Recurrent Pneumonitis in Patients with Melanoma Treated with Immune Checkpoint Inhibitors.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have changed the oncologic landscape in the past few years. Alongside impressive antitumor responses, new novel immune-related adverse events (irAEs) have emerged; pneumonitis is an irAE that can potentially be fatal and necessitates a proper management. No consensus exists regarding steroid treatment duration or drug rechallenge options. Our study describes the clinical and radiological course of melanoma patients diagnosed with immune-related pneumonitis that has recurred because of rechallenge attempt or despite complete treatment discontinuation (unprovoked). MATERIALS AND METHODS: The study population was composed of patients with metastatic melanoma who were treated with anti-programmed cell death 1 (PD-1) as monotherapy or in combination with anti-cytotoxic T lymphocyte antigen-4 and who were diagnosed with immune-related pneumonitis. For recurrent cases after clinical and radiological resolution, we explored the differences from cases with no recurrence. RESULTS: Nineteen out of 386 (4.8%) patients treated with ICI were diagnosed with pneumonitis. Median age was 66 years, and 53% were male. Compared with single-agent nivolumab, patients treated with ipilimumab-nivolumab combination presented with an earlier onset (27.5 vs. 10.3 weeks, respectively, p = .015) and had higher grades of severity. After complete resolution, rechallenge was attempted in seven patients; three of them had recurrent pneumonitis. Three other patients experienced recurrent pneumonitis despite complete discontinuation of the drug (unprovoked by rechallenge). The latter were characterized with an earlier onset of the first pneumonitis compared with those who did not experience recurrence (median, 12.4 vs. 26.4 weeks) and a shorter course of steroid treatment at first episode (median, 5.1 vs. 10 weeks). Recurrent cases were generally more severe than the first episode. CONCLUSION: Unprovoked recurrent pneumonitis is a new, poorly reported entity that requires further investigation. Our observations suggest that cases of pneumonitis that present early in the course of immunotherapy treatment may recur despite treatment discontinuation, thus necessitating closer monitoring and a longer course of steroid treatment. IMPLICATIONS FOR PRACTICE: This article sheds light on a poorly described immune-related adverse event: recurrent pneumonitis despite complete discontinuation of immunotherapy (unprovoked), in patients with advanced melanoma.

Adoptive T cell therapy: An overview of obstacles and opportunities.

The therapeutic potential of adoptive cell therapy (ACT) in cancer patients was first acknowledged 3 decades ago, but it was an esoteric approach at the time. In recent years, technological advancements have transformed ACT into a viable therapeutic option that can be curative in some patients. In fact, current ACT response rates are 80% to 90% for hematological malignancies and 30% for metastatic melanoma refractory to multiple lines of therapy. Although these results are encouraging, there is still much to be done to fulfill ACT's potential, specifically with regard to improving clinical efficacy, expanding clinical indications, reducing toxicity, and increasing production and cost-effectiveness. This review addresses the current major obstacles to ACT and presents potential solutions. Cancer 2017;123:2154-62. © 2017 American Cancer Society.

Comparison of Two Intraosseous Devices: The NIO Versus the EZ-IO by Novice Users-A Randomized Cross Over Trial.

BACKGROUND: During resuscitation in the field, intraosseous (IO) access may be achieved using a variety of available devices, often attempted by inexperienced users. AIM: We sought to examine the success rate and ease-of-use ratings of an IO device, the NIO® (New Intraosseous Persys Medical, Houston, TX, USA) in comparison to the Arrow® EZ-IO® (Teleflex Medical Research Triangle Park, NC, USA) by novice users. METHODS: We performed a randomized crossover trial. The study model was a porcine hind leg which was cut distally in order to expose the marrow. The Study population was composed of pre-graduate medical students without prior experience in IO use, all designated future field physicians. The students underwent instruction and practiced the use of both devices. After practice completion, each student attempted a single IO insertion with both devices sequentially in randomized fashion. Success was defined as a flow of fluid through the bone marrow after a single IO attempt. Investigators which determined the success rate were blinded to the used device. RESULTS: 50 users (33 males, 17 females) participated in the trial, mean age of 21.7 years (±1). NIO users were successful in 92% (46/50) attempts while EZ-IO user success rate was 88% (44/50). NIO success rates were comparable to those of EZ-IO (p = NS). Results were similar when examining only the initial device used. Median score of ease of use was 4 (5 point Likert scale) in both devices (p = NS). 54% (27/50) of the participants preferred using the EZ-IO over the NIO (p = NS). CONCLUSION: Novice users were equally successful in establishing IO access with the NIO® in comparison to the EZ-IO® in a porcine model.

Immune co-culture cell microarray - a feasible tool for high-throughput functional investigation of lymphocyte-cancer interactions.

Omics analyses often result in dozens to hundreds of potential targets, requiring validation for their biological relevance. Current high-throughput functional investigation methods are frequently labor-intensive, expensive, and display low reproducibility. The Immune Co-Culture Cell Microarray (ICCM) is a formalin-fixed paraffin-embedded cell block microarray based on co-cultures of patient-derived tumor-infiltrating lymphocytes and their autologous melanoma cells. Each ICCM slide represents the same experiment and can be stained using standard immunohistochemistry and immunofluorescence techniques. Functional dynamics assessment of both proteins and microRNAs using ICCM stained slides demonstrated similar findings to flow cytometry assays and to previously published patient-derived biopsy reports.

ADAR1-mediated regulation of melanoma invasion.

Melanoma cells use different migratory strategies to exit the primary tumor mass and invade surrounding and subsequently distant tissues. We reported previously that ADAR1 expression is downregulated in metastatic melanoma, thereby facilitating proliferation. Here we show that ADAR1 silencing enhances melanoma cell invasiveness and ITGB3 expression. The enhanced invasion is reversed when ITGB3 is blocked with antibodies. Re-expression of wild-type or catalytically inactive ADAR1 establishes this mechanism as independent of RNA editing. We demonstrate that ADAR1 controls ITGB3 expression both at the post-transcriptional and transcriptional levels, via miR-22 and PAX6 transcription factor, respectively. These are proven here as direct regulators of ITGB3 expression. miR-22 expression is controlled by ADAR1 via FOXD1 transcription factor. Clinical relevance is demonstrated in patient-paired progression tissue microarray using immunohistochemistry. The novel ADAR1-dependent and RNA-editing-independent regulation of invasion, mediated by ITGB3, strongly points to a central involvement of ADAR1 in cancer progression and metastasis.

Clinical Significance of Pancreatic Atrophy Induced by Immune-Checkpoint Inhibitors: A Case-Control Study.

Immune-checkpoint inhibitor (ICI)-related diarrhea is attributed to inflammatory colitis, with no other drug-related differential diagnosis. Here, we investigated the occurrence of pancreatic atrophy (PA) in ICI-treated cancer patients and its correlation to exocrine pancreatic insufficiency (EPI). Metastatic melanoma, non-small cell lung carcinoma, and head and neck squamous cell carcinoma patients (n = 403) treated with anti-PD-1 (n = 356) or anti-CTLA-4 (n = 47) were divided into a case group (radiologic evidence of PA); control group matched by age, gender, and previous lines of treatment; and colitis group (ICI-induced colitis). Quantitative pancreatic volumetry was used for calculation of the decrease in pancreatic volume over time (atrophy rate). Thirty-one patients (7.7%) developed PA compared with 41 matched controls (P = 0.006). Four patients developed EPI, all from the anti-PD-1-treated group, which resolved with oral enzyme supplementation. The atrophy rate did not correlate with EPI (P = 0.87). EPI-related diarrhea presented at a median of 9 months, whereas the diarrhea of anti-PD-1-induced colitis patients (n = 22) was presented at a median of 2 months (P = 0.029). ICI-induced PA is irreversible and can result in EPI. EPI should be suspected in cases of late-onset steroid-resistant diarrhea with features of steatorrhea and treated with oral enzyme supplements.

Augmentation of point of injury care: Reducing battlefield mortality-The IDF experience.

STUDY OBJECTIVE: In 2012, the Israel Defense Forces Medical Corps (IDF-MC) set a goal of reducing mortality and eliminating preventable death on the battlefield. A force buildup plan entitled "My Brother's Keeper" was launched addressing: trauma medicine, training, change of Clinical Practice Guidelines (CPGs), injury prevention, data collection, global collaboration and more. The aim of this article is to examine how military medical care has evolved due "My Brother's Keeper" between Second Lebanon War (SLW, 2006) to Operation Protective Edge (OPE, 2014). METHODS: Records of all casualties during OPE and SLW were extracted and analyzed from the I.D.F Trauma Registry. Noncombat injuries and civilian injuries from missile attacks were excluded from this analysis. RESULTS: The plans main impacts were; incorporation of a physician or paramedic as an integral part of each fighting company, implementation of new CPGs, introduction of new approaches for extremity haemorrhage control and Remote Damage Control Resuscitation at point of injury (POI) using single donor reconstituted freeze dried plasma (25 casualties) and transexamic acid (98 casualties). During OPE, 704 soldiers sustained injuries compared with 833 casualties during SLW. Fatalities were 65 and 119, respectively, cumulating to Case Fatality Rate of 9.2% and 14.3%, respectively. CONCLUSIONS: Significant changes in the way the IDF-MC provides combat casualty care have been made in recent years. It is the transformation from concept to doctrine and integration into a structured and Goal-Oriented Casualty Care System, especially POI care that led to the unprecedented survival rates in IDF as shown in this conflict.