Oncologic Emergencies: Immune-Based Cancer Therapies and Complications

Cancer therapies have undergone several recent advancements. Current cancer treatments include immune-based therapies comprised of checkpoint inhibitors, and adoptive immunotherapy; each treatment has the potential for complications that differ from chemotherapy and radiation. This review evaluates immune-based therapies and their complications for emergency clinicians. Therapy complications include immune-related adverse events (irAE), cytokine release syndrome (CRS), autoimmune toxicity, and chimeric antigen receptor (CAR) T-cell-related encephalopathy syndrome (CRES). Immune-related adverse events are most commonly encountered with checkpoint inhibitors and include dermatologic complications, pneumonitis, colitis/diarrhea, hepatitis, and endocrinopathies. Less common irAEs include nephritis, myocardial injury, neurologic toxicity, ocular diseases, and musculoskeletal complications. CRS and CRES are more commonly associated with CAR T-cell therapy. CRS commonly presents with flu-like illness and symptoms resembling sepsis, but severe myocardial and pulmonary disease may occur. Critically ill patients require resuscitation, broad-spectrum antibiotics, and hematology/oncology consultation

The Effects of Novel Design Strategies on the Risks and Benefits of Phase I Oncology Trials

Considerable ethical debate surrounding the risks and benefits of Phase I oncology trials is based on older response and toxicity data that does not account for recent changes in the types of agents and trial design. This study aims to not only update these data, but to investigate the impact of novel trial designs on various clinical outcomes. We performed a review of the literature using the Medline database. Part I included nearly all phase I trials published in 2002. Part II identified phase I studies of cytotoxic agents alone, published from 2002 through 2004. 221 Phase I oncology studies, consisting of 6,008 patients, were studied in Part I, while 149 studies, comprising 4,532 patients, were analyzed in Part II. Overall, the response rate for Phase I oncology trials in 2002 was 19%, the mortality rate was 1.1%, and the rates of severe hematologic and non-hematologic toxicities were 19% and 22%, respectively. Classic phase I trials of single agent cytotoxic drugs accounted for only 18% of trials, while more than half (55%) included at least one FDA approved therapy. The response and toxicity rates varied with the class of agent (e.g. cytotoxic, biologic, vaccine), and the combinations of agents (e.g. approved, investigational) studied. Only 34% of studies utilized aggressive dose escalation schemes, 22% permitted intra-patient dose escalation, and only 28% enrolled fewer than 3 patients to any dose level before proceeding to the next higher dose level. Studies that allowed intra-patient dose escalation or used fewer than three patients per dose were not associated with rates of response or toxicity that differed from trials using a more traditional design, nor did they increase the percentage of patients who received the recommended phase II dose. However, aggressive dose escalations were associated with increased rates of both hematologic (17% vs.10%) and non-hematologic (17% vs. 13%) toxicity for participating patients without increasing response rates. None of these novel design strategies were associated with a smaller patient requirement. Phase I oncology trials represent a spectrum of different classes of agents and design strategies that are often associated with distinct clinical outcomes. Accounting for this variety is critical when evaluating their risk-benefit profiles and ethics. While some innovations in trial design do not appear to be any more helpful or harmful than standard methods in phase I trials of single agent cytotoxic drugs, using aggressive dose escalations may, in fact, be more hazardous for patients. These findings highlight the need for continued effort towards improving trial design and its impact on our patients

Crush syndrome

AbstractThe first detailed cases of crush syndrome were described in 1941 in London after victims trapped beneath bombed buildings presented with swollen limbs, hypovolemic shock, dark urine, renal failure, and ultimately perished. The majority of the data and studies on this topic still draw from large databases of earthquake victims. However, in Africa, a continent with little seismic activity, the majority of crush syndrome cases are instead victims of severe beatings rather than earthquake casualties, and clinical suspicion by emergency personnel must be high in this patient group presenting with oliguria or pigmenturia. Damaged skeletal muscle fibres and cell membranes lead to an inflammatory cascade resulting in fluid sequestration in the injured extremity, hypotension, hyperkalemia and hypocalcemia and their complications, and renal injury from multiple sources. Elevations in the serum creatinine, creatine kinase (CK), and potassium levels are frequent findings in these patients, and can help guide critical steps in management. Fluid resuscitation should begin prior to extrication of trapped victims or as early as possible, as this basic intervention has been shown to in large part prevent progression of renal injury to requiring haemodialysis. Alkalinization of the urine and use of mannitol for forced diuresis are recommended therapies under specific circumstances and are supported by studies done in animal models, but have not been shown to change clinical outcomes in human crush victims. In the past 70years the crush syndrome and its management have been studied more thoroughly, however clinical practice guidelines continue to evolve

Clinical review of malaria for the emergency physician

AbstractMalaria is a disease caused by parasites of the Plasmodium genus, and is one of the most prevalent diseases in Africa and around the world. Emergency physicians in both endemic and non-endemic regions often encounter initial presentations of malaria, and knowledge about the pathophysiology, diagnosis, and treatment of this disease is crucial in caring for these patients. This article covers briefly the epidemiology of malaria and the lifecycle of the Plasmodium parasite. This is followed by a discussion of the clinical evaluation, diagnosis, and management of patients with malaria, as pertinent to the African emergency physician

The Search for Existential Meaning: Tracing Leo Tolstoy’s Nihilism Through his Later Works

In this senior thesis, I explore the writings of acclaimed 19th-century author Leo Tolstoy through the lens of existential and ethical nihilism: a philosophical ideology espousing an assertion of a meaningless existence shaped by similarly meaningless governing social, political, and religious conventions. Prior to the author’s religious conversion at the age of 50, Tolstoy’s writings reflected a nihilistic worldview that opposed any socially accepted definition of a meaningful existence. Although within the span of 1800s Russia nihilism was strongly associated with atheism and terrorism, Tolstoy distanced himself from any accepted cultural value or label—including the negative political associations and other philosophical debates around the term “nihilism” itself. This thesis argues that Tolstoy’s later works served as a consequential explosive rejection of meaningless conventions that he himself had participated within, such as materialistic consumption, corrupt religious practices, and the literary genre of fiction itself. The structure of this paper builds on the author’s biography and a historical view of guiding values within Russian society in the 1800s, connecting scenes from Tolstoy’s life with a close reading of passages from his late novellas and non-fiction writings: The Death of Ivan Ilyich, A Confession, and The Kreutzer Sonata. His work defied the beliefs of other popular writers, common social aspirations for wealth and fame, and the authority of the Russian Orthodox Church, pointing to his inability to accept any codified outline of existential meaning or moral behaviors

PLK4 as a Novel Therapeutic Target in TP53-mutant Acute Myeloid Leukemia

https://openworks.mdanderson.org/sumexp23/1059/thumbnail.jp

Association of Disease Recurrence With Survival Outcomes in Patients With Cutaneous Squamous Cell Carcinoma of the Head and Neck Treated With Multimodality Therapy

IMPORTANCE It has previously been demonstrated that immunosuppressed patients with cutaneous squamous cell cancer of the head and neck (cSCC-HN) treated with surgery and postoperative radiotherapy have significantly inferior disease-related outcomes compared with immunocompetent patients, but data on outcomes after disease recurrence are limited. OBJECTIVES To report survival outcomes in patients with cSCC-HN after disease recurrence after surgery and postoperative radiotherapy and to investigate the association of immune status with disease-related outcomes. DESIGN, SETTING, AND PARTICIPANTS A multi-institutional study of 205 patients treated at the Cleveland Clinic, Washington University in St Louis, and the University of California, San Francisco, in which patients who underwent surgical resection and postoperative radiotherapy for primary or recurrent stage I to IV (nonmetastatic) cSCC-HN between January 1, 1995, and December 31, 2014, were identified. Patients with any disease recurrence, defined as local, regional, and/or distant failure, were included. Patients were categorized as immunosuppressed if they received a diagnosis of chronic hematologic malignant neoplasm or HIV or AIDS, or were treated with immunosuppressive therapy for organ transplantation 6 months or more before diagnosis. Statistical analysis was conducted from January 1, 1995, to December 31, 2015. MAIN OUTCOMES AND MEASURES Overall survival calculated using the Kaplan-Meier method and compared using the log-rank test. RESULTS Of the 205 patients in the original cohort, 72 patients (63 men and 9 women; median age, 71 years [range, 43-91 years]) developed disease recurrence after surgery and postoperative radiotherapy. Forty patients (55.6%) were immunosuppressed, and 32 patients (44.4%) were immunocompetent. Locoregional recurrence was the most common first pattern of failure for both groups (31 immunosuppressed patients [77.5%]; 21 immunocompetent patients [65.6%]). After any recurrence, 1-year overall survival was 43.2%(95% CI, 30.9%-55.4%), and median survival was 8.4 months. For patients for whom information on salvage treatment was available (n = 45), those not amenable to surgical salvage had significantly poorer median cumulative incidence of survival compared with those who were amenable to surgical salvage (4.7 months; 95% CI, 3.7-7.0 months vs 26.1 months; 95% CI, 6.6 months to not reached; P=.01), regardless of their immune status. CONCLUSIONS AND RELEVANCE Results of this study suggest that patients with cSCC-HN who experience disease recurrence after definitive treatment with surgery and postoperative radiotherapy have poor survival, irrespective of immune status. Survival rates are low for patients with recurrent disease that is not amenable to surgical salvage. The low rate of successful salvage underscores the importance of intensifying upfront treatment to prevent recurrence.12 month embargo; published online: 27 February 2019This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Case Report Traumatic Page Kidney Induced Hypertension in Critical Care: Immediately Resolved or Long-Term Resistant Problem

Page kidney is a well-known phenomenon causing hypertension, due to compression of renal parenchyma by a subcapsular hematoma, of either traumatic or non-traumatic origin. The main therapeutic approach is based on surgical approach (nephrectomy or hematoma evacuation) and antihypertensive treatment. In this paper we present a post-traumatic case of Page Kidney in a Critical Care unit. We discuss different therapeutical opportunities to extremely elevated systemic blood pressure resistant to traditional drug therapy

Evaluation of the utility of localized adjuvant radiation for node-negative primary cutaneous squamous cell carcinoma with clear histologic margins

Background Though NCCN recommends consideration of localized adjuvant radiation following clear-margin surgery for cutaneous squamous cell carcinoma (CSCC) with large caliber (≥0.1mm) nerve invasion (LCNI) and other high-risk features, only a single small study has compared surgery plus adjuvant radiation (S+ART) to surgical monotherapy (SM) for CSCC. Objectives Compare surgery plus adjuvant radiation (S+ART) to surgical monotherapy (SM) for primary CSCCs with LCNI and other risk factors. Methods Matched retrospective cohort study of primary CSCCs (matched on gender, age, immune status, type of surgery, diameter, differentiation, depth and LCNI) treated with S+ART versus SM. Subgroup analysis of CSCCs with LCNI was performed. Results 62 CSCCs were included in matched analysis (S + ART: 31, SM: 31) and 33 in LCNI analysis (S+ART: 16, SM: 17). There was no significant difference in local recurrence (LR), metastasis, or death from disease in either analysis. Risk of LR was low (7, 8%) with 3 of the LRs being effectively treated upon recurrence. Limitations Single academic center, non-randomized design. Conclusion Adjuvant radiation did not improve outcomes compared to SM due to a low baseline risk of recurrence; although ART for named nerve invasion and LCNI of 3 or more nerves has been shown to improve outcomes in a prior study. Randomized studies are needed to define the subset of CSCC for whom adjuvant radiation has utility