A mass spectrometry assay for detection of endogenous and lentiviral engineered hemoglobin in cultured cells and sickle cell disease mice.

Sickle cell disease (SCD) results from a sequence defect in the ß-globin chain of adult hemoglobin (HbA) leading to expression of sickle hemoglobin (HbS). It is traditionally diagnosed by cellulose-acetate hemoglobin electrophoresis or high-performance liquid chromatography. While clinically useful, these methods have both sensitivity and specificity limitations. We developed a novel mass spectrometry (MS) method for the rapid, sensitive and highly quantitative detection of endogenous human ß-globin and sickle hß-globin, as well as lentiviral-encoded therapeutic hßAS3-globin in cultured cells and small quantities of mouse peripheral blood. The MS methods were used to phenotype homozygous HbA (AA), heterozygous HbA-HbS (AS) and homozygous HbS (SS) Townes SCD mice and detect lentiviral vector-encoded hßAS3-globin in transduced mouse erythroid cell cultures and transduced human CD34+ cells after erythroid differentiation. hßAS3-globin was also detected in peripheral blood 6 weeks post-transplant of transduced Townes SS bone marrow cells into syngeneic Townes SS mice and persisted for over 20 weeks post-transplant. As several genome-editing and gene therapy approaches for severe hemoglobin disorders are currently in clinical trials, this MS method will be useful for patient assessment before treatment and during follow-up.

Immune checkpoint inhibitor-related adverse events: Real-world experience from a single veterans' affairs medical center.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are antineoplastic agents associated with a multitude of immune-related adverse events (irAEs). Available data from clinical trials include highly selective patient populations which may limit their applicability to real-world clinical practice. METHODS: We present a retrospective cohort study of cancer patients treated with ICI therapy at the Zablocki VA Medical Center between 2014 and 2021. Information on demographics, cancer diagnosis, type of therapy, treatment duration, comorbidities, irAE type, and overall survival were collected. RESULTS: We identified 187 patients who received at least one dose of ICI. About half the patients experienced at least one irAE, the most common categories being fatigue, pulmonary, and endocrine irAEs. Approximately half of the irAEs were diagnosed within the first three months of starting ICI therapy, and 60.38% of those who experienced irAEs discontinued ICI therapy. Patients who experienced endocrine or intestinal irAEs had a significantly longer overall survival. CONCLUSION: Immune-related complications due to ICI therapy are common and can frequently lead to treatment discontinuation in the real-world setting. Endocrine and intestinal irAEs may correlate with improved survival. The ICI-treated patients who received palliative radiation therapy to the bone had less irAEs, possibly due to immunogenic cell death.

Severe terminal ileitis induced by single-agent nivolumab administered every four weeks.

INTRODUCTION: Use of immune checkpoint inhibitors has expanded to a variety of malignancies including hepatocellular carcinoma, where nivolumab and pembrolizumab have shown durable responses in approximately a sixth of patients. CASE REPORT: We report herein a patient with metastatic hepatocellular carcinoma who achieved a durable response to the second-line agent nivolumab administered intravenous 240 mg every two weeks. After 18 months of therapy, nivolumab schedule was changed to intravenous 480 mg every four weeks, per patient's request and for convenience of administration. Four days after this change, the patient developed severe terminal ileitis.Management and outcome: This condition was managed in hospital with intravenous steroids. The patient improved clinically and was discharged on an oral steroid taper. A month later, nivolumab was reinstated at 200 mg intravenous infusions every two weeks, without any re-occurrence of terminal ileitis to date as of six months after the probable drug reaction. DISCUSSION: To our knowledge, this is the first report of terminal ileitis with nivolumab administered every four weeks. As postmarketing evaluation of nivolumab continues, similar side effects may be observed. Prompt diagnosis and steroid therapy in these cases are imperative to ensure a favorable outcome. Resuming immunotherapy once the adverse event has resolved appears to be a safe option.

Systemic therapy for relapsed/refractory meningioma: Is there potential for antiangiogenic agents?

Effective therapies for relapsed/refractory meningioma after surgery and radiation therapy represent an unmet need. Most meningiomas are highly vascularized tumors and, therefore, potentially amenable to antiangiogenic therapy. Herein, we review comprehensively the scientific literature on systemic therapy options for relapsed, persistent or metastatic meningioma, not amenable to local therapy. Also, this review offers insights into the function of vascular endothelial growth factor/receptor pathway both in health and disease. Further, we address the current status of the preclinical and clinical studies targeting vascular endothelial growth factor/receptor signaling in meningioma. Most relevant publications were identified through searching the PubMed/Medline database for articles published from inception to 1 February 2018. Vascular endothelial growth factor pathway activation might represent the primary driver of angiogenesis in meningioma. Positive findings of two prospective phase II trials, supported by the results of several retrospective cohorts, suggest a clinical benefit for the vascular endothelial growth factor inhibitor bevacizumab in refractory meningioma. Bevacizumab causes both peritumoral brain edema reduction and true meningioma shrinkage. Patients with WHO grades II-III meningioma appear to benefit more than patients with grade I disease. Similarly, responses have been documented with certain oral targeted anti-vascular endothelial growth factor/receptor agents. Further exploration of the role of vascular endothelial growth factor/receptor inhibitors in refractory meningioma seems warranted.

Longitudinal thumbnail fissures due to erlotinib therapy for lung cancer.

While therapy with epidermal growth factor receptor inhibitors leads to meaningful clinical responses in several tumor types, it has also been linked with perplexing toxic effects. Skin effects of these agents such as generalized papulo-pustular rash, trichomegaly, fingertip fissures, xerosis, pruritus and paronichias are now well characterized. Though uncommon, nail atrophic changes have also been described in subjects treated with these classes of agents. We describe herein unusual longitudinal thumbnail fissures caused by erlotinib therapy for metastatic lung cancer. Unique features are bilateral thumbnail involvement and central location in the nail bed. This side effect of erlotinib has not been previously reported in the medical literature.

Retroperitoneal fibrosis due to B-cell non-Hodgkin lymphoma: Responding to rituximab!

Retroperitoneal fibrosis is a rare disease manifesting as chronic soft tissue fibrosis in the retroperitoneum, with potential anatomic and/or functional compromise of adjacent organs. It can be primary (idiopathic) or secondary to other conditions such as cancers, autoimmune disorders, or drugs. We report herein a 66-year-old patient with symptomatic retroperitoneal fibrosis leading to bilateral hydronephrosis and renal failure, in whom, after a complex diagnostic work-up and protracted clinical course, a B-cell non-Hodgkin lymphoma in the retroperitoneal space and several vertebral bodies was identified. The patient was treated with radiation therapy and weekly rituximab infusions, with resolution of hydronephrosis and lower back pain. We include a thorough literature review on etiopathogenesis, diagnosis, therapy, and prognosis of retroperitoneal fibrosis. A meticulous search for malignancy is necessary in this rare condition that, if positive, may have significant therapeutic and prognostic implications.

Synchronous Tumors: Adenocarcinoma of the Esophagus and Clear Cell Renal Carcinoma.

Synchronous cancers in patients with esophageal cancer are rare. We present a female nonsmoker with gastrointestinal symptoms that led to the diagnosis of HER-2/neu positive esophageal adenocarcinoma. During the staging workup, she was found to have a synchronous early-stage clear cell renal carcinoma. The patient underwent an esophagogastrectomy and radical nephrectomy and remains disease-free at a 12-month follow-up visit. We offer a detailed literature review on esophageal cancer and second primary malignancies seen in this context. Our case is unique as the literature suggests more advanced staging at diagnosis and poorer prognosis in persons with synchronous or metachronous cancers of esophagus and kidney. We believe that studies involving more patients are needed for the long-term prognosis assessment in these patients.

CD5 negative mantle cell lymphoma: a different clinical entity?

We report herein a 77-year-old patient with CD5 negative mantle cell lymphoma (MCL). We further review the existing literature on clinicolaboratory features of this rare MCL subtype. Although most of the patients in the literature (including ours) had advanced stage at diagnosis, splenomegaly, and bone marrow involvement, they displayed prompt and durable responses to conventional treatment. We postulate that CD5 surface antigen expression could have prognostic implications in MCL. Further research and a larger number of patients are necessary in order to validate these findings.

Pathophysiological characterization of the Townes mouse model for sickle cell disease.

A deeper pathophysiologic understanding of available mouse models of sickle cell disease (SCD), such as the Townes model, will help improve preclinical studies. We evaluated groups of Townes mice expressing either normal adult human hemoglobin (HbA), sickle cell trait (HbAS), or SCD (HbS), comparing younger versus older adults, and females versus males. We obtained hematologic parameters in steady-state and hypoxic conditions and evaluated metabolic markers and cytokines from serum. Kidney function was evaluated by measuring the urine protein/creatinine ratio and urine osmolality. In vivo studies included von Frey assay, non-invasive plethysmography, and echocardiography. Histopathological evaluations were performed in lung, liver, spleen, and kidney tissues. HbS mice displayed elevated hemolysis markers and white blood cell counts, with some increases more pronounced in older adults. After extended in vivo hypoxia, hemoglobin, platelet counts, and white blood cell counts decreased significantly in HbS mice, whereas they remained stable in HbA mice. Cytokine analyses showed increased TNF-alpha in HbS mice. Kidney function assays revealed worsened kidney function in HbS mice. The von Frey assay showed a lower threshold to response in the HbS mice than controls, with more noticeable differences in males. Echocardiography in HbS mice suggested left ventricular hypertrophy and dilatation. Plethysmography suggested obstructive lung disease and inflammatory changes in HbS mice. Histopathological studies showed vascular congestion, increased iron deposition, and disruption of normal tissue architecture in HbS mice. These data correlate with clinical manifestations in SCD patients and highlight analyses and groups to be included in preclinical therapeutic studies.

Survival to leukemia and lymphomas in children at a University Hospital in Cali, Colombia.

INTRODUCTION: Leukemia and lymphomas are the 2 most frequent malignancies among children in Cali, Colombia, although survival information for these malignancies remains limited in both Cali and throughout all of Colombia. OBJECTIVE: To estimate the 5-year survival rate in children diagnosed with leukemia and lymphomas in the University Hospital of Valle, at Cali, Colombia. METHODS: Three hundred and twenty-four patients younger than 15 years of age were included, diagnosed with either leukemia or lymphomas from 1998 to 2006. Active follow-up was conducted by clinical records reviewing and phone contacting. The cumulative survival rate was estimated to be from 1 to 5 years from diagnosis using the actuarial method. The Cox regression model was used to determine some of the factors associated with the prognosis. RESULTS: Of all cases, 61.8% were male patients, 75.3% corresponded to leukemia, and the rest to lymphomas. The global cumulated survival rate at 1 and 5 years were 71% and 50%, respectively. The risk of death from lymphomas was lower compared with leukemia, hazard ratio=0.36 (P<0.01). The highest cumulated survival rate was found in the group 5 to 9 years old (61%), followed by the group 0 to 4 years old (48%) and the group 10 to 14 years old (41%), all results reaching statistical significance (P<0.01), and showing lower survival rates than the data from international literature. CONCLUSIONS: The survival rates for leukemia and lymphomas in Cali are lower compared with the data of developed countries, suggesting that there are deficiencies in early diagnosis and in access to medication and opportune treatment.

Durvalumab in cancer medicine: a comprehensive review.

Introduction: The U.S. FDA has approved durvalumab for the treatment of advanced urothelial and non-small cell lung cancers. However, this immunotherapy agent is also being explored in other cancers. There is also ongoing research to better predict the responses to this drug. Areas covered: We summarize the literature regarding durvalumab pharmacology, safety and efficacy in several tumor types. We searched PubMed/Medline database from inception to 20 April 2019, performed a snowball method, and visited independent websites such as the U.S. FDA ( https://www.fda.gov ), ClinicalTrials.gov, among others. Expert opinion: Advanced phase clinical trials have shown benefit of durvalumab in advanced urothelial and non-small cell lung cancers, and suggest benefit in several other tumor types. This agent has a tolerable toxicity profile and seems more effective in patients with a higher PDL-1 expression, although this correlation is not perfect. An improved method to predict a response to durvalumab would be beneficial to best tailor therapy and minimize medical care costs. More research is needed to establish its efficacy in different disease stages and applicability in other tumor types. Hopefully, prospective, randomized trials of durvalumab, alone and/or in combination with other agents, will bring answers to these questions in the near future.

Bevacizumab in refractory higher-grade and atypical meningioma: the current state of affairs.

INTRODUCTION: Historically, systemic agents had shown limited efficacy in meningioma, at the expense of significant pharmacologic and/or financial toxicity. As meningiomas are highly vascularized, they might derive benefit from antiangiogenic therapy. AREAS COVERED: This review summarizes the literature regarding bevacizumab pharmacology, safety and efficacy in patients with refractory meningioma. We have searched PubMed/Medline database for pertinent articles published from inception to 1 September 2018. EXPERT COMMENTARY: Results of two prospective phase II trials, supported by several retrospective cohorts, suggest a clinical benefit for the vascular endothelial growth factor inhibitor bevacizumab in meningiomas refractory to surgery and radiation therapy. This agent has a tolerable toxicity profile and seems more effective in higher-grade histologies and atypical meningioma, although responses in low-grade meningiomas have also been documented. Our conclusions are restricted due to a small size and lack of control in the prospective trials as well as the retrospective design of other studies. Further study of bevacizumab in refractory higher-grade meningiomas seems warranted.

ASXL1 mutations in myeloid neoplasms: pathogenetic considerations, impact on clinical outcomes and survival.

BACKGROUND: ASXL1 gene mutations include nonsense, missense, and frameshift mutations. Although their clinical significance is still debated, they may play an important role in the pathogenesis of several hematologic malignancies. METHODS: Herein, we offer a comprehensive review on ASXL1 mutations, and link them with survival and clinical outcomes in patients with various myeloid neoplasms. Most relevant publications were identified through searching the PubMed/Medline database for articles published from inception to February 2016. FINDINGS: In acute myeloid leukemia (AML), ASXL1 mutations tend to correlate with older age and male gender, and affect predominantly patients with secondary AML. De novo AML patients with ASXL1 mutations had significantly lower complete remission rates after standard high-dose chemotherapy and shorter survival. In chronic myelomonocytic leukemia and low- or intermediate-risk myelodysplastic syndromes, frameshift and nonsense mutations correlated with shorter survival and a higher risk of leukemic transformation. Overall survival was also shorter in primary myelofibrosis in the presence of ASXL1 mutations. CONCLUSIONS: Further research on the role of ASXL1 mutations and therapeutic implications in neoplastic myeloid disorders is stringently needed. Given the relatively high prevalence of ASXL1 mutations, larger studies involving patients affected by these mutations will be feasible in the near future.

Autoimmune manifestations in patients with multiple myeloma and monoclonal gammopathy of undetermined significance.

BACKGROUND: Multiple myeloma (MM) and its precursor, monoclonal gammopathy of undetermined significance (MGUS), have been linked with several autoimmune conditions in the medical literature. Yet, significance of these associations is not well understood. METHODS: Herein, we provide a comprehensive literature review on autoimmune disorders identified in patients with MM and MGUS. Most relevant papers were identified via searching the PubMed/Medline and EMBASE databases for articles published from inception until May 1, 2016. FINDINGS: Scientific literature on autoimmune conditions in patients with MM and MGUS consists of several case series and a multitude of case reports. Our analysis suggests an increased prevalence of autoimmune conditions in patients with MM and monoclonal gammopathy of undetermined significance (MGUS), including various autoimmune hematologic and rheumatologic conditions among other entities. Conversely, persons with various autoimmune conditions tend to have a higher prevalence of MGUS and MM than the general population. CONCLUSIONS: Future research is required to explore further the link between MGUS/MM and autoimmune disorders. Inflammation in the setting of autoimmunity may serve as a trigger for MGUS and MM. In addition, a common genetic susceptibility for developing both an autoimmune disease and MM/MGUS might also exist. Autoimmune hematologic and rheumatologic diseases may pose important clinical problems for the MM patients. Therefore, a catalogue of these problems is important so that physicians are able to consider, identify and address them promptly.

Autoimmune disorders in patients with T-cell lymphoma: a comprehensive review.

BACKGROUND: Increased risk of B-cell lymphoma in patients with autoimmune diseases is well known. Medical literature also links various autoimmune conditions with T-cell lymphomas (TCLs), a rarer but very heterogeneous group of generally aggressive neoplasms. METHODS: Herein, we provide a comprehensive analysis of the available peer-reviewed literature on epidemiology, clinico-laboratory features and management of autoimmune diseases in patients with TCL. Most relevant publications were identified through searching the PubMed/Medline database for articles published from inception to June 2014. FINDINGS: Prevalence of various hematologic and non-hematologic autoimmune conditions in patients with TCL appears to be increased. Due to the rarity of TCL, scientific literature on autoimmune conditions in these patients consists mainly of case series and isolated reports. CONCLUSIONS: Autoimmune disorders can develop prior to, during or after the onset of TCL. The diagnosis of TCL should prompt early recognition of certain autoimmune disorders if clinical suspicion exists. A dysfunctional immune response in these patients may be responsible for the occurrence of autoimmunity. Conversely, autoimmune conditions might create a favorable milieu for T-cell lymphoma pathogenesis. Therefore, their presence should increase the suspicion of TCL in an appropriate clinico-laboratory context. There is need for larger studies to assess further the TCL-autoimmunity relationship as prognosis and management of these patients can be considerably affected.

Autoimmune disorders in patients with hairy cell leukemia: are they more common than previously thought?

BACKGROUND: For a number of decades, hairy cell leukemia (HCL) has been linked with polyarthritis, vasculitis, symptomatic cytopenias and thrombosis in the medical literature. Notwithstanding, the significance of these associations has not been well understood. Therefore, we have decided to analyze them further. METHODS: We provide herein a comprehensive literature review of the prevalence of autoimmune disorders in patients with HCL. Most relevant publications were identified through searching the PubMed/Medline database for articles published from inception to February 2014. FINDINGS: Perhaps due to the rarity of HCL, scientific literature on autoimmune conditions in patients with HCL consists mainly of published case series and isolated reports. Our analysis identified increased prevalence of various autoimmune conditions in patients with HCL, including various vasculitides, immune cytopenias and antiphospholipid antibody syndrome (APS) among others. CONCLUSIONS: Presence of certain autoimmune disorders should increase the suspicion of HCL in an appropriate clinico-laboratory context. Conversely, the diagnosis of HCL should prompt early recognition of certain autoimmune disorders if clinical suspicion exists. While some of these autoimmune diseases are thought to be secondary to the dysfunctional immune response associated with underlying malignant process, others could be primary and might even play a role in the HCL pathogenesis. The autoimmune complications can pose important clinical problems for the HCL patients. Therefore, a catalogue of these problems is important for alerting physicians to watch for them and diagnose them promptly.

Decision boxes for clinicians to support evidence-based practice and shared decision making: the user experience.

BACKGROUND: This project engages patients and physicians in the development of Decision Boxes, short clinical topic summaries covering medical questions that have no single best answer. Decision Boxes aim to prepare the clinician to communicate the risks and benefits of the available options to the patient so they can make an informed decision together. METHODS: Seven researchers (including four practicing family physicians) selected 10 clinical topics relevant to primary care practice through a Delphi survey. We then developed two one-page prototypes on two of these topics: prostate cancer screening with the prostate-specific antigen test, and prenatal screening for trisomy 21 with the serum integrated test. We presented the prototypes to purposeful samples of family physicians distributed in two focus groups, and patients distributed in four focus groups. We used the User Experience Honeycomb to explore barriers and facilitators to the communication design used in Decision Boxes. All discussions were transcribed, and three researchers proceeded to thematic content analysis of the transcriptions. The coding scheme was first developed from the Honeycomb's seven themes (valuable, usable, credible, useful, desirable, accessible, and findable), and included new themes suggested by the data. Prototypes were modified in light of our findings. RESULTS: Three rounds were necessary for a majority of researchers to select 10 clinical topics. Fifteen physicians and 33 patients participated in the focus groups. Following analyses, three sections were added to the Decision Boxes: introduction, patient counseling, and references. The information was spread to two pages to try to make the Decision Boxes less busy and improve users' first impression. To try to improve credibility, we gave more visibility to the research institutions involved in development. A statement on the boxes' purpose and a flow chart representing the shared decision-making process were added with the intent of clarifying the tool's purpose. Information about the risks and benefits according to risk levels was added to the Decision Boxes, to try to ease the adaptation of the information to individual patients. CONCLUSION: Results will guide the development of the eight remaining Decision Boxes. A future study will evaluate the effect of Decision Boxes on the integration of evidence-based and shared decision making principles in clinical practice.