Psychological mobile app for patients with acute myeloid leukemia: A pilot randomized clinical trial.

BACKGROUND: Patients with acute myeloid leukemia (AML) experience a substantial decline in quality of life (QoL) and mood during their hospitalization for intensive chemotherapy, yet few interventions have been developed to enhance patient-reported outcomes during treatment. METHODS: We conducted a pilot randomized trial (ClinicalTrials.gov identifier NCT03372291) of DREAMLAND, a psychological mobile application for patients with a new diagnosis of AML who are receiving intensive chemotherapy. Patients were randomly assigned to DREAMLAND or usual care. DREAMLAND included four required modules focused on: (1) supportive psychotherapy to help patients deal with the initial shock of diagnosis, (2) psychoeducation to manage illness expectations, (3) psychosocial skill-building to promote effective coping, and (4) self-care. The primary end point was feasibility, which was defined as ≥60% of eligible patients enrolling and 60% of those enrolled completing ≥60% of the required modules. We assessed patient QoL (the Functional Assessment of Cancer Therapy-Leukemia), psychological distress (the Hospital Anxiety and Depression Scale and the Patient Health Questionnaire-9), symptom burden (the Edmonton Symptom Assessment Scale), and self-efficacy (the Cancer Self-Efficacy Scale) at baseline and at day 20 after postchemotherapy. RESULTS: We enrolled 60 of 90 eligible patients (66.7%), and 62.1% completed ≥75% of the intervention modules. At day 20 after chemotherapy, patients who were randomized to DREAMLAND reported improved QoL scores (132.06 vs. 110.72; p =.001), lower anxiety symptoms (3.54 vs. 5.64; p = .010) and depression symptoms (Hospital Anxiety and Depression Scale: 4.76 vs. 6.29; p = .121; Patient Health Questionnaire-9: 4.62 vs. 8.35; p < .001), and improved symptom burden (24.89 vs. 40.60; p = .007) and self-efficacy (151.84 vs. 135.43; p = .004) compared with the usual care group. CONCLUSIONS: A psychological mobile application for patients with newly diagnosed AML is feasible to integrate during hospitalization for intensive chemotherapy and may improve QoL, mood, symptom burden, and self-efficacy.

NCCN Guidelines Insights: Management of Immunotherapy-Related Toxicities, Version 1.2020.

The NCCN Guidelines for Management of Immunotherapy-Related Toxicities provide interdisciplinary guidance on the management of immune-related adverse events (irAEs) resulting from cancer immunotherapy. These NCCN Guidelines Insights describe symptoms that may be caused by an irAE and should trigger further investigation, and summarize the NCCN Management of Immunotherapy-Related Toxicities Panel discussions for the 2020 update to the guidelines regarding immune checkpoint inhibitor-related diarrhea/colitis and cardiovascular irAEs.

Management of Immunotherapy-Related Toxicities, Version 1.2019.

The aim of the NCCN Guidelines for Management of Immunotherapy-Related Toxicities is to provide guidance on the management of immune-related adverse events resulting from cancer immunotherapy. The NCCN Management of Immunotherapy-Related Toxicities Panel is an interdisciplinary group of representatives from NCCN Member Institutions and ASCO, consisting of medical and hematologic oncologists with expertise in a wide array of disease sites, and experts from the fields of dermatology, gastroenterology, neuro-oncology, nephrology, emergency medicine, cardiology, oncology nursing, and patient advocacy. Several panel representatives are members of the Society for Immunotherapy of Cancer (SITC). The initial version of the NCCN Guidelines was designed in general alignment with recommendations published by ASCO and SITC. The content featured in this issue is an excerpt of the recommendations for managing toxicity related to immune checkpoint blockade and a review of existing evidence. For the full version of the NCCN Guidelines, including recommendations for managing toxicities related to chimeric antigen receptor T-cell therapy, visit NCCN.org.

Challenges of Toxicity Management in Immuno-Oncology.

Immunotherapies are conveying unprecedented efficacy in some tumor types, but with this success comes challenges in managing toxicities that are distinct from those of cytotoxic agents. Although most immune-related adverse events can be ameliorated by temporarily withholding the drug and administering steroids, grade 3 to 4 toxicities can be challenging and some adverse effects can be long-lasting. NCCN has developed an immunotherapy teaching and monitoring tool that can help in evaluating and managing these autoimmune-mediated inflammatory conditions, which can affect virtually all organ systems.

New-onset toxicity with programmed death-1 inhibitor rechallenge.

Immunotherapy has become a mainstay in the treatment of metastatic melanoma. Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) inhibitors and programmed death-1 (PD-1) inhibitors, which have been added more recently, represent two of the main classes of immunomodulating agents. PD-1 inhibitors are well tolerated and are known to have a decreased rate of occurrence of adverse effects compared with CTLA-4 inhibitors. However, the risk remains for serious immune-mediated adverse reactions. Given their long half and extended efficacy, treatment with a CTLA-4 inhibitor before use of a PD-1 inhibitor may increase the risk of adverse effects. In addition, caution should be exercised when rechallenging grade 3 or 4 adverse effects with the same agent or a different agent of the same class. The re-emergence of a previous toxicity may occur or, as found in this case, a new severe effect may arise. This article will present a case of fatal immune-related hepatoxicity in a patient treated with a CTLA-4 inhibitor, followed by treatment with a PD-1 inhibitor. The mechanisms of action and safety profiles for both classes of drugs will also be reviewed.

Primer on immuno-oncology and immune response.

Advances in the understanding of the immunogenicity of tumors have provided the basis for immuno-oncology, the development of immunotherapeutic agents that augment the patient's antitumor immunity and disrupt the immune-regulatory circuits that allow tumors to evade the immune system. Two immunomodulatory agents recently have been introduced for the treatment of malignancy: sipuleucel-T and ipilimumab. Unlike cytotoxic chemotherapy, immunotherapies stimulate the patient's immune system to mount or augment existing endogenous antitumor immune responses. Both agents have demonstrated significant improvements in long-term overall survival in patients. Like other immunotherapies, sipuleucel-T and ipilimumab also are characterized by adverse events that manifest as immune-related inflammatory conditions that typically are low grade. Management guidelines have been developed and emphasize early recognition of the signs and symptoms of immune-related adverse events and treatment with corticosteroids. Because these events can manifest even after the cessation of therapy, patients treated with immunotherapies should continue to be followed by their oncology team and other healthcare providers.

Characteristics and management of immunerelated adverse effects associated with ipilimumab, a new immunotherapy for metastatic melanoma.

When diagnosed in its early stages, melanoma is highly treatable and associated with good long-term outcomes; however, the prognosis is much poorer for patients diagnosed with advanced or metastatic melanoma. For decades, available treatments were effective in only a few patients and associated with significant safety concerns. Ipilimumab is a novel immunotherapy which has proved to be an exciting breakthrough in the treatment of melanoma. It is the first drug approved for the treatment of melanoma by the Food and Drug Administration (FDA) which has shown a survival benefit in a randomized Phase III clinical trial. The objective of this review is to provide information on the administration, treatment responses, and expected outcomes of treatment of metastatic melanoma with the new immunotherapeutic agent, ipilimumab, a drug with a unique mechanism of action that differentiates it from current treatments. Guidelines for the management of immune-related adverse events associated with ipilimumab therapy are also presented. These stress vigilance, prompt intervention, and the use of corticosteroids as appropriate. Various ipilimumab-associated immune-related adverse events, both common (enterocolitis, dermatitis) and less frequent (hepatitis, hypophysitis), are illustrated in case studies. Nurses are uniquely positioned to provide patient and caregiver education on how this new therapy differs from traditional cytotoxic agents, to recognize the signs and symptoms of immune-related adverse events, and to report them immediately, and finally, to be aware of the patterns of response that are commonly observed in patients receiving ipilimumab therapy.

Phase I trial of interleukin-12 plasmid electroporation in patients with metastatic melanoma.

PURPOSE: Gene-based immunotherapy for cancer is limited by the lack of safe, efficient, reproducible, and titratable delivery methods. Direct injection of DNA into tissue, although safer than viral vectors, suffers from low gene transfer efficiency. In vivo electroporation, in preclinical models, significantly enhances gene transfer efficiency while retaining the safety advantages of plasmid DNA. PATIENTS AND METHODS: A phase I dose escalation trial of plasmid interleukin (IL)-12 electroporation was carried out in patients with metastatic melanoma. Patients received electroporation on days 1, 5, and 8 during a single 39-day cycle, into metastatic melanoma lesions with six 100-mus pulses at a 1,300-V/cm electric field through a penetrating six-electrode array immediately after DNA injection. Pre- and post-treatment biopsies were obtained at defined time points for detailed histologic evaluation and determination of IL-12 protein levels. RESULTS: Twenty-four patients were treated at seven dose levels, with minimal systemic toxicity. Transient pain after electroporation was the major adverse effect. Post-treatment biopsies showed plasmid dose proportional increases in IL-12 protein levels as well as marked tumor necrosis and lymphocytic infiltrate. Two (10%) of 19 patients with nonelectroporated distant lesions and no other systemic therapy showed complete regression of all metastases, whereas eight additional patients (42%) showed disease stabilization or partial response. CONCLUSION: This report describes the first human trial, to our knowledge, of gene transfer utilizing in vivo DNA electroporation. The results indicated this modality to be safe, effective, reproducible, and titratable.

Phenotypic and functional analysis of dendritic cells and clinical outcome in patients with high-risk melanoma treated with adjuvant granulocyte macrophage colony-stimulating factor.

PURPOSE: Granulocyte macrophage colony-stimulating factor (GM-CSF) can induce differentiation of dendritic cells (DCs) in preclinical models. We hypothesized that GM-CSF-stimulated DC differentiation may result in clinical benefit in patients with high-risk melanoma. PATIENTS AND METHODS: We conducted a prospective trial in patients with high-risk (stage III B/C, IV), resected melanoma, with GM-CSF 125 microg/m(2)/d administered for 14 days every 28 days. Patients underwent clinical restaging every four cycles, with DC analysis performed at baseline and at 2, 4, 8, and 12 weeks. RESULTS: Of 42 patients enrolled, 39 were assessable for clinical outcome and DC analysis. Median overall survival was 65 months (95% CI, 43 to 67 months) and recurrence-free survival was 5.6 months (95% CI, 3 to 11 months). GM-CSF treatment caused an increase in mature DCs, first identified after 2 weeks of treatment, normalizing by 4 weeks. Patients with decreased DCs at baseline had significant increases in DC number and function compared with those with "normal" parameters at baseline. No change was observed in the number of myeloid-derived suppressor cells (MDSCs). Early recurrence (< 90 days) correlated with a decreased effect of GM-CSF on host DCs, compared with late or no (evidence of) recurrence. CONCLUSION: GM-CSF treatment was associated with a transient increase in mature DCs, but not MDSCs. Greater increase of DCs was associated with remission or delayed recurrence. The prolonged overall survival observed warrants further exploration.

Elevated serum tobramycin concentrations after treatment with tobramycin inhalation in a preterm infant.

High-dose inhaled tobramycin has been increasingly used for treatment and suppression of Pseudomonas aeruginosa pulmonary infections, especially in patients with cystic fibrosis. The advantage of inhalation over other routes of administration is minimal systemic absorption, which reduces the potential for adverse effects. However, cases of adults who had elevated serum concentrations and experienced systemic adverse effects due to excessive systemic absorption after inhaled tobramycin have been reported. We describe a prematurely born infant with numerous congenital and acquired disorders who required assisted mechanical ventilation and a 60-day stay in the neonatal intensive care unit (NICU). Tracheostomy and mechanical ventilatory support were required throughout the infant's hospital stay. The patient developed several pulmonary infections caused by various bacteria. He was treated with multiple antibiotics, including two different dose preparations of inhaled tobramycin 80 mg and 300 mg, administered through the tracheostomy and the ventilator. The infant was given a total of five preparations of tobramycin 80 mg/dose and three of 300 mg/dose, for a total cumulative dose of 1,300 mg over a 6-day period. His tobramycin concentrations increased, prompting discontinuation of the inhaled tobramycin. The infant died on day 60. To our knowledge, this is the first report of elevated tobramycin concentrations after inhalation in an infant. Although studies have found that tobramycin is safe and effective, certain patient populations are more at risk for toxicity. Tobramycin concentrations should be closely monitored in patients with significant underlying renal disorders, especially those in age-group extremes.

The safety and tolerability of galantamine in patients with epilepsy and memory difficulties.

Individuals with epilepsy commonly experience memory loss. We investigated the safety and tolerability of galantamine in treatment of memory loss in a pilot study of 28 patients with epilepsy, randomly assigned to galantamine (n=13) or placebo (n=15) and followed for a total of 12 weeks. Participants underwent blinded memory assessment at baseline and 12 weeks (Selective Reminding Test, 7/24 Spatial Recall). One participant in the galantamine group had a suspected recurrence of brain neoplasm and increased seizures; all other participants receiving galantamine showed no increase in seizure activity during the trial. Patients in both groups reported mild, tolerable side effects (headache, appetite suppression), with no difference between groups. No significant differences were observed on the memory measures when both groups were retested at Week 12. Galantamine appears to be safe and tolerable in patients with epilepsy. Further studies with larger samples and comparison with other cholinesterase inhibitors should be considered.

Overall and progression-free survival in metastatic melanoma: analysis of a single-institution database.

BACKGROUND: Many new agents are currently in trial in melanoma. It remains unclear, however, what the benefit of a given therapy may be since information on progression-free and overall survival of untreated patients is limited. Since few trials in melanoma have had a non-treated cohort, it remains unclear what survival can be expected in patients who are not treated with chemotherapy. METHODS: To help develop parameters for future trials, we analyzed treatment history and survival in 212 patients with metastatic melanoma seen at our institution between January 1998 and September 2003. A retrospective analysis was done using a database created for melanoma patients at our center. Patient survival information was determined from this database, tumor registry, Social Security index, and direct patient calls. Patient staging information was determined according to the 2001 guidelines. Non-chemotherapy-treated patients with M1c disease were used as "controls." RESULTS: The median survival of stage M1c melanoma was 6.0 months. Survival was longer for stage M1a and M1b and shorter in older patients. No significant differences were found in survival based on gender. Among chemotherapy-treated patients, those with progressive disease on treatment or with increased lactate dehydrogenase (LDH) fared worse than those with a clinical response or normal LDH, respectively. Patients treated with either biochemotherapy or temozolomide and thalidomide survived longer than those who received no chemotherapy treatment. Dacarbazine (DTIC) treatment did not prolong survival. CONCLUSIONS: In this retrospective review of patients treated at a single institution, those treated with multiagent chemotherapy but not with single-agent DTIC appeared to have had a survival benefit.

Survival after surgical resection of isolated pulmonary metastases from malignant melanoma.

BACKGROUND: The overall prognosis for patients with metastatic malignant melanoma remains poor. However, careful staging and identification of patients with limited metastatic disease offers the opportunity for surgical salvage and improved survival for selected patients. METHODS: We reviewed the experience over the last 17 years at our institute with isolated pulmonary metastasectomy in 86 patients with advanced malignant melanoma. RESULTS: Our data demonstrate an overall median time to relapse of approximately 8.4 months and a median survival of 35 months. The 5-year survival rate is estimated at 33%, and 16% remain continuously free of disease after a median follow-up of 35 months. Resection of properly staged and evaluated patients with limited pulmonary metastases appears to convey a significant survival benefit. Patients with a single metastasis fare best. CONCLUSIONS: These encouraging results offer a rationale for the careful follow-up of resected patients. One third of all relapses will be limited and additional surgery contributes to their overall survival.

The DNA sequence of human chromosome 7.

Human chromosome 7 has historically received prominent attention in the human genetics community, primarily related to the search for the cystic fibrosis gene and the frequent cytogenetic changes associated with various forms of cancer. Here we present more than 153 million base pairs representing 99.4% of the euchromatic sequence of chromosome 7, the first metacentric chromosome completed so far. The sequence has excellent concordance with previously established physical and genetic maps, and it exhibits an unusual amount of segmentally duplicated sequence (8.2%), with marked differences between the two arms. Our initial analyses have identified 1,150 protein-coding genes, 605 of which have been confirmed by complementary DNA sequences, and an additional 941 pseudogenes. Of genes confirmed by transcript sequences, some are polymorphic for mutations that disrupt the reading frame.