Very Late Relapse in Pediatric Acute Myeloid Leukemia: A Case Report and Brief Literature Review.

Acute myeloid leukemia (AML) is a heterogenous group of diseases affecting ~500 children in the United States annually. With current therapy, 90% of these children will obtain complete remission. However, 30% to 40% of these patients will relapse, most commonly within the first 3 years. Very late relapses, defined as relapse occurring >5 years after complete remission, are rare, accounting for 1% to 3% of relapses. We describe a patient with AML harboring an AFDN/KMT2A translocation who relapsed 12 years after matched sibling stem cell transplant, provide a brief review of the relevant literature, and describe proposed mechanisms to explain very late relapse AML.

Improving Inferior Vena Cava Filter Retrieval and Success Rates Using an Office Endovascular Center.

BACKGROUND: The Food and Drug Administration recommends that retrievable inferior vena cava filters (IVCFs) be removed 29-54 days postinsertion. Nationally, the retrieval rate is around 23-25%. The objectives of this study are to assess the effect of a plan for IVCF retrieval and access to an office endovascular center (OEC) on filter removal rates and to assess the safety of the procedure in an OEC. METHODS: In this institutional review board-exempt retrospective study, the medical records of all patients who had an IVCF placed or removed in the hospital and OEC setting by one group of vascular surgeons between January 2011 and February 2017 were analyzed. Informed consent was not required for this retrospective chart review. The following data were abstracted: filter model, procedure site, retrieval plan, number of removal attempts, complications attributed to removal, success of removal, and the duration that the filter was in place. Anticoagulation was not discontinued before filter retrieval. Filters were removed under local anesthesia with or without mild conscious sedation. RESULTS: IVCF removal was attempted in all eligible patients, 120 of 191 with IVCFs, whereas 71 patients were lost to follow-up (46), died (19), or the indication changed (6). Of the patients who had filters placed in the hospital (n = 161), 62% were removed (n = 101), of which 86% had a removal attempt in the OEC, whereas 14% had the filter removed in the hospital. Sixty-three percent of patients who had filters placed in the OEC (n = 30) had the filter removed in the OEC (n = 19). All patients with a newly placed filter were given an office appointment with a vascular surgeon for evaluation and removal planning. Of patients who had their filter removed at the OEC, all were removed via the jugular approach, resulting in 103 of 106 (97%) successful removals in the OEC. Visipaque (GE Healthcare, Chicago, IL) contrast was used during filter removal. Intravascular ultrasound was not used because the study predates the insurance coverage of this technology in the office laboratory. There was no mortality related to filter removal. In addition, there were no bleeding complications, despite patients remaining on anticoagulant therapy during the removal. In 4% of patients, the filter was removed in less than 3 weeks, 30% of patients between 3 and 6 weeks, 26% of patients between 6 weeks and 3 months, and 40% of patients after 3 months. CONCLUSIONS: Having access to both an OEC and a documented retrieval plan increases the frequency of IVCF removal in a community compared with national rates. Retrievable filters can be safely removed in an OEC with extremely high success and safety. Anticoagulation therapy can be continued during retrieval attempt without increased risk of bleeding.

Perceived Barriers and Trends in HPV Vaccination via Patient Survey Responses at Kalamazoo, Michigan's Federally-Qualified Health Center.

Human Papillomavirus (HPV) is the most common sexually transmitted infection (STI) in the United States. Despite numerous studies proving the safety and efficacy of the HPV vaccine, immunization rates remain low, especially among underserved populations. To identify factors contributing to low HPV vaccination rates, patients at a federally qualified health center in Kalamazoo MI were surveyed. Surveys were administered during routine patient visits to determine self-reported vaccination status and vaccination barriers. A total of 98 vaccine-eligible (males/females, ages 9-26 years old) patients/guardians completed the survey. In all, 46% of respondents completed the multi-dose vaccination course, and 56% of those identified as female. White patients reported higher vaccination rates (50%) than patients of color (45%). Of those vaccinated, the most common reason was "physician recommendation" (39%). Those not fully vaccinated most commonly reported being "too young" (39%). Importantly, individuals who had begun, but not completed, the vaccination course reported that their provider had not spoken to them about future vaccines in the series (74%). This study revealed disparities in vaccination rates between the sexes and racial groups, and emphasized the influential role of physician's recommendation on vaccination. Interestingly, other frequently cited barriers to vaccination-an association with sex, personal/religious beliefs, efficacy-proved to be insignificant barriers for this population. Instead, age-related misunderstandings and lack of consistent physician communication about vaccination provided significant barriers. Based on our results, education and reminders about the HPV vaccine by providers is a significant tool to maximize vaccination coverage.

Preclinical characterization of signal transducer and activator of transcription 3 small molecule inhibitors for primary and metastatic brain cancer therapy.

Signal transducer and activator of transcription 3 (STAT3) has been implicated as a hub for multiple oncogenic pathways. The constitutive activation of STAT3 is present in several cancers, including gliomas (GBMs), and is associated with poor therapeutic responses. Phosphorylation of STAT3 triggers its dimerization and nuclear transport, where it promotes the transcription of genes that stimulate tumor growth. In light of this role, inhibitors of the STAT3 pathway are attractive therapeutic targets for cancer. To this end, we evaluated the STAT3-inhibitory activities of three compounds (CPA-7 [trichloronitritodiammineplatinum(IV)], WP1066 [(S,E)-3-(6-bromopyridin-2-yl)-2-cyano-N-(1-phenylethyl)acrylamide, C17H14BrN3O], and ML116 [4-benzyl-1-{thieno[2,3-d]pyrimidin-4-yl}piperidine, C18H19N3S]) in cultured rodent and human glioma cells, including GBM cancer stem cells. Our results demonstrate a potent induction of growth arrest in GBM cells after drug treatment with a concomitant induction of cell death. Although these compounds were effective at inhibiting STAT3 phosphorylation, they also displayed variable dose-dependent inhibition of STAT1, STAT5, and nuclear factor κ light-chain enhancer of activated B cells. The therapeutic efficacy of these compounds was further evaluated in peripheral and intracranial mouse tumor models. Whereas CPA-7 elicited regression of peripheral tumors, both melanoma and GBM, its efficacy was not evident when the tumors were implanted within the brain. Our data suggest poor permeability of this compound to tumors located within the central nervous system. WP1066 and ML116 exhibited poor in vivo efficacy. In summary, CPA-7 constitutes a powerful anticancer agent in models of peripheral solid cancers. Our data strongly support further development of CPA-7-derived compounds with increased permeability to enhance their efficacy in primary and metastatic brain tumors.

Resolution of metabolic dysfunction-associated steatohepatitis with estradiol in a transgender female: A case report.

A 16-year-old trans female patient presented to our Gender Health Program for gender-affirming care. Her intake evaluation revealed signs of hepatocellular injury and fibrosis concerning for metabolic dysfunction-associated steatohepatitis (MASH) and she was referred to a Pediatric Hepatologist. Subsequent delays in initiating hormone therapy caused a decline in her mental health, and she began experiencing suicidal ideations. Gender-affirming hormone therapy has been shown to significantly reduce depressive symptoms and suicidal ideations in transgender and gender diverse youth, and studies in animal models suggest improvement in hepatic steatosis in response to estrogen. A multidisciplinary meeting with Gender Health, Psychiatry, and Hepatology appropriately weighed the benefits of life-saving hormone therapy and the possibility of an improvement in her comorbid liver condition with the risk of further liver damage from estrogen therapy. The teams and the patient agreed to start estradiol with subsequent resolution of laboratory and radiographic evidence of MASH.

Safety profile, efficacy, and biodistribution of a bicistronic high-capacity adenovirus vector encoding a combined immunostimulation and cytotoxic gene therapy as a prelude to a phase I clinical trial for glioblastoma.

Adenoviral vectors (Ads) are promising gene delivery vehicles due to their high transduction efficiency; however, their clinical usefulness has been hampered by their immunogenicity and the presence of anti-Ad immunity in humans. We reported the efficacy of a gene therapy approach for glioma consisting of intratumoral injection of Ads encoding conditionally cytotoxic herpes simplex type 1 thymidine kinase (Ad-TK) and the immunostimulatory cytokine fms-like tyrosine kinase ligand 3 (Ad-Flt3L). Herein, we report the biodistribution, efficacy, and neurological and systemic effects of a bicistronic high-capacity Ad, i.e., HC-Ad-TK/TetOn-Flt3L. HC-Ads elicit sustained transgene expression, even in the presence of anti-Ad immunity, and can encode large therapeutic cassettes, including regulatory elements to enable turning gene expression "on" or "off" according to clinical need. The inclusion of two therapeutic transgenes within a single vector enables a reduction of the total vector load without adversely impacting efficacy. Because clinically the vectors will be delivered into the surgical cavity, normal regions of the brain parenchyma are likely to be transduced. Thus, we assessed any potential toxicities elicited by escalating doses of HC-Ad-TK/TetOn-Flt3L (1×10(8), 1×10(9), or 1×10(10) viral particles [vp]) delivered into the rat brain parenchyma. We assessed neuropathology, biodistribution, transgene expression, systemic toxicity, and behavioral impact at acute and chronic time points. The results indicate that doses up to 1×10(9) vp of HC-Ad-TK/TetOn-Flt3L can be safely delivered into the normal rat brain and underpin further developments for its implementation in a phase I clinical trial for glioma.

Combination Therapy With Bortezomib in Renal Medullary Carcinoma: A Case Series.

BACKGROUND: Renal medullary carcinoma (RMC) is a very rare, aggressive neoplasm occurring almost exclusively in adolescents and young adults with sickle cell trait. Given the rare nature of this tumor, accounting for less than 0.5% of all renal carcinomas, most of the published data on therapies is from case reports and small case series, and current treatments are insufficient, with most patients succumbing to their disease in months. We report our experience with a cytotoxic chemotherapy regimen consisting of platinum-based therapy, doxorubicin, and bortezomib. METHODS: Three patients with metastatic RMC at a single institution were treated off-label with a perioperative chemotherapy regimen for 4 cycles of 2 alternating regimens: regimen A consisting of cisplatin, doxorubicin, and bortezomib; regimen B consisting of carboplatin, paclitaxel, and gemcitabine. A radical nephrectomy was performed on all patients. Surveillance imaging was performed on all patients to assess response and disease burden. Patients received up to 12 months of maintenance therapy with everolimus. RESULTS: Three African American patients - 2 males and 1 female aged 14, 28, and 31 - with sickle cell trait and metastatic disease were treated with this regimen. The median follow-up was 18 months. All had resection of the primary tumor - 2 patients after receiving neoadjuvant therapy, and one patient underwent resection prior to referral. All 3 patients achieved complete responses based on imaging, 2 of which lasted for 12 months, and another is still in remission over 7 years after diagnosis. CONCLUSIONS: This regimen of alternating cycles of platinum-based chemotherapy with bortezomib appeared to be active against RMC and was generally well-tolerated. Given the extremely rare nature of this disease and dismal prognosis, new treatment modalities should be pursued, and whenever possible, patients should be enrolled in a clinical trial. We propose that a multiinstitution clinical trial of this regiment may be warranted.

Encephalitis with coinfection by Jamestown canyon virus (JCV) and varicella zoster virus (VZV).

We present the case of a 59-year-old Midwestern farmer who presented with altered mental status, dysarthria, urinary incontinence, and a right-sided L5 dermatomal rash; he had recently received a course of oral corticosteroids for treatment of radicular low back pain. Lumbar puncture revealed the presence of varicella zoster virus (VZV) and IgM antibodies against a California-group encephalitis virus, later confirmed as Jamestown Canyon virus (JCV). Unfortunately, the patient's health declined despite aggressive treatment, developing progressive subarachnoid hemorrhage. He died after withdrawal of supportive care following 3 weeks in the intensive care unit. To our knowledge, this is the first documented case of encephalitis associated with coinfection by VZV and JCV. While the relative contributions of these viral pathogens to the patient's illness are difficult to ascertain, the clinical features of this case are consistent with co-pathogenesis, possibly driven by antecedent corticosteroid use. This case highlights the emerging role of viral coinfections in the etiology of viral illnesses.

Preclinical Efficacy and Safety Profile of Allometrically Scaled Doses of Doxycycline Used to Turn "On" Therapeutic Transgene Expression from High-Capacity Adenoviral Vectors in a Glioma Model.

Glioblastoma multiforme (GBM) is the most commonly occurring primary brain cancer in adults, in whom its highly infiltrative cells prevent total surgical resection, often leading to tumor recurrence and patient death. Our group has discovered a gene therapy approach for GBM that utilizes high-capacity "gutless" adenoviral vectors encoding regulatable therapeutic transgenes. The herpes simplex type 1-thymidine kinase (TK) actively kills dividing tumor cells in the brain when in the presence of the prodrug, ganciclovir (GCV), whereas the FMS-like tyrosine kinase 3 ligand (Flt3L) is an immune-stimulatory molecule under tight regulation by a tetracycline-inducible "Tet-On" activation system that induces anti-GBM immunity. As a prelude to a phase I clinical trial, we evaluated the safety and efficacy of Food and Drug Administration (FDA)-approved doses of the tetracycline doxycycline (DOX) allometrically scaled for rats. DOX initiates the expression of Flt3L, which has been shown to recruit dendritic cells to the brain tumor microenvironment-an integral first step in the development of antitumor immunity. The data revealed a highly safe profile surrounding these human-equivalent doses of DOX under an identical therapeutic window as proposed in the clinical trial. This was confirmed through a neuropathological analysis, liver and kidney histopathology, detection of neutralizing antibodies, and systemic toxicities in the blood. Interestingly, we observed a significant survival advantage in rats with GBM receiving the 300 mg/day equivalent dosage of DOX versus the 200 mg/day equivalent. Additionally, rats rejected "recurrent" brain tumor threats implanted 90 days after their primary brain tumors. We also show that DOX detection within the plasma can be an indicator of optimal dosing of DOX to attain therapeutic levels. This work has significant clinical relevance for an ongoing phase I clinical trial in humans with primary GBM and for other therapeutic approaches using Tet-On transactivation system in humans.

Marmosets as a preclinical model for testing "off-label" use of doxycycline to turn on Flt3L expression from high-capacity adenovirus vectors.

We developed a combined conditional cytotoxic, i.e., herpes simplex type 1-thymidine kinase (TK), plus immune-stimulatory, i.e., fms-like tyrosine kinase ligand-3-mediated gene therapy for glioblastoma multiforme (GBM). Therapeutic transgenes were encoded within high-capacity adenoviral vectors (HC-Ad); TK was expressed constitutively, while Flt3L was under the control of the TetOn regulatable promoter. We previously assessed efficacy and safety in intracranial GBM rodent models. But, since this approach involves expression of a cytokine within the brain, we chose the nonhuman primate, i.e., Callithrix jaccus (marmoset) as it has been established that its immune response shares similarities with man. We characterized the safety, cell-type specific expression, and doxycycline (DOX)-inducibility of HC-Ad-TetOn-Flt3L delivered within the striatum. We used allometrically scaled DOX doses delivered orally, twice daily for one month, mimicking the route and duration of DOX administration planned for the GBM trial. Flt3L was effectively expressed within astrocytes, microglia, oligodendrocytes, and neurons. No evidence of brain or systemic toxicities due to the treatment was encountered. Our data indicate that DOX doses equivalent to those used in humans to treat infections can be safely used "off-label" to turn "on" therapeutic gene expression from HC-Ad-TetOn-Flt3L; providing evidence for the safety of this approach in the clinic.

Effectiveness and preclinical safety profile of doxycycline to be used "off-label" to induce therapeutic transgene expression in a phase I clinical trial for glioma.

Glioblastoma multiforme (GBM) is the most common malignant primary brain cancer in adults; it carries a dismal prognosis despite improvements in standard of care. We developed a combined gene therapy strategy using (1) herpes simplex type 1-thymidine kinase in conjunction with the cytotoxic prodrug ganciclovir to kill actively proliferating tumor cells and (2) doxycycline (DOX)-inducible Fms-like tyrosine kinase 3 ligand (Flt3L), an immune stimulatory molecule that induces anti-GBM immunity. As a prelude to a phase I clinical trial, we examined the efficacy and safety of this approach (Muhammad et al., 2010, 2012). In the present article, we investigated the efficacy and safety of the "off-label" use of the antibiotic DOX to turn on the high-capacity adenoviral vector (HC-Ad) encoding therapeutic Flt3L expression. DOX-inducible Flt3L expression in male Lewis rats was assessed using DOX doses of 30.8 mg/kg/day (low-DOX) or 46.2 mg/kg/day (high-DOX), which are allometrically equivalent (Voisin et al., 1990) to the human doses that are recommended for the treatment of infections: 200 or 300 mg/day. Naïve rats were intracranially injected with 1×10(9) viral particles of HC-Ad-TetOn-Flt3L, and expression of the therapeutic transgene, that is, Flt3L, was assessed using immunohistochemistry in brain sections after 2 weeks of DOX administration via oral gavage. The results show robust expression of Flt3L in the rat brain parenchyma in areas near the injection site in both the low-DOX and the high-DOX groups, suggesting that Flt3L will be expressed in human glioma patients at a DOX dose of 200 or 300 mg/day. These doses have been approved by the U.S. Food and Drug Administration to treat infections in humans and would thus be considered safe for an off-label use to treat GBM patients undergoing HC-Ad-mediated gene therapy in a phase I clinical trial.