Dear Label_Name,

Greetings! I hope you are well.

I am writing on behalf of an international publishing house, Science and Education Publishing, USA (http://www.sciepub.com).

Science and Education Publishing (SciEP) is a multidisciplinary open access publisher of Journals covering the fields of Science, Technology and Medicine. All SciEP publications are subject to high-quality peer review, editorial and production processes and are freely available online.

Welcome to the April, 2013 edition of SciEP newsletter, providing monthly summaries of articles on science & education related topics of interest to scientist and professionals. The mission of our journals is to provide an open access forum for publishing new findings on issues pertinent to scientific and academic field. We also invite you to submit original research papers, review articles, short reports, or case studies are considered for publication in our Multidisciplinary Journals.

American Journal of Public Health Research
DOI: 10.12691/ajphr-1-1-3

The Implementation of a Tele-Homecare System with Service Oriented Architecture and HL7 Message Transmission Standard
Ching-Sung Wang

American Journal of Medical and Biological Research
DOI: 10.12691/ajmbr-1-1-2

The Influence of Ethanol on Pyruvate Kinases Activity in Vivo, in Vitro, in Silico
Lelevich Sergey Vladimirovich, Khrustalev Vladislav Victorovich, Barkovsky Eugene Victorovich, Shedogubova Tatyana Aleksandrovna

American Journal of Medical Sciences and Medicine
DOI: 10.12691/ajmsm-1-1-1

Clinical and Histological Features in Wegener Granulomatosis
Li Cavoli Gioacchino, Passantino Rita, Bono Luisa, Tortorici Calogera, Ferrantelli Angelo, Giammarresi Carlo, Rotolo Ugo

American Journal of Infectious Diseases and Microbiology
DOI: 10.12691/ajidm-1-1-2

The Curse of Lymphatic Filariasis: Would the Continual Use of Diethylcarbamazine Eliminate this Scourge in Papua New Guinea?
Anne Lanham, Lillian Mwanri

We have released issues of some journals on February 2013.
American Journal of Public Health Research
American Journal of Medical Sciences and Medicine
American Journal of Medical and Biological Research
American Journal of Pharmacological Sciences
American Journal of Clinical Medicine Research
American Journal of Nursing Research
American Journal of Cancer Prevention
American Journal of Medicine Studies
American Journal of Infectious Diseases and Microbiology
American Journal of Cardiovascular Disease Research
American Journal of Biomedical Research
American Journal of Mechanical Engineering
American Journal of Microbiological Research
Journal of Preventive Medicine
American Journal of Food and Nutrition
American Journal of Hypertension Research
American Journal of Sports Science and Medicine
Journal of Cancer Research and Treatment
American Journal of Zoological Research
Journal of Biomedical Engineering and Technology
American Journal of Microbiological Research
Biomedical Science and Engineering

We are pleased to announce that submissions are now being accepted for peer review for all the journals across all our subject areas in SciEP.

Please submit your manuscript via our online submission system:
http://www.sciepub.com/author/signin

To unsubscribe from our mailing list, please click on the following link: unsubscribe

I am looking forward to hearing from you.

Kind regards,

David Rain
Email:join@sciepub.com
Science and Education Publishing (http://www.sciepub.com)

A Very Rare Case of Esophagitis Due to Nivolumab Immunotherapy

Sujata Sajjan*, Deepika Savant, Rebecca Thomas, Nina Haghi, Margaret Cho

Department of Pathology and Laboratory Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, 6 Ohio Drive, Suite 202, Lake Success, New York, 11042.

Abstract: A 72-year-old woman with Renal Cell Carcinoma, on Nivolumab therapy for extensive metastatic disease, presented with dysphagia. Endoscopy revealed Grade 2 esophagitis with biopsy confirming active esophagitis. There was no histological evidence of an infectious or lymphoproliferative etiology. Nivolumab-induced esophagitis was suspected, and the medication was discontinued. There was dramatic clinical improvement with steroids. Immune checkpoint inhibitors are novel immunotherapeutic agents designed to restore the patient’s own antitumor immune responses. Nivolumab, an IgG4 monoclonal antibody that acts as an inhibitor of programmed death-1, is currently approved for clinical use in treatment of advanced stage malignancies. As Nivolumab is increasingly used in clinical oncology due to its efficacy and better tolerance compared to other chemotherapeutic agents, we present the second reported case of Nivolumab-associated esophagitis. Pathologists and clinicians should be aware of this possible complication to ensure its timely diagnosis and management.

Keywords: nivolumab, esophagitis, immunotherapy, cancer chemotherapy

Received April 14, 2019; Revised May 18, 2019; Accepted June 01, 2019

Citation: Sujata Sajjan, Deepika Savant, Rebecca Thomas, Nina Haghi, Margaret Cho, A Very Rare Case of Esophagitis Due to Nivolumab Immunotherapy. American Journal of Medical Case Reports, 7 (6). 97-99. January 2019. doi:10.12691/ajmcr-7-6-1

1. Introduction

Recent advances in the understanding of immunology and cancer biology have resulted in the development of newer classes of drugs, specifically immunomodulatory therapy in the management of cancers. Nivolumab, an IgG4 monoclonal antibody that inhibits the programmed death-1 (PD-1) receptor, has revolutionized management of patients with cancer, and has been approved for treatment of metastatic melanoma, advanced non-small cell carcinoma (NSCLC) and renal cell carcinoma. As Nivolumab is increasingly used in oncology, the immune-related adverse events may be more frequently being observed. Therefore, early recognition of pathological injury is critical.

2. Case Report

A 72-year-old woman with stage 4 Renal Cell Carcinoma, status post nephrectomy with lung and liver metastases, on Nivolumab therapy for the last 9 months, presented with difficulty in swallowing both liquids and solids of one-week duration. There was no history of diarrhea, constipation, abdominal pain or fever. An upper gastrointestinal endoscopy revealed Grade 2 esophagitis (Figure 1).

Figure 1. Upper gastrointestinal endoscopy revealing Grade 2 esophagitis

Figure 2. Active esophagitis with intraepithelial lymphocytes, scattered eosinophils, and few neutrophils with dyskeratotic keratinocytes (H&E Original magnification × 400)

Figure 3. Granulation tissue with lymphocytes, plasma cells, neutrophils, and scattered eosinophils in the lamina propria (H&E Original magnification x 400)

Esophageal biopsy demonstrated active esophagitis with intraepithelial lymphocytes, scattered eosinophils and few neutrophils with dyskeratotic keratinocytes (Figure 2). Granulation tissue was present with lymphocytes, plasma cells, neutrophils, and scattered eosinophils in the lamina propria (Figure 3).

There was no histological evidence of fungal (Grocott's methenamine silver stain was negative) or viral infections (Cytomegalovirus immunostain and Epstein-Bar Virus-Encoded RNA (Ribonucleic Acid) In Situ Hybridization were negative). There was no evidence of a lymphoproliferative disorder; immunohistochemical stains showed a mixture of T-cells (CD3, CD5, Bcl-2, and CD43) and B-cells (CD20, Pax-5; negative for CD5, CD43); Cyclin D1 was negative; CD138 highlighted plasma cells which were polytypic (supported by kappa and lambda in situ hybridization). Nivolumab-induced esophagitis was suspected, and the medication was discontinued. There was a dramatic clinical improvement with initiation of steroids. The patient continued to do well and did not report dysphagia on follow up visits over the next two months.

3. Discussion

Targeted therapies acting on specific molecular targets are the new frontiers of cancer management. Immunotherapy is one such therapeutic approach in several malignancies such as non-small cell carcinoma of the lung, renal cell carcinoma, Hodgkin’s lymphoma and melanoma. Checkpoint inhibitors, like Pembrolizumab and Nivolumab are increasingly used in management of metastatic malignancies because of their greater efficacy and tolerance [1,2,3].

Nivolumab is a fully human immunoglobulin (IgG4) monoclonal antibody that interacts with the programmed death-1 (PD1), a cell surface transmembrane immune checkpoint receptor present on activated T-cells that plays a vital role in immune inhibition and antineoplastic activities. Blockade of the interaction of PDL1 with PD1 enhances immune function and mediates antitumor T-cell activity against tumor cells. Since the mechanism of action includes promoting T-cell responses, enhanced autoimmunity involving various organ systems, including the skin (rash and pruritus), gastrointestinal system (colitis and gastritis), endocrinopathies (hypophysitis, hypothyroidism), liver (hepatitis), kidneys (nephritis) and lungs (pneumonitis) are described side effects. [4,5,6,7] Unlike other are IgG1 subtype and cause antibody-related cell cytotoxicity.

Since Nivolumab is an IgG4 subtype of monoclonal antibody, it is not associated with antibody-related cell cytotoxicity, resulting in improved tolerance. In phase I human studies, skin (20%), gastrointestinal (15%), and pulmonary (9%) toxicities were observed, while in the phase II studies skin (31%), rash (12%), pruritus (9%), vitiligo (3%), gastrointestinal (11%), and pulmonary (3%) were reported. In general, toxicities with anti-PD-1 antibodies appear to be less common and less severe when compared with anti-CTLA-4 monoclonal antibodies [8,9,10]. Dermatologic toxicity is the most common immune-related adverse event associated with checkpoint inhibitors which is usually seen 3-4 weeks after the initiation of therapy. Diarrhea/colitis is the most common gastrointestinal symptom presenting approximately 6-8 weeks after the commencement of therapy. [2,8,9,10,11]

Boike et al. have previously reported endoscopic and histopathological features of esophagitis related to Nivolumab therapy. [2] They noted marked intraepithelial T-cell lymphocytic infiltrates with dyskeratotic keratinocytes. Similar to our case symptoms improved dramatically with steroid therapy. Nivolumab associated colitis is characterized by lymphocytic infiltration in the lamina propria and epithelium of the involved mucosa. In some cases, it is characterized by active colitis with neutrophilic crypt microabscesses, prominent crypt epithelial cell apoptosis and crypt atrophy/dropout. After exclusion of other etiologies, management includes initiation of corticosteroid therapy and cessation of Nivolumab in severe cases. [2,10] Interestingly, involvement of the rest of the gastrointestinal tract is rarely reported in the literature.

4. Conclusion

Advances in immuno-oncology have led to the development of newer immune-response-modifying agents like Nivolumab. Although promising, physicians and pathologists should be vigilant for toxicities associated with this medication, such as esophagitis, that will likely become more commonplace with the emergence of additional formulations and indications. Awareness of this clinical scenario should allow pathologists and physicians to facilitate its timely diagnosis and management.

Statement of Competing Interest

The authors declare that they have no competing interests.

References

[1]   | H. Semper, F. Mühlberg, J. Schulz-Menger, M. Allewelt, C. Grohé, Drug-induced myocarditis after nivolumab treatment in a patient with PDL-1-negative squamous cell carcinoma of the lung, in: Pneumologie, Georg Thieme Verlag KG, 2017: p. P127.
[2]   | J. Boike, T. Dejulio, Severe Esophagitis and Gastritis from Nivolumab Therapy, ACG Case Rep J. 4 (2017) e57.
[3]   | R. Neril, J. Lorton, J. Zonszein, Nivolumab-induced isolated adrenal insufficiency: a case report, AACE Clinical Case Reports. 3 (2016) e210-e212.
[4]   | J. Villadolid, A. Amin, Immune checkpoint inhibitors in clinical practice: update on management of immune-related toxicities, Transl Lung Cancer Res. 4 (2015) 560-575.
[5]   | V.A. Boussiotis, Molecular and Biochemical Aspects of the PD-1 Checkpoint Pathway, N Engl J Med. 375 (2016) 1767-1778.

[6]  
S.L. Topalian, M. Sznol, D.F. McDermott, H.M. Kluger, R.D. Carvajal, W.H. Sharfman, J.R. Brahmer, D.P. Lawrence, M.B. Atkins, J.D. Powderly, P.D. Leming, E.J. Lipson, I. Puzanov, D.C. Smith, J.M. Taube, J.M. Wigginton, G.D. Kollia, A. Gupta, D.M. Pardoll, J.A. Sosman, F.S. Hodi, Survival, Durable Tumor Remission, and Long-Term Safety in Patients With Advanced Melanoma Receiving Nivolumab, J Clin Oncol. 32 (2014) 1020-1030.

[7]   | D.E. Dolan, S. Gupta, PD-1 pathway inhibitors: changing the landscape of cancer immunotherapy, Cancer Control. 21 (2014) 231-237.
[8]   | J. Naidoo, D.B. Page, B.T. Li, L.C. Connell, K. Schindler, M.E. Lacouture, M.A. Postow, J.D. Wolchok, Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies, Ann. Oncol. 26 (2015) 2375-2391.
[9]   | J.H. Chen, M.K. Pezhouh, G.Y. Lauwers, R. Masia, Histopathologic Features of Colitis Due to Immunotherapy With Anti-PD-1 Antibodies, Am. J. Surg. Pathol. 41 (2017) 643-654.
[10]   | F.K. Akarca, O. Can, S. Yalcinli, Y.A. Altunci, Nivolumab, a new immunomodulatory drug, a new adverse effect; adrenal crisis, Turk J Emerg Med. 17 (2017) 157-159.
[11]   | M.A. Postow, Managing immune checkpoint-blocking antibody side effects, Am Soc Clin Oncol Educ Book. (2015) 76-83.