Emerging therapeutic options for periorbital and orbital cutaneous basal and squamous cell carcinomas.

PURPOSE: Recently, several new therapies have emerged to address locally advanced cutaneous basal cell and squamous cell carcinomas. Given the constraints of the ocular adnexa and orbit, this review was designed to discuss the role of these modalities in this region. METHODS: A PubMed search was carried out to analyze the utility of United States Food and Drug Administration-approved therapies to address these malignancies. The data presented in the identified investigations were analyzed and abstracted. RESULTS: Multiple novel interventions may be useful in the management of periocular cutaneous basal cell and squamous cell carcinomas, including imiquimod, hedgehog inhibitors, and immunotherapy. While many of these treatments have not been specifically explored in the orbit and ocular adnexa, the literature generally shows favorable response rates. However, adverse events were common in these studies. CONCLUSIONS: Several novel treatments may address periorbital cutaneous malignancies, and these therapies may be particularly useful in patients with unresectable disease and those who are poor surgical candidates.

T-cell prolymphocytic leukaemia associated with immune checkpoint inhibitor (pembrolizumab).

We describe the case of a man in his 60s with squamous cell carcinoma of the lung with brain metastasis treated with pembrolizumab who subsequently developed T-cell prolymphocytic leukaemia. He was transferred to our hospital with worsening dyspnoea, suspected hyperviscosity syndrome and tumour lysis syndrome. He was intubated and admitted to our critical care unit. Emergent leucapheresis was started due to worsening renal function in the setting of tumour lysis and hyperviscosity syndromes. He continued to deteriorate and required continuous renal replacement therapy. Unfortunately, he eventually died from haemodynamic decompensation. There are only a few anecdotal cases pointing at a possible association between the use of immune checkpoint inhibitors and the progression or exacerbation of secondary haematological malignancies. The poor prognosis of these haematological malignancies warrants further investigation to determine if checkpoint inhibitors increase the risk of developing or propagating these potentially fatal diseases.

Primary Intramedullary Spinal Melanoma: A Rare Disease of the Spinal Cord.

Primary malignant melanoma of the intramedullary region of the spinal cord has rarely been reported in the literature. These tumors can have variable appearance on magnetic resonance imaging (MRI) due to different extents of melanin and hemorrhage. Histopathologic confirmation and a comprehensive workup to rule out extra-spinal melanoma are required to make definitive diagnosis. We present a case of a patient diagnosed with primary intramedullary spinal melanoma in his lower thoracic spinal cord who was effectively treated with surgical resection, adjuvant radiation, and adjuvant immunotherapy. Gross total resection (GTR) is most vital in the management of this spinal tumor. Although several studies have established the efficacy of immunotherapy agents in advanced malignant melanoma, the use of these agents has not been studied in primary central nervous system melanomas. This case provides insight into the diagnostic approach and treatment options for this unique malignancy.

Inhibition of Bruton tyrosine kinase in patients with severe COVID-19.

Patients with severe COVID-19 have a hyperinflammatory immune response suggestive of macrophage activation. Bruton tyrosine kinase (BTK) regulates macrophage signaling and activation. Acalabrutinib, a selective BTK inhibitor, was administered off-label to 19 patients hospitalized with severe COVID-19 (11 on supplemental oxygen; 8 on mechanical ventilation), 18 of whom had increasing oxygen requirements at baseline. Over a 10-14 day treatment course, acalabrutinib improved oxygenation in a majority of patients, often within 1-3 days, and had no discernable toxicity. Measures of inflammation - C-reactive protein and IL-6 - normalized quickly in most patients, as did lymphopenia, in correlation with improved oxygenation. At the end of acalabrutinib treatment, 8/11 (72.7%) patients in the supplemental oxygen cohort had been discharged on room air, and 4/8 (50%) patients in the mechanical ventilation cohort had been successfully extubated, with 2/8 (25%) discharged on room air. Ex vivo analysis revealed significantly elevated BTK activity, as evidenced by autophosphorylation, and increased IL-6 production in blood monocytes from patients with severe COVID-19 compared with blood monocytes from healthy volunteers. These results suggest that targeting excessive host inflammation with a BTK inhibitor is a therapeutic strategy in severe COVID-19 and has led to a confirmatory international prospective randomized controlled clinical trial.

Genetic profiles of plasmacytoid (BDCA-4 expressing) DC subtypes-clues to DC subtype function in vivo.

Among the dendritic cell (DC) subsets, plasmacytoid DC's (pDC) are thought to be important in the generation of both antiviral and antitumor responses. While pDC may be useful in developing dendritic cell-based tumor vaccines, the low frequency of these cells in the peripheral blood has hampered attempts to understand their biology. To provide better insight into the biology of pDC, we isolated these unperturbed cells from the peripheral blood of healthy donors in order to further characterize their gene expression. Using gene array technology we compared the genetic profiles of these cells to those of CD14+ monocytes isolated from the same donors and found several immune related genes upregulated in this cell population. This is the first description, to our knowledge, of gene expression in this subset of DCs obtained from the peripheral blood of adult human donors without exposure in vitro to cytokine or growth factors. Understanding the natural genetic profiles of this dendritic cell subtype as well as others such as the BDCA-1 expressing myeloid DCs may enable us to manipulate these cells ex-vivo to generate enhanced DC-based tumor vaccines inducing more robust antitumor responses.

Imatinib mesylate (Gleevec) induced unilateral optic disc edema.

PURPOSE: Imatinib mesylate (Gleevec) is a chemotherapy medication developed to treat chronic myelogenous leukemia as well as gastrointestinal stromal tumors (Savage, N Engl J Med 2002;346:683-93). Ocular side effects are commonly reported with the use of imatinib mesylate, such as periorbital edema and epiphora. More serious ocular side effects, such as optic disc edema, are rarely reported. CASE REPORT: This case is of a patient who presented with monocular painless loss of vision in the left eye from a previously documented 20/20 to 20/70 shortly after starting treatment with imatinib mesylate. RESULTS: Every aspect of the ocular presentation and clinical history were addressed to unveil the cause of the disc edema. After ruling out all other causes, the patient was later diagnosed with unilateral optic disc edema as a related side effect of the toxicity from imatinib mesylate. CONCLUSIONS: The properties of imatinib mesylate and the possible etiology of secondary optic disc edema are discussed. This study aims to highlight the importance of systemic medications review for possible etiology of ocular disease as well as the multidisciplinary approach to managing oncology patients with ocular side effects.

Combination delivery of TGF-ß inhibitor and IL-2 by nanoscale liposomal polymeric gels enhances tumour immunotherapy.

The tumour microenvironment thwarts conventional immunotherapy through multiple immunologic mechanisms, such as the secretion of the transforming growth factor-ß (TGF-ß), which stunts local tumour immune responses. Therefore, high doses of interleukin-2 (IL-2), a conventional cytokine for metastatic melanoma, induces only limited responses. To overcome the immunoinhibitory nature of the tumour microenvironment, we developed nanoscale liposomal polymeric gels (nanolipogels; nLGs) of drug-complexed cyclodextrins and cytokine-encapsulating biodegradable polymers that can deliver small hydrophobic molecular inhibitors and water-soluble protein cytokines in a sustained fashion to the tumour microenvironment. nLGs releasing TGF-ß inhibitor and IL-2 significantly delayed tumour growth, increased survival of tumour-bearing mice, and increased the activity of natural killer cells and of intratumoral-activated CD8(+) T-cell infiltration. We demonstrate that the efficacy of nLGs in tumour immunotherapy results from a crucial mechanism involving activation of both innate and adaptive immune responses.

Systemic therapy in hepatocellular carcinoma.

Many potential systemic therapies are being investigated for the treatment of hepatocellular carcinoma (HCC). The incidence of this malignancy is rising sharply and the vast majority of patients present at advanced stages. Although the earlier dismal results with cytotoxic chemotherapies made way for the development of locoregional therapies that provided improved overall survival, truly personalized therapy will require the selection of phenotypically similar stages of disease and populations, an understanding of the complex molecular and genetic pathways leading to HCC, and a keen understanding of the pathobiology of cirrhosis. Only then will we understand how to offer a particular patient at a specific stage of disease the appropriate therapy to truly prolong survival.

Mouse mammary tumor virus in anti-mitochondrial antibody producing mouse models.

BACKGROUND & AIMS: A human betaretrovirus resembling the mouse mammary tumor virus (MMTV) has been characterized in primary biliary cirrhosis (PBC) and associated with aberrant pyruvate dehydrogenase complex (PDC)-E2-like expression. As MMTV is prevalent in mice as either an exogenous or endogenous infection, we tested the hypothesis that MMTV is linked with anti-mitochondrial antibody (AMA) production in models with severe immune dysfunction. METHODS: Evidence for MMTV was assessed in the liver and spleen of mice by PCR and immunochemistry and PDC-E2-like protein by immunochemistry. ELISA and Western blot were used to investigate AMA and anti-MMTV antibody production. RESULTS: Increased MMTV gag or env expression was detected in the livers of AMA producing mice including NOD.c3c4, CD4 directed dominant negative TGF-ß receptor II and IL-2 receptor α knockout mice as well as the NOD parental strain when compared to healthy strains and biliary disease control mice. The NOD.c3c4 mice expressed MMTV surface and capsid proteins and aberrant PDC-E2-like protein in the bile ducts, whereas IL-2 receptor α knockout mice, NOD.c3c4 and the NOD mice expressed MMTV proteins and aberrant PDC-E2-like protein in the spleen. A significant correlation between anti-MMTV antibody production and AMA production was observed in the sera of NOD and NOD.c3c4 mice (p<0.0001). CONCLUSIONS: The association of betaretroviral protein production and aberrant PDC-E2-like protein expression in the NOD.c3c4, NOD, and the IL-2 receptor α knockout mice is comparable to observations in patients with PBC. The correlation of AMA and anti-MMTV suggests the hypothesis that MMTV infection may trigger the production of AMA.

The polarization of immune cells in the tumour environment by TGFbeta.

Transforming growth factor-beta (TGFbeta) is an immunosuppressive cytokine produced by tumour cells and immune cells that can polarize many components of the immune system. This Review covers the effects of TGFbeta on natural killer (NK) cells, dendritic cells, macrophages, neutrophils, CD8(+) and CD4(+) effector and regulatory T cells, and NKT cells in animal tumour models and in patients with cancer. Collectively, many recent studies favour the hypothesis that blocking TGFbeta-induced signalling in the tumour microenvironment enhances antitumour immunity and may be beneficial for cancer therapy. An overview of the current drugs and reagents available for inhibiting TGFbeta-induced signalling and their phase in clinical development is also provided.

Antigen presentation on artificial acellular substrates: modular systems for flexible, adaptable immunotherapy.

BACKGROUND: Recent findings on T cells and dendritic cells have elucidated principles that can be used for a bottom-up approach to engineering artificial antigen presentation on synthetic substrates. OBJECTIVE/METHODS: To compare the latest artificial antigen-presenting cell (aAPC) technology, focussing on acellular systems because they offer advantages such as easy tunability and rapid point-of-care application compared with cellular systems. We review acellular aAPC performance and discuss their promise for clinical applications. RESULTS/CONCLUSION: Acellular aAPCs are a powerful alternative to natural-cell-based therapies, offering flexibility and modularity for incorporation oSf a variety of stimuli, hence increasing precision. Current technologies should adapt physiologically important signals within safe materials to more closely approximate their cellular counterparts. These constructs could be administered parenterally as APC replacements for active vaccines or used ex vivo for adoptive immunotherapy.

Chimeric receptor mRNA transfection as a tool to generate antineoplastic lymphocytes.

mRNA transfection is a useful approach for temporal cell reprogramming with minimal risk of transgene-mediated mutagenesis. We applied this to redirect lymphocyte cytotoxicity toward malignant cells. Using the chimeric immune receptor (CIR) constructs anti-CD19 CIR and 8H9 CIR, we achieved uniform expression of CIRs on virtually the entire population of lymphocytes. We reprogrammed CD3+ CD8+, CD3+ CD4+, and natural killer (NK ) cells toward autologous and allogeneic targets such as B cells, Daudi lymphoma, primary melanoma, breast ductal carcinoma, breast adenocarcinoma, and rhabdomyosarcoma. The reprogramming procedure is fast. Although most of the experiments were performed on lymphocytes obtained after 7-day activation, only 1-day activation of T cells with anti-CD3, anti-CD28 antibodies, and interleukin-2 is sufficient to develop both lymphocyte cytotoxicity and competence for mRNA transfer. The entire procedure, which includes lymphocyte activation and reprogramming, can be completed in 2 days. The efficiency of mRNA-modified human T cells was tested in a murine xenograft model. Human CD3+CD8+ lymphocytes expressing anti-CD19 CIR mRNA inhibited Daudi lymphoma growth in NOD=SCID mice. These results demonstrate that a mixed population of cytotoxic lymphocytes, including T cells together with NK cells, can be quickly and simultaneously reprogrammed by mRNA against autologous malignancies. With relatively minor modifications the described method of lymphocyte reprogramming can be scaled up for cancer therapy.

Transforming growth factor-beta and the immune response: implications for anticancer therapy.

Immune homeostasis is a delicate balance between the immune defense against foreign pathogens and suppression of the immune system to maintain self-tolerance and prevent autoimmune disease. Maintenance of this balance involves several crucial networks of cytokines and various cell types. Among these regulators, transforming growth factor-beta (TGF-beta) is a potent cytokine with diverse effects on hematopoietic cells. Its pivotal function within the immune system is to maintain tolerance via the regulation of lymphocyte proliferation, differentiation, and survival. In addition, TGF-beta controls the initiation and resolution of inflammatory responses through the regulation of chemotaxis and activation of leukocytes in the periphery, including lymphocytes, natural killer cells, dendritic cells, macrophages, mast cells, and granulocytes. Through its pleiotropic effects on these immune cells, TGF-beta prevents the development of autoimmune diseases without compromising immune responses to pathogens. However, overactivation of this pathway can lead to several immunopathologies under physiologic conditions including cancer progression, making it an attractive target for antitumor therapies. This review discusses the biological functions of TGF-beta and its effects on the immune system and addresses how immunosuppression by this cytokine can promote tumorigenesis, providing the rationale for evaluating the immune-enhancing and antitumor effects of inhibiting TGF-beta in cancer patients.

Successful desensitization to oxaliplatin with incorporation of calcium gluconate and magnesium sulfate.

Since the results of the MOSAIC trial demonstrated an improved disease-free survival in stage III colorectal patients treated with oxaliplatin combined with 5-fluorouracil and folinic acid when they were compared with those treated with 5-fluorouracil and folinic acid alone, the addition of this organoplatin to 5-fluorouracil and folinic acid has become first-line adjuvant treatment for stage III colorectal cancer. Unfortunately, there is a small population of patients who develop grade III/IV hypersensitivity reactions to oxaliplatin which, until recently, have interfered with further treatment with oxaliplatin-containing regimens. Successful oxaliplatin desensitization protocols for patients having severe oxaliplatin hypersensitivity reactions have been reported. However, none of these protocols, have incorporated magnesium and calcium salts. Retrospective data has suggested that pretreating colorectal cancer patients with magnesium sulfate and calcium gluconate before the administration of oxaliplatin may reduce the incidence of neurotoxicities induced by this drug. Therefore, we modified a previously published oxaliplatin-desensitization protocol by incorporating intravenous calcium gluconate and magnesium sulfate, and report a patient with stage IIIc colorectal cancer and prior severe hypersensitivity reactions to oxaliplatin who underwent successful oxaliplatin desensitization using this protocol.

Proinflammatory cytokine gene induction by human T-cell leukemia virus type 1 (HTLV-1) and HTLV-2 Tax in primary human glial cells.

Infection with human T-cell leukemia virus type 1 (HTLV-1) can result in the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a chronic inflammatory disease of the central nervous system (CNS). HTLV-2 is highly related to HTLV-1 at the genetic level and shares a high degree of sequence homology, but infection with HTLV-2 is relatively nonpathogenic compared to HTLV-1. Although the pathogenesis of HAM/TSP remains to be fully elucidated, previous evidence suggests that elevated levels of the proinflammatory cytokines in the CNS are associated with neuropathogenesis. We demonstrate that HTLV-1 infection in astrogliomas results in a robust induction of interleukin-1beta (IL-1beta), IL-1alpha, tumor necrosis factor alpha (TNF-alpha), TNF-beta, and IL-6 expression. HTLV encodes for a viral transcriptional transactivator protein named Tax that also induces the transcription of cellular genes. To investigate and compare the effects of Tax1 and Tax2 expression on the dysregulation of proinflammatory cytokines, lentivirus vectors were used to transduce primary human astrocytomas and oligodendrogliomas. The expression of Tax1 in primary human astrocytomas and oligodendrogliomas resulted in significantly higher levels of proinflammatory cytokine gene expression compared to Tax2. Notably, Tax1 expression uniquely sensitized primary human astrocytomas to apoptosis. A Tax2/Tax1 chimera encoding the C-terminal 53 amino acids of the Tax1 fused to the Tax2 gene (Tax(221)) demonstrated a phenotype that resembled Tax1, with respect to proinflammatory cytokine gene expression and sensitization to apoptosis. The patterns of differential cytokine induction and sensitization to apoptosis displayed by Tax1 and Tax2 may reflect differences relating to the heightened neuropathogenicity associated with HTLV-1 infection and the development of HAM/TSP.

Acute monocular blindness resulting from transformation of von Recklinghausen's neurofibromatosis to malignant melanocytic schwannomas.

A 59-year-old male was transferred to our facility after initial workup for left eye blindness revealed multiple brain lesions. The patient presented with scant pedunculated skin lesions on his neck and arms, axillary freckling and bilateral subcutaneous ankle nodules suggestive of neurofibromatosis type 1 (NF-1). Neurological examination revealed left-sided blindness, diminished pupillary response to light, incomplete eyelid closure and facial droop. A CT series of the chest/abdomen/pelvis demonstrated several lesions in the lungs, liver and left kidney. CT-guided biopsy of the renal lesion was "consistent with metastatic melanoma" based on the presence of malignant cell staining for the melanocyte differentiation antigen MART-1, as well as the calcium binding protein S-100. A dermatology consultant confirmed neurofibromas and a café au lait macule. No dysplastic nevi or primary melanoma were identified. An ophthalmology consultant noted gray choroidal lesions on fundoscopic examination thought to be metastatic disease of unknown primary. Despite treatment with whole brain irradiation and intravenous steroids, the patient died on hospital day 10. A full autopsy showed diffuse neurofibromas and café au lait macules consistent with NF-1 and malignant melanocytic schwannomas with multiple metastases.

Human T-cell leukemia virus type 1 tax oncoprotein suppression of multilineage hematopoiesis of CD34+ cells in vitro.

Human T-cell leukemia virus type 1 (HTLV-1) and HTLV-2 are highly related viruses that differ in disease manifestation. HTLV-1 is the etiologic agent of adult T-cell leukemia and lymphoma, an aggressive clonal malignancy of human CD4-bearing T lymphocytes. Infection with HTLV-2 has not been conclusively linked to lymphoproliferative disorders. We previously showed that human hematopoietic progenitor (CD34(+)) cells can be infected by HTLV-1 and that proviral sequences were maintained after differentiation of infected CD34(+) cells in vitro and in vivo. To investigate the role of the Tax oncoprotein of HTLV on hematopoiesis, bicistronic lentiviral vectors were constructed encoding the HTLV-1 or HTLV-2 tax genes (Tax1 and Tax2, respectively) and the green fluorescent protein marker gene. Human hematopoietic progenitor (CD34(+)) cells were infected with lentivirus vectors, and transduced cells were cultured in a semisolid medium permissive for the development of erythroid, myeloid, and primitive progenitor colonies. Tax1-transduced CD34(+) cells displayed a two- to fivefold reduction in the total number of hematopoietic clonogenic colonies that arose in vitro, in contrast to Tax2-transduced cells, which showed no perturbation of hematopoiesis. The ratio of colony types that developed from Tax1-transduced CD34(+) cells remained unaffected, suggesting that Tax1 inhibited the maturation of relatively early, uncommitted hematopoietic stem cells. Since previous reports have linked Tax1 expression with initiation of apoptosis, lentiviral vector-mediated transduction of Tax1 or Tax2 was investigated in CEM and Jurkat T-cell lines. Ectopic expression of either Tax1 or Tax2 failed to induce apoptosis in T-cell lines. These data demonstrate that Tax1 expression perturbs development and maturation of pluripotent hematopoietic progenitor cells, an activity that is not displayed by Tax2, and that the suppression of hematopoiesis is not attributable to induction of apoptosis. Since hematopoietic progenitor cells may serve as a latently infected reservoir for HTLV infection in vivo, the different abilities of HTLV-1 and -2 Tax to suppress hematopoiesis may play a role in the respective clinical outcomes after infection with HTLV-1 or -2.