAMA Oncol 2019 Jul 18. Epub 2019 Jul 18.

Department of Dermatology, Johns Hopkins Medical Institutions, Baltimore, Maryland.

Importance: PD-L1 (programmed cell death ligand 1) immunohistochemistry (IHC), tumor mutational burden (TMB), gene expression profiling (GEP), and multiplex immunohistochemistry/immunofluorescence (mIHC/IF) assays have been used to assess pretreatment tumor tissue to predict response to anti-PD-1/PD-L1 therapies. However, the relative diagnostic performance of these modalities has yet to be established.

Objective: To compare studies that assessed the diagnostic accuracy of PD-L1 IHC, TMB, GEP, and mIHC/IF in predicting response to anti-PD-1/PD-L1 therapy.

Evidence Review: A search of PubMed (from inception to June 2018) and 2013 to 2018 annual meeting abstracts from the American Association for Cancer Research, American Society of Clinical Oncology, European Society for Medical Oncology, and Society for Immunotherapy of Cancer was conducted to identify studies that examined the use of PD-L1 IHC, TMB, GEP, and mIHC/IF assays to determine objective response to anti-PD-1/PD-L1 therapy. For PD-L1 IHC, only clinical trials that resulted in US Food and Drug Administration approval of indications for anti-PD-1/PD-L1 were included. Studies combining more than 1 modality were also included. Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines were followed. Two reviewers independently extracted the clinical outcomes and test results for each individual study.

Main Outcomes And Measures: Summary receiver operating characteristic (sROC) curves; their associated area under the curve (AUC); and pooled sensitivity, specificity, positive and negative predictive values (PPV, NPV), and positive and negative likelihood ratios (LR+ and LR-) for each assay modality.

Results: Tumor specimens representing over 10 different solid tumor types in 8135 patients were assayed, and the results were correlated with anti-PD-1/PD-L1 response. When each modality was evaluated with sROC curves, mIHC/IF had a significantly higher AUC (0.79) compared with PD-L1 IHC (AUC, 0.65, P < .001), GEP (AUC, 0.65, P = .003), and TMB (AUC, 0.69, P = .049). When multiple different modalities were combined such as PD-L1 IHC and/or GEP + TMB, the AUC drew nearer to that of mIHC/IF (0.74). All modalities demonstrated comparable NPV and LR-, whereas mIHC/IF demonstrated higher PPV (0.63) and LR+ (2.86) than the other approaches.

Conclusions And Relevance: In this meta-analysis, tumor mutational burden, PD-L1 IHC, and GEP demonstrated comparable AUCs in predicting response to anti-PD-1/PD-L1 treatment. Multiplex immunohistochemistry/IF and multimodality biomarker strategies appear to be associated with improved performance over PD-L1 IHC, TMB, or GEP alone. Further studies with mIHC/IF and composite approaches with a larger number of patients will be required to confirm these findings. Additional study is also required to determine the most predictive analyte combinations and to determine whether biomarker modality performance varies by tumor type.
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http://dx.doi.org/10.1001/jamaoncol.2019.1549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646995PMC
July 2019