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  Most popular articles (Since November 13, 2017)

 
 
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EDITORIAL
Being realistic and optimistic in curing cancer
Aung Naing
October-December 2018, 1(2):53-55
DOI:10.4103/JIPO.JIPO_20_18  
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ORIGINAL ARTICLES
Erlotinib in patients with advanced non-small cell lung cancer in Middle Eastern population
Abdul Rahman Jazieh, Turki M Fayea, Mervat Mahrous, Tarek Darwish, Essam Fawzi, Ashwaq A Alolayan, Nagham Sheblaq, Mohammed Alkaiyat, Yosra Ali
July-September 2018, 1(1):19-25
DOI:10.4103/JIPO.JIPO_2_18  
Background: Although erlotinib is widely used in the management of non-small cell lung cancer (NSCLC), no prior studies were conducted in Middle Eastern population. Our study aims at evaluating erlotinib prospectively in this population. Patients and Methods: This open-label, prospective, single-arm, multicenter Phase IV clinical trial of erlotinib as single agent evaluated safety and efficacy of Erlotinib in Middle Eastern patients with advanced NSCLC. Results: A total of 56 patients were enrolled in five sites in Saudi Arabia. Majority of patients were males (60%) with median age of 57 years (34–80), Stage IV (98%), and adenocarcinoma (84%). Eastern Cooperative Oncology Group performance Status III (41.1%). Epidermal growth factor receptor (EGFR) mutations were present in 24 patients out of 36 patients tested (67%). The most common reported adverse events (AEs) were rash 36 (64%), diarrhea 29 (52%), fatigue 10 (18%), and anorexia 5 (9%). Grade 4 or 5 AEs were not observed. Complete response was achieved in 2 (3.6%) and overall disease control was 60.8%. Median overall survival (OS) was significantly longer in patients with EGFR mutation than wild type (20 vs. 3 months, P = 0.002). Progression-free survival was 10 months and significantly longer in patients with EGFR mutation than wild type (16 vs. 6 months, P = 0.037). Patients with unknown EGFR status had PSF and OS better than wild-type patients and worse than patients with EGFR mutation. Cox regression analysis showed that older age (P = 0.029, HR 1.064), EGFR wild type (P = 0.014, hazard ratio [HR]: 8.497), and receiving radiation (P = 0.033, HR 6.433) significantly increase risk of death for patients receiving erlotinib. Conclusion: Erlotinib has efficacy and safety profile in Middle Eastern population similar to the reported literature. The empiric use of erlotinib in patients with unknown EGFR status in our patient population is warranted due to high prevalence of the mutation. However, it should not be used in confirmed wild-type disease.
  1,331 93 -
REVIEW ARTICLES
Pneumonitis after precision oncology therapies: A concise review
Akash Jain, Vickie R Shannon, Ajay Sheshadri
July-September 2018, 1(1):26-37
DOI:10.4103/JIPO.JIPO_9_18  
With greater understanding of the molecular biology of cancer, precision oncology therapies are becoming increasingly prevalent. Adverse events associated with these therapies may cause significant harm to patients if not promptly recognized and treated. In this review, we focus on pneumonitis that occurs as a side effect of treatment with precision oncology agents. We discuss the incidence and time to onset of pneumonitis associated with a broad array of precision oncology agents. We highlight the common patterns of pneumonitis and offer a comprehensive approach to evaluation and treatment with therapy-specific guidelines where available.
  1,004 135 -
Cardiotoxicity of FDA-approved immune checkpoint inhibitors: A rare but serious adverse event
Abdulrazzak Zarifa, Mohammed Salih, Juan Lopez-Mattei, Hun Ju Lee, Cezar Iliescu, Saamir Hassan, Nicolas Palaskas, Jean-Bernard Durand, Elie Mouhayar, Joseph Kim, Peter Kim
October-December 2018, 1(2):68-77
DOI:10.4103/JIPO.JIPO_15_18  
Refractory cancer represents a challenge for oncologists in providing treatment options without excessive toxicity and has led to the investigation of immune mechanisms. Immune checkpoint inhibitors (ICIs) directly interfere with the tumor cells' ability to evade the innate and adaptive immune system by targeting specific proteins such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein-1 (PD-1), and programmed cell death protein-ligand 1 (PD-L1), which are involved as negative regulators of T-cell function. Their growing success has led to the investigation for frontline treatment in several types of cancers. Even though these ICIs have demonstrated efficacy in the treatment of a variety of cancers, their use has been associated with the development of rare but severe adverse events. These events are the result of targeting specific checkpoint proteins on normal cells of the body as well as secondary downstream off-target effects on normal tissue. Similar to combined conventional cancer treatment, treating with combined ICIs are also associated with a higher risk of adverse events. Although cardiotoxicities related to immunotherapy are reportedly rare, they can be severe and associated with life-threatening conditions such as fulminant heart failure, hemodynamic instability, and cardiac arrest. Oncologists must carefully weigh the risk versus the therapeutic benefit of these agents in determining the best option for improving overall survival and minimizing morbidity and mortality of their patients. Our review focuses on the approved ICIs, their mechanism of action, their oncologic efficacy, and the associated potential for cardiovascular toxicity.
  904 134 -
ORIGINAL ARTICLES
The impact of immune checkpoint inhibitor-related adverse events and their immunosuppressive treatment on patients' outcomes
Hamzah Abu-Sbeih, Tenglong Tang, Faisal Shaukat Ali, Daniel Hartman Johnson, Wei Qiao, Adi Diab, Yinghong Wang
July-September 2018, 1(1):7-18
DOI:10.4103/JIPO.JIPO_12_18  
Background: Immune checkpoint inhibitors (ICPIs) are gaining more popularity as a treatment for advanced cancers. However, immune-related adverse events (irAEs) limit their use. We aimed to assess the impact of irAEs and their treatment on clinical and survival outcomes. Materials and Methods: We retrospectively reviewed records of the patients who received ICPIs between 2011 and 2017. Descriptive analyses were employed to compare different groups. Kaplan–Meier curves and log-rank tests were used to estimate and compare overall survival durations. Results: Of 427 identified patients, 202 (47.3%) had one or more irAEs. Overall, the patients who developed irAEs had better overall survival than did patients with no-irAEs, regardless of immunosuppressant treatment (P < 0.01). Patients with mild irAEs who did not require immunosuppressive treatment had longer overall survival duration than did patients without irAEs (P < 0.01). Patients with three or more irAEs had longer median overall survival compared to patients with two or less irAEs (P = 0.01). Infliximab was associated with shorter duration of steroid use as compared to steroid treatment only (2 months [standard deviation (SD), 8] vs. 4 months [SD, 4]). Steroid treatment for >30 days was associated with higher rate of infections compared to shorter duration (P = 0.03). Conclusion: IrAEs are associated with favorable overall survival, regardless of immunosuppression treatment requirement. IrAEs involving multiple organs appeared to be beneficial for overall survival. Early infliximab use shortens the duration of steroid treatment and therefore balances better cancer outcomes with decreased risk of infection.
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Pembrolizumab in advanced gastrointestinal malignancies with defective dna mismatch repair: A case series
David D Stenehjem, Courtney C Cavalieri, Eric Swanson, Benjamin Solomon, Jonathan Whisenant, Dao Tran, John Weis, G Weldon Gilcrease, Sunil Sharma, Ignacio Garrido-Laguna
July-September 2018, 1(1):1-6
DOI:10.4103/JIPO.JIPO_5_18  
Background: Tumors with deficient mismatch repair (dMMR) have a favorable immunological phenotype permitting exploitation by immunotherapies. We aimed to assess our institutional experience of dMMR advanced gastrointestinal (GI) cancers treated with the PD-1 inhibitor pembrolizumab. Materials and Methods: We conducted an observational cohort study of a clinical series of patients with dMMR metastatic GI cancers treated with pembrolizumab from 2015 to 2017. Patients were assessed for best response, time to and reason for discontinuation, and adverse events. Results: A total of 13 patients received at least one dose of pembrolizumab. Median age was 62 years (range 33–74 years). Diagnoses included colorectal (colorectal cancer [CRC], n = 7); extrahepatic and intrahepatic cholangiocarcinoma (EHCC, n = 2; n = 1); pancreatic (pancreatic ductal adenocarcinoma [PDAC], n = 2); and adenocarcinoma of the appendix (n = 1). Five patients received concurrent chemotherapy (FOLFOX or capecitabine) with pembrolizumab (200 mg intravenous [IV] q 2 weeks with FOLFOX or 2 mg/kg IV q 3 weeks with capecitabine). Pembrolizumab was administered 2 mg/kg IV q 3 weeks to all patients who received single-agent treatment. Eleven patients were evaluable for response assessment. Three patients had a complete response (CRC and two EHCC) and one of these patients received concomitant pembrolizumab and FOLFOX. Two patients had a partial response, one with PDAC (−88% per RECIST, continues on treatment after 15.7 months) and the other with CRC (−45% per RECIST, continues after 14.6 months), both patients received concomitant pembrolizumab and FOLFOX and are now maintained on single-agent pembrolizumab. The objective response rate was 42%. Three patients experienced immune-related adverse events requiring discontinuation. Conclusions: This single-institution case series confirms the activity of pembrolizumab in various GI cancers harboring dMMR. Future studies are warranted to determine the role of combinatorial treatment with chemotherapy and/or novel immunotherapies in this population.
  801 103 -
REVIEW ARTICLES
Understanding the toxicity of cancer immunotherapies: Use of patient-reported outcomes
Tito R Mendoza
July-September 2018, 1(1):38-45
DOI:10.4103/JIPO.JIPO_10_18  
Immunotherapy has transformed the treatment of various cancers by strengthening suppressed immune systems for antitumor effects. However, altering the immune balance also produces unconventional adverse events (AEs) that are collectively referred to as immune-related AEs. These AEs, which can be thought of as symptomatic toxicities, are typically reported via tabulation of AEs from the National Cancer Institute's Common Terminology Criteria for AEs. These AEs are reported by clinicians. However, it is well known that clinicians' reports of their patients' symptoms are underestimates and in some cases may not be consistent with patients' reports. The symptomatic adverse effects of immunotherapy are best reported by the patients themselves, known as patient-reported outcomes (PROs). This review describes the use of PROs specifically pertaining to symptom burden in cancer patients. The review also discusses challenges in the use of PROs in patients undergoing immunotherapy and provides recommendations for future research.
  732 145 -
Personalized cancer immunotherapy: Today's challenge and tomorrow's promise
Malaka Ameratunga, Wen Xu, Juanita Lopez
October-December 2018, 1(2):56-67
DOI:10.4103/JIPO.JIPO_13_18  
Precision medicine continues to be the benchmark toward which we strive in cancer research. Conventionally, it is the term applied to the use of genomic information to guide molecularly targeted therapy. However, the advent of clinically effective cancer immunotherapies has posed a challenge for this concept of precision medicine, as robust biomarkers that can differentiate responders from nonresponders have not been described. Here, we review the current scientific efforts using novel technologies to develop biomarkers for immunotherapeutics, to ultimately achieve “personalized immunotherapy.” We first examine the role of programmed death ligand 1 expression and tumor mutational burden, the two most-studied tumoral response biomarkers; and subsequently discuss innovative candidate biomarkers including integrated “omics” approaches utilizing serial tumor, blood, and microbiome sampling. We also detail the challenges in unifying these approaches into a patient-focused immunogram to truly personalize immunotherapy.
  706 106 -
CASE REPORTS
Bronchiolitis obliterans after combination immunotherapy with pembrolizumab and ipilimumab
Amulya Balagani, Muhammad H Arain, Ajay Sheshadri
July-September 2018, 1(1):49-52
DOI:10.4103/JIPO.JIPO_8_18  
Checkpoint inhibitor therapies are members of a new, groundbreaking class of drugs that reinvigorate the immune system to directly attack tumors. A rare side effect of checkpoint inhibitor therapy is pneumonitis, which typically presents as an interstitial lung disease. In this case report, we present a patient in whom combination therapy with the PD-1 inhibitor pembrolizumab and the CTLA-4 inhibitor ipilimumab induced severe airflow obstruction. This is the first report that shows that checkpoint inhibitors may induce airflow limitation.
  525 45 -
Toxic epidermal necrolysis during cotherapy with ipilimumab and nivolumab
Shelby L Kubicki, Macartney E Welborn, Anisha B Patel
October-December 2018, 1(2):78-81
DOI:DOI: 10.4103/JIPO.JIPO_7_18  
Ipilimumab and nivolumab are human monoclonal antibodies used in cancer therapy. Ipilimumab targets cytotoxic T-lymphocyte-associated antigen and nivolumab acts against programmed death receptor-1. Both drugs have extensive side effect profiles with high rates of cutaneous involvement. We present a 57-year-old male with stage IV esophageal/gastroesophageal junction adenocarcinoma that developed histologically confirmed toxic epidermal necrolysis (TEN) 6 days after cotreatment with ipilimumab and nivolumab. He presented with diffuse erythematous macules with confluence and large flaccid bullae with scrotal and mucosal involvement. He improved significantly following drug cessation, steroids, and antibiotics. TEN has been reported with ipilimumab and/or nivolumab, as have other severe drug reactions including Stevens–Johnson syndrome and erythema multiforme major. As a true dermatologic emergency, TEN should be recognized as a potential complication of ipilimumab, nivolumab, and other immune checkpoint inhibitors, so clinicians can quickly recognize the condition and initiate therapy.
  504 63 -
ORIGINAL ARTICLES
The Study of Druggable Targets in Nonsquamous Non-Small-Cell Lung Cancer in the Middle East and North Africa
Abdul Rahman Jazieh, Adda Bounedjar, Fouad Al Dayel, Shamayel Fahem, Arafat Tfayli, Kakil Rasul, Hassan Jaafar, Mohammad Jaloudi, Turki Al Fayea, Hatim Q Al Maghrabi, Hanaa Bamefleh, Khaled Al Kattan, Blaha Larbaoui, Taha Filali, Hamed Al Husaini, Yosra Ali, in collaboration with the Arab Collaborative Hematology Oncology Group (ACHOG)
0, 0(0):0-0
DOI:10.4103/JIPO.JIPO_22_18  
Background: Druggable molecular targets are very important in the management of non-small-cell lung cancer (NSCLC). The purpose of our study is to determine the pattern of testing and mutation prevalence in the Middle East and North Africa population. Patients and Methods: Data of consecutive patients with nonsquamous NSCLC were collected from 10 centers in five countries; Saudi Arabia, UAE, Qatar, Lebanon, and Algeria. Statistical analysis was performed to delineate the prevalence of druggable targets and other relevant information. Results: Five hundred and sixty-six patients were included in the study. Majority were males (78.1%) with a median age of 61 years (22–89), 50% were current or ex-smokers and 370 patients (65.4%) were Stage IV. The epidermal growth factor receptor (EGFR) testing was performed on 164 patients of all stages. EGFR mutation was detected in 30 out of 96 patients (31.3%) with metastatic disease and in 12 out of 68 patients (17.6%) with Stage I to III. Female sex (39.5% vs. 22% males, P = 0.032), Stage IV (31.2% vs. 17.6% in Stage I to III, P = 0.049), and positive immunohistochemical-TTF1 (31.4% vs. 8.7% negative, P = 0.026) were predictors of mutation on univariate analysis. The multivariate analysis showed that patients with stage IV have three times higher positivity than lower stages (odds ratio = 3.495, P = 0.036). Anaplastic lymphoma kinase fusion was present in seven out of 89 patients (7.8%) of all stages, and only three out of 52 patients (5.8%) with metastatic disease. The reasons for not performing the tests in all of the 370 patients with metastatic disease were: physicians do not know where and how to send the test (62.3%), lack of funding to perform the test (11.1%), insufficient tissue (10.1%), and other reasons (16.6%). Conclusions: Only a small fraction of patients with NSCLC are tested for druggable targets and the prevalence of EGFR mutation is prevalence higher than the Western population. Overcoming the challenges of testing requires systematic plans to address education and resource allocation.
  525 12 -
CASE REPORTS
Pyoderma gangrenosum following initiation of immune checkpoint inhibitor therapy
Macartney E Welborn, Shelby L Kubicki, Anisha B Patel
October-December 2018, 1(2):82-84
DOI:10.4103/JIPO.JIPO_11_18  
Pyoderma gangrenosum (PG) is an ulcerating neutrophilic dermatosis that is often associated with the underlying systemic disease. For example, PG is often a common presenting symptom in patients with hematologic malignancies, most commonly myelodysplastic syndrome (MDS). Here, we present the case of a patient who developed PG and a lichenoid drug eruption after the initiation of ipilimumab and nivolumab immune checkpoint inhibitor (ICPI) therapy. Lichenoid drug eruptions are well known to be associated with ICPI therapy, particularly nivolumab. However, only one case of PG has been reported in association with ipilimumab and no cases have ever been reported with nivolumab. Awareness that PG can be associated with ICPI therapy in patients with MDS can allow physicians to be better prepared to help in early recognition and early treatment to prevent the spread of disease.
  403 55 -
Inflammatory colitis after treatment of melanoma with talimogene laherparepvec (T-VEC)
Jennifer Gardner, Teresa Hyun, Gideon Steinbach, John Thompson
July-September 2018, 1(1):46-48
DOI:10.4103/JIPO.JIPO_3_18  
Talimogene laherparepvec (T-VEC) is an intralesional oncolytic viral therapy for the treatment of recurrent, unresectable cutaneous, subcutaneous, and nodal melanoma. It is thought to work through direct tumor oncolysis and by eliciting a tumor-specific systemic immune response. Immune-related adverse events have been reported only rarely with this therapy. We report a case of culture-negative, biopsy-proven colitis following pathologic complete response of recurrent, and intransit cutaneous melanoma to T-VEC. To the best of our knowledge, this is the first report of immune-related colitis following T-VEC.
  411 27 -
EDITORIAL
Optimizing Precision Oncology and Immunotherapy Strategies: Moving into the Next Stage of Cancer Medicine
Phoebe Lewis, Timothy A Yap
0, 0(0):0-0
DOI:10.4103/JIPO.JIPO_26_18  
  24 11 -
SPECIAL ARTICLE
5th Annual immuno-oncology 360° conference: What to expect, february, 6–8, 2019, crown plaza times square, New York City, NY
Kate Woda
0, 0(0):0-0
DOI:10.4103/2590-017X.249502  
  24 9 -
REVIEW ARTICLES
Extracellular signal-regulated kinase (ERK) inhibitors in oncology clinical trials
Haelee M Chin, David K Lai, Gerald S Falchook
0, 0(0):0-0
DOI:10.4103/JIPO.JIPO_17_18  
The mitogen-activated protein kinase (MAPK) pathway consists of the series of protein kinases RAS-RAF-MEK- Extracellular signal-regulated kinase (ERK), and its function is important to cell proliferation, differentiation, motility, and survival. Certain mutations in the pathway, such as KRAS or BRAF V600 mutations are associated with cancer. Inhibitors of this pathway, including some MEK and BRAF inhibitors, are already being used in the clinic, but a variety of selective ERK inhibitors are still being tested in clinical studies. To date, common adverse events associated with ERK inhibitors include diarrhea, nausea, fatigue, and rash. ERK inhibitors have demonstrated preliminary antitumor activity and may be most effective against cancers with RAS, RAF, or MAPK pathway alterations. This review discusses the MAPK pathway, the biological rationale for ERK inhibitors, and clinical trials involving ERK inhibitors.
  17 5 -
CASE REPORTS
Vedolizumab Achieved Clinical and Histologic Remission in a Patient with Lung Cancer Who Had a Steroid-Refractory Upper Gastrointestinal Injury Due to Nivolumab Treatment
Cynthia Nguyen Tran, Hamzah Abu-Sbeih, Wenyi Luo, Yang Lu, Yinghong Wang
0, 0(0):0-0
DOI:10.4103/JIPO.JIPO_18_18  
Immune checkpoint inhibitors (ICIs) have emerged as a novel therapeutic class for various malignancies. Their immune upregulation promotes significant anti-tumor effect, but simultaneously, can also result in treatment-limiting immune-related adverse events (irAEs). The data on upper gastrointestinal (GI) tract irAEs are sparse. We herein describe a case of steroid-dependent upper GI toxicity with nivolumab (an anti-programmed death [PD] protein-1) that achieved clinical and histological remission with vedolizumab treatment (a GI tract targeted anti-integrin antibody). A 65-year-old male patient with progressive lung cancer was treated with nivolumab and following 16 cycles, developed severe nausea, vomiting, and epigastric abdominal cramps requiring five hospitalizations. His initial esophagogastroduodenoscopy (EGD) showed active inflammation in both the stomach and duodenum. Nivolumab was discontinued, but despite treatment with multiple steroid courses, his symptoms always recurred during prednisone taper. Clinical remission was ultimately achieved with vedolizumab. His last EGD after five infusions of vedolizumab demonstrated resolution of inflammation. His lung cancer has since relapsed and the treatment plan was to resume nivolumab concurrently with vedolizumab. In conclusion, ICIs, such as nivolumab, have emerged as therapy for various malignancies. Their use can be associated with various irAEs including the upper GI adverse events which is uncommon. This case scenario showed that vedolizumab can provide a steroid-sparing therapeutic effect to achieve remission of upper GI irAEs even in cases where multiple steroid courses have failed.
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