Early Increases in Blood Pressure and Major Adverse Cardiovascular Events in Patients With Renal Cell Carcinoma and Thyroid Cancer Treated With VEGFR TKIs.

BACKGROUND: Although VEGFR tyrosine kinase inhibitors (TKIs) are a preferred systemic treatment approach for patients with advanced renal cell carcinoma (RCC) and thyroid carcinoma (TC), treatment-related cardiovascular (CV) toxicity is an important contributor to morbidity. However, the clinical risk assessment and impact of CV toxicities, including early significant hypertension, among real-world advanced cancer populations receiving VEGFR TKI therapies remain understudied. METHODS: In a multicenter, retrospective cohort study across 3 large and diverse US health systems, we characterized baseline hypertension and CV comorbidity in patients with RCC and those with TC who are newly initiating VEGFR TKI therapy. We also evaluated baseline patient-, treatment-, and disease-related factors associated with the risk for treatment-related early hypertension (within 6 weeks of TKI initiation) and major adverse CV events (MACE), accounting for the competing risk of death in an advanced cancer population, after VEGFR TKI initiation. RESULTS: Between 2008 and 2020, 987 patients (80.3% with RCC, 19.7% with TC) initiated VEGFR TKI therapy. The baseline prevalence of hypertension was high (61.5% and 53.6% in patients with RCC and TC, respectively). Adverse CV events, including heart failure and cerebrovascular accident, were common (occurring in 14.9% of patients) and frequently occurred early (46.3% occurred within 1 year of VEGFR TKI initiation). Baseline hypertension and Black race were the primary clinical factors associated with increased acute hypertensive risk within 6 weeks of VEGFR TKI initiation. However, early significant "on-treatment" hypertension was not associated with MACE. CONCLUSIONS: These multicenter, real-world findings indicate that hypertensive and CV morbidities are highly prevalent among patients initiating VEGFR TKI therapies, and baseline hypertension and Black race represent the primary clinical factors associated with VEGFR TKI-related early significant hypertension. However, early on-treatment hypertension was not associated with MACE, and cancer-specific CV risk algorithms may be warranted for patients initiating VEGFR TKIs.

Rituximab in the Treatment of Acquired Angioedema Secondary to Marginal Zone Lymphoma of the Spleen.

Angioedema occurs in less than 1-2% of the population and amongst these cases, those with acquired angioedema are less prevalent than hereditary angioedema. Amongst cases of acquired angioedema, studies have shown that they were highly linked with an associated lymphoproliferative disorder, suspected secondary to the production of neutralizing autoantibodies from pathological B cell proliferation. We present a case of a patient who presented with recurrent episodes of angioedema and was found to have low C4 and C1 esterase function, initially concerning for a hereditary angioedema variant, who was subsequently found to have marginal B cell lymphoma mimicking hereditary angioedema.

The Impact of a Hematopoietic Cellular Therapy Pharmacist on Clinical and Humanistic Outcomes: A RE-AIM Framework Analysis.

The hematopoietic cellular therapy (HCT) pharmacist is an essential member of the multidisciplinary care team. Yet, standardized incorporation of a pharmacist at transplantation centers remains challenging. Implementation science uses theory-driven and systematic approaches to integrate interventions into clinical practice. We describe our experience implementing an HCT pharmacist at our center and conducted a program evaluation using the Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) framework. We implemented 1 full-time equivalent pharmacist to provide medication management services through a collaborative practice agreement (CPA) to the allogeneic transplantation population at a medium-sized center in rural Pennsylvania over a 2-year period. The HCT pharmacist documented all in-person and telephonic care encounters in the electronic medical record. A pharmacist intervention tool was developed to document identified medication-related problems with corresponding interventions and magnitude of intervention. Summary statistics including frequency and percentages were presented for categorical variables in RE-AIM domain. Over the 2-year period, the HCT pharmacist monitored 40 allogeneic patients at our institution accounting for 1531 patient encounters. The average duration of follow-up was 299 days. The HCT pharmacist medication therapy services were able to reach all allogeneic transplants at our institute. The HCT pharmacist managed 388 medications and identified 2156 medication related problems for which the pharmacist provided 2959 interventions. Time in therapeutic range of immunosuppression was 73.9% when managed by the HCT pharmacist through a CPA. Of the 24 patients and 9 caregivers who completed the patient satisfaction survey, 25 (76%) were strongly satisfied with their care. Pharmacy services were gradually adopted and expanded to incorporate additional populations, including 121 autologous transplant and 272 hematology patient encounters. The role of the HCT pharmacist was justified with hospital administration and sustained as a designated pharmacist role at our center. The implementation of an HCT pharmacist service can positively impact patient care. The RE-AIM framework provides a methodological approach for programmatic evaluation and generalizability. © 2022 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Case series review of neuroradiologic changes associated with immune checkpoint inhibitor therapy.

While immuno-oncotherapy (IO) has significantly improved outcomes in the treatment of systemic cancers, various neurological complications have accompanied these therapies. Treatment with immune checkpoint inhibitors (ICIs) risks multi-organ autoimmune inflammatory responses with gastrointestinal, dermatologic, and endocrine complications being the most common types of complications. Despite some evidence that these therapies are effective to treat central nervous system (CNS) tumors, there are a significant range of related neurological side effects due to ICIs. Neuroradiologic changes associated with ICIs are commonly misdiagnosed as progression and might limit treatment or otherwise impact patient care. Here, we provide a radiologic case series review restricted to neurological complications attributed to ICIs, anti-CTLA-4, and PD-L-1/PD-1 inhibitors. We report the first case series dedicated to the review of CNS/PNS radiologic changes secondary to ICI therapy in cancer patients. We provide a brief case synopsis with neuroimaging followed by an annotated review of the literature relevant to each case. We present a series of neuroradiological findings including nonspecific parenchymal and encephalitic, hypophyseal, neural (cranial and peripheral), meningeal, cavity-associated, and cranial osseous changes seen in association with the use of ICIs. Misdiagnosis of radiologic abnormalities secondary to neurological immune-related adverse events can impact patient treatment regimens and clinical outcomes. Rapid recognition of various neuroradiologic changes associated with ICI therapy can improve patient tolerance and adherence to cancer therapies.

Early imaging marker of progressing glioblastoma: a window of opportunity.

PURPOSE: Therapeutic intervention at glioblastoma (GBM) progression, as defined by current assessment criteria, is arguably too late as second-line therapies fail to extend survival. Still, most GBM trials target recurrent disease. We propose integration of a novel imaging biomarker to more confidently and promptly define progression and propose a critical timepoint for earlier intervention to extend therapeutic exposure. METHODS: A retrospective review of 609 GBM patients between 2006 and 2019 yielded 135 meeting resection, clinical, and imaging inclusion criteria. We qualitatively and quantitatively analyzed 2000+ sequential brain MRIs (initial diagnosis to first progression) for development of T2 FLAIR signal intensity (SI) within the resection cavity (RC) compared to the ventricles (V) for quantitative inter-image normalization. PFS and OS were evaluated using Kaplan-Meier curves stratified by SI. Specificity and sensitivity were determined using a 2 × 2 table and pathology confirmation at progression. Multivariate analysis evaluated SI effect on the hazard rate for death after adjusting for established prognostic covariates. Recursive partitioning determined successive quantifiers and cutoffs associated with outcomes. Neurological deficits correlated with SI. RESULTS: Seventy-five percent of patients developed SI on average 3.4 months before RANO-assessed progression with 84% sensitivity. SI-positivity portended neurological decline and significantly poorer outcomes for PFS (median, 10 vs. 15 months) and OS (median, 20 vs. 29 months) compared to SI-negative. RC/V ratio ≥ 4 was the most significant prognostic indicator of death. CONCLUSION: Implications of these data are far-reaching, potentially shifting paradigms for glioma treatment response assessment, altering timepoints for salvage therapeutic intervention, and reshaping glioma clinical trial design.

Case Report of Immuno-Oncotherapy (IO) Provoked Encephalitis Mimicking Brain Metastasis in a Patient with History of Traumatic Brain Injury.

BACKGROUND: Immuno-oncotherapy (IO) has revolutionized systemic cancer care but remains experimental in brain tumors. IO treatment risks multiorgan autoimmune inflammatory responses that limit its use. The central nervous system (CNS) is an immune-specialized compartment with restricted cellular access, thus fewer cases are reported for immune-mediated encephalitis. Interestingly, patients with history of blood-brain barrier compromise are potentially at higher risk for immune cell trafficking to the CNS. CASE DESCRIPTION: We report the first case, to our knowledge, of a 70-year-old man with clear cell renal cell carcinoma with pulmonary metastases treated with lung irradiation, nephrectomy, and chemotherapy prior to switching to single-agent nivolumab IO. The patient presented with new-onset generalized tonic-clonic seizure and left visual field-cut. Review of patient history revealed remote traumatic brain injury (TBI). Brain imaging noted a solid-enhancing right occipital mass that was presumed metastasis versus lymphoma. Cerebrospinal fluid cytology was negative for malignancy but concerning for lymphoproliferative process not determined to be malignant. The patient started steroids and anti-epileptic therapy. After negative systemic cancer re-staging, IO was discontinued and steroids were initiated with demonstrated patient clinical improvement. CONCLUSIONS: We concluded the diagnosis of immune-mediated encephalitis secondary to IO with collection of reactive T-cells within the area of encephalomalacia. The area of encephalomalacia from prior TBI served to compartmentalize the reactive lymphocytes, giving the appearance of a mass. Taken together, new onset seizure in patients on IO might signal encephalitis and CNS metastatic mimicry should be considered in patients with a prior history of TBI and encephalomalacia.

Feasibility of blood testing combined with PET-CT to screen for cancer and guide intervention.

Cancer treatments are often more successful when the disease is detected early. We evaluated the feasibility and safety of multicancer blood testing coupled with positron emission tomography-computed tomography (PET-CT) imaging to detect cancer in a prospective, interventional study of 10,006 women not previously known to have cancer. Positive blood tests were independently confirmed by a diagnostic PET-CT, which also localized the cancer. Twenty-six cancers were detected by blood testing. Of these, 15 underwent PET-CT imaging and nine (60%) were surgically excised. Twenty-four additional cancers were detected by standard-of-care screening and 46 by neither approach. One percent of participants underwent PET-CT imaging based on false-positive blood tests, and 0.22% underwent a futile invasive diagnostic procedure. These data demonstrate that multicancer blood testing combined with PET-CT can be safely incorporated into routine clinical care, in some cases leading to surgery with intent to cure.

Pegylated interferon alfa-2a for polycythemia vera or essential thrombocythemia resistant or intolerant to hydroxyurea.

Prior studies have reported high response rates with recombinant interferon-α (rIFN-α) therapy in patients with essential thrombocythemia (ET) and polycythemia vera (PV). To further define the role of rIFN-α, we investigated the outcomes of pegylated-rIFN-α2a (PEG) therapy in ET and PV patients previously treated with hydroxyurea (HU). The Myeloproliferative Disorders Research Consortium (MPD-RC)-111 study was an investigator-initiated, international, multicenter, phase 2 trial evaluating the ability of PEG therapy to induce complete (CR) and partial (PR) hematologic responses in patients with high-risk ET or PV who were either refractory or intolerant to HU. The study included 65 patients with ET and 50 patients with PV. The overall response rates (ORRs; CR/PR) at 12 months were 69.2% (43.1% and 26.2%) in ET patients and 60% (22% and 38%) in PV patients. CR rates were higher in CALR-mutated ET patients (56.5% vs 28.0%; P = .01), compared with those in subjects lacking a CALR mutation. The median absolute reduction in JAK2V617F variant allele fraction was -6% (range, -84% to 47%) in patients achieving a CR vs +4% (range, -18% to 56%) in patients with PR or nonresponse (NR). Therapy was associated with a significant rate of adverse events (AEs); most were manageable, and PEG discontinuation related to AEs occurred in only 13.9% of subjects. We conclude that PEG is an effective therapy for patients with ET or PV who were previously refractory and/or intolerant of HU. This trial was registered at www.clinicaltrials.gov as #NCT01259856.

Current advances in Hodgkin's lymphoma.

Hodgkin's lymphoma is a highly treatable malignancy. It has high cure rates yet there are many patients who relapse or are refractory to treatment. Traditionally, treatment has been with conventional chemotherapy; however, the development of brentuximab vedotin and immune checkpoint inhibitors has revolutionized the care of Hodgkin's lymphoma. This is a review of the current advances in the management of Hodgkin's lymphoma and a review of ongoing clinical trials in the field.

Thrombotic Microangiopathy Secondary to Intravenous Abuse of Opana® ER.

Opana ER (oxymorphone) is an opioid drug available throughout the United States, and intravenous abuse of the crushed oral formulation has been associated with drug-induced thrombotic microangiopathy. In this abstract, we describe two young patients who lived together and used Opana ER intravenously. Both presented with microangiopathic hemolytic anemia that mimicked thrombotic thrombocytopenic purpura (TTP). Treating this condition poses a clinical challenge, as it is difficult to distinguish it from TTP. The role for plasma exchange is not clear but can be used while awaiting the results of the ADAMTS-13 activity, but ultimately supportive care with drug discontinuation is the recommended therapy of choice. Patients should be counseled against Opana ER's intravenous use, and users should be offered drug rehabilitation therapy.

Etiologies and Short-Term Mortality in Patients with Ultraelevated Serum Ferritin.

OBJECTIVES: Hyperferritinemia is common in states of iron overload, inflammation, and malignancy. There is evidence that higher ferritin levels may be associated with worse outcomes in several clinical conditions. Available data have been drawn primarily from cases of serum ferritin between 1000 and 5000 ng/mL and from relatively few cases of serum ferritin >5000 ng/mL. In addition, most studies have allowed for the assignment of only a single etiology per case of hyperferritinemia, when many cases may result from a combination of multiple etiologies. This study evaluates the distribution of etiologies and short-term mortality in patients with ultrahyperferritinemia (defined as a serum ferritin concentration >5000 ng/mL). METHODS: We retrospectively identified 405 patients older than 18 years who had serum ferritin concentrations >5000 ng/mL measured within the Geisinger Health System between 2004 and 2014. For each patient, we evaluated demographics, serum ferritin concentration, contributing etiologies, and mortality at 30 days and 6 months following index serum ferritin measurement. RESULTS: Ultrahyperferritinemia was caused by a combination of multiple etiologies in 51% of cases, a single etiology in 44% of cases, and an undetermined etiology in 5% of cases. The majority of all cases were the result, at least in part, of chronic blood transfusions (48%), acute liver injury (44%), malignancy (33%), myelodysplastic syndrome (11%), or end-stage renal disease (ESRD;10%). Acute liver injury accounted for the majority of cases (73%) of ultrahyperferritinemia caused by a single etiology, whereas neither myelodysplastic syndrome nor ESRD was the sole etiology for a single case. Hemophagocytic lymphohistiocytosis and macrophage activation syndrome were associated with the highest mean serum ferritin levels by far, but acute liver injury remained the most common cause of single-etiology cases across all ferritin levels and accounted for 92% of cases >20,000 ng/mL. Mortality increased substantially between 30 days and 6 months for patients with ultrahyperferritinemia caused by malignancy (from 64% to 93%) but only modestly for patients with ultrahyperferritinemia caused by acute liver injury (from 33% to 39%). CONCLUSIONS: Many cases of ultrahyperferritinemia are caused by a combination of multiple distinct etiologies. Cases of ultrahyperferritinemia among patients with ESRD and myelodysplastic syndrome may be partially explained by their often concomitant chronic blood transfusions. Acute liver injury is by far the most common cause of ultrahyperferritinemia caused by a single etiology, even at the most astronomically elevated serum ferritin concentrations. Finally, patients with ultrahyperferritinemia caused by malignancy appear to have poor 30-day survival and abysmal 6-month survival.

Gastrointestinal stromal tumors: management of metastatic disease and emerging therapies.

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Before the advent of tyrosine kinase inhibitors (TKIs) there were few treatment options available to patients with metastatic GIST. Surgery was the mainstay of treatment and the prognosis was dismal. With the advent of imatinib and second-line TKIs the prognosis of metastatic GIST has improved dramatically; however, there is still a need for therapies for patients with disease refractory to TKI therapy. Newer agents are under investigation and may have promise. This article discusses the current standard of care in terms of standard and investigational pharmacotherapy in the management of metastatic GIST.

Personalized medicine and treatment approaches in non-small-cell lung carcinoma.

Chemotherapy has been the traditional backbone for the management of metastatic lung cancer. Multiple trials have shown the benefits of treatment with platinum doublets in lung cancer. This "one treatment fits all" approach was further refined by the introduction of targeted agents and discovery of subpopulations of patients who benefited from treatment with these agents. It has also become evident that certain histologic subtypes of non-small-cell lung cancer respond better to one cytotoxic chemotherapy versus others. This has led to the concept of using histology to guide therapy. With the introduction of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and the discovery of activating mutations in the EGFR gene, further personalization of treatment for subgroups of patients has become a reality. More recently, the presence of a fusion gene, echinoderm microtubule-associated protein-like 4 - anaplastic lymphoma kinase (EML4-ALK), was identified as the driver mutation in yet another subgroup of patients, and subsequent studies have led to approval of crizotinib in this group of patients. In this article, efforts in personalizing delivery of care based on the histological subtypes of lung cancer and the role of K-RAS and EGFR mutations, EML4/ALK translocation, and ERCC1 (excision repair cross-complementing 1) and EGFR expression in choosing appropriate treatments for patients with advanced lung cancer are discussed. This article also reviews the problem of resistance to EGFR tyrosine kinase inhibitors and the ongoing trials that target novel pathways and mechanisms that are implicated in resistance.

Targeting CD30 in anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL) is a lymphoid neoplasm characterized by strong and uniform expression of the CD30 antigen on the cell surface. Current standard frontline therapy of ALCL is anthracycline-based combination chemotherapy, usually CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or CHOP-like regimens. Despite aggressive chemotherapy a significant number of patients relapse. Newer agents and strategies are needed in the management of this challenging disease especially in ALK-negative and high-risk ALK-positive patients who tend to have a poor prognosis. In this review we discuss the different approaches to targeting CD30 including naked antibodies, "enhanced antibodies", antibody drug-toxin conjugates, radioimmunoconjugates, CD30-ligand-toxin conjugates, bispecific antibodies and T cell-based immune therapies.