Retinoid Therapy Research Articles

Vascularized Tissue-Engineered Model for Studying Drug Resistance in Neuroblastoma.

Neuroblastoma is a vascularized pediatric tumor derived from neural crest stem cells that displays vasculogenic mimicry and can express a number of stemness markers, such as SOX2 and NANOG. Tumor relapse is the major cause of succumbing to this disease, and properties attributed to cancer stem-like cells (CSLC), such as drug-resistance and cell plasticity, seem to be the key mechanisms. However, the lack of controllable models that recapitulate the features of human neuroblastoma limits our understanding of the process and impedes the development of new therapies. In response to these limitations, we engineered a perfusable, vascularized in vitro model of three-dimensional human neuroblastoma to study the effects of retinoid therapy on tumor vasculature and drug-resistance.METHODS: The in vitro model of neuroblastoma was generated using cell-sheet engineering and cultured in a perfusion bioreactor. Firstly, we stacked three cell sheets containing SKNBE(2) neuroblastoma cells and HUVEC. Then, a vascular bed made of fibrin, collagen I and HUVEC cells was placed onto a collagen-gel base with 8 microchannels. After gelling, the stacked cell sheets were placed on the vascular bed and cultured in the perfusion bioreactor (perfusion rate: 0.5 mL/min) for 4 days. Neuroblastoma models were treated with 10μM isotretionin in single daily doses for 5 days.RESULTS: The bioengineered model recapitulated vasculogenic mimicry (vessel-like structure formation and tumor-derived endothelial cells-TECs), and contained CSLC expressing SOX2 and NANOG. Treatment with Isotretinoin destabilized vascular networks but failed to target vasculogenic mimicry and augmented populations of CSLCs expressing high levels of SOX2. Our results suggest that CSLCs can transdifferentiate into drug resistant CD31+-TECs, and reveal the presence of an intermediate state STEC (stem tumor-derived endothelial cell) expressing both SOX2 and CD31.CONCLUSION: Our results reveal some roles of SOX2 in drug resistance and tumor relapse, and suggest that SOX2 could be a therapeutic target in neuroblastoma.

Side effects of retinoid therapy on the quality of vision.

Retinoids are compounds chemically related to vitamin A, which are frequently used in dermatological practice (1). They are characterized by numerous mechanisms of action leading to normalization of keratinocyte proliferation and maturation. They have anti-seborrhoeic, immunomodulatory and anti-inflammatory effects (1, 2). A number of side effects to retinoid treatment have been recorded; one group of such side effects relates to eyes and vision. Dry eye syndrome and blepharoconjunctivitis are the most common side effects, appearing in 20-50 % of patients treated with retinoids. They often contribute to the occurrence of other side-effects such as eye discomfort and contact lens intolerance. Due to the widespread use in clinical practice, the adverse effects, including ocular side effects, should be studied. To confirm the variety of adverse effects of retinoids, several case reports of rare side-effects are presented.

Skeletal impact of retinoid therapy in childhood cancer survivors.

Skeletal impact of retinoid therapy in childhood cancer survivors.

Preclinical Evaluation of UAB30 in Pediatric Renal and Hepatic Malignancies.

Rare tumors of solid organs remain some of the most difficult pediatric cancers to cure. These difficult tumors include rare pediatric renal malignancies, such as malignant rhabdoid kidney tumors (MRKT) and non-osseous renal Ewing sarcoma, and hepatoblastoma, a pediatric liver tumor that arises from immature liver cells. There are data in adult renal and hepatic malignancies demonstrating the efficacy of retinoid therapy. The investigation of retinoic acid therapy in cancer is not a new strategy, but the widespread adoption of this therapy has been hindered by toxicities. Our laboratory has been investigating a novel synthetic rexinoid, UAB30, which exhibits a more favorable side-effect profile. In this study, we hypothesized that UAB30 would diminish the growth of tumor cells from both rare renal and liver tumors in vitro and in vivo We successfully demonstrated decreased cellular proliferation, invasion and migration, cell-cycle arrest, and increased apoptosis after treatment with UAB30. Additionally, in in vivo murine models of human hepatoblastoma or rare human renal tumors, there were significantly decreased tumor xenograft growth and increased animal survival after UAB30 treatment. UAB30 should be further investigated as a developing therapeutic in these rare and difficult-to-treat pediatric solid organ tumors. Mol Cancer Ther; 15(5); 911-21. ©2016 AACR.

Response to 13 cis retinoic acid in metatstatic neuroblastoma

Neuroblastoma is the most common extra cranial solid tumour of childhood, with 5 year survival rate of 40%-50% in high risk group. Surgery, chemotherapy, radiotherapy, high dose chemotherapy with stem cell transplant and retinoid therapy are treatment options for neuroblastoma. Here we present a 5 year female child presenting with abdominal pain for 1 month and abdominal distension for 3 weeks, and underwent biopsy after necessary investigations, and diagnosed to have high risk neuroblastoma and treated with multiple lines of chemotherapy and attained complete response after retinoid therapy. The case is presented because of complete response achieved with retinoid therapy with tolerable side effects.

Increasing Numbers of Mast Cells in Skin Lesions of Hyperpigmented Mycosis Fungoides with Large-Cell Transformation.

Dear Editor: Mycosis fungoides (MF) is a common type of cutaneous T-cell lymphoma. In recent years, several reports have been published on an uncommon and rare form of MF: hyperpigmented MF1,2,3,4. Herein, we report a case of hyperpigmented MF and discuss the mechanisms of hyperpigmentation. A 55-year-old Japanese man presented at the dermatological outpatient clinic of our hospital for widespread, pruritic, hyperpigmented plaques. The lesions, which first appeared nearly 15 years ago, gradually developed; they were diagnosed as MF, and were subsequently treated with topical corticosteroids and/or radiation with narrow-band ultraviolet B (UVB). However, no therapeutic response was observed and small nodular lesions developed. On physical examination of the patient, we observed hyperpigmented plaques with no atrophy on the face, trunk, and extremities (Fig. 1A). We found small nodules on the back. Blood cell count, urinalysis, and serum chemistry were within normal limits. Anti-human T-cell leukemia virus type I antibody was negative. Computed tomography scan from the neck to the pelvic area was normal. Histopathological analysis of skin specimens collected from a hyperpigmented plaque on the buttocks revealed slight acanthosis with atypical lymphocytic infiltration within the epidermis and upper dermis, containing some inflammatory cells and abundant melanophages (Fig. 1B). Rearrangement of the T-cell receptor (β chain) was detected using reverse transcriptase polymerase chain reaction method, but not Southern blot analysis. Immunohistochemically, most of the atypical lymphoid cells were CD4-positive (Fig. 1C and D). We diagnosed the lesions as MF, particularly, hyperpigmented MF. After X-ray irradiation to the nodules on the back, oral retinoid plus long-wave UVA therapy was started. Although CD30 (+) large-cell transformation was found during the therapeutic course, the patient's general health and skin improved over time. Fig. 1 (A) Clinical manifestation. Hyperpigmented plaques on the trunk. (B) Histology of the lesional skin of a hyperpigmented plaque. Slight acanthosis with atypical lymphocytic infiltration within the epidermis and upper dermis, containing abundant melanophages ... So far, the etiology of hyperpigmentation in certain MF cases is not clear. Pavlovsky et al.4 reported that hyperpigmented MF was characterized by a predominantly CD8-positive phenotype. Those authors speculated that CD8-positive tumor cells could have stronger cytotoxicity and affect neighboring cells such as melanocytes or basal keratinocytes, thereby causing interface changes and marked melanin incontinence, leading to the clinical appearance of hyperpigmentation4. However, in the present case, CD4-positive cells were dominant; therefore, hyperpigmentation cannot be attributed to this hypothesis. Yamamoto et al.1 reported the association of mast cell number with hyperpigmented MF. Melanocytes are strongly stimulated by stem cell factor (SCF), which also activates the mast cells. Increasing numbers of mast cells in the skin with lesions and an upregulation of SCF in sera of hyperpigmented MF cases were found1. Thus, we compared the numbers of mast cells in the skin with lesion with normal skin controls and non-pigmented MF cases. Mast cell counts were averaged from three random fields (cells/high-power field) in toluidine blue-stained skin specimens (Fig. 1E). As shown in Table 1, compared with normal and non-pigmented MF skin, the numbers of mast cells clearly increased in skin lesions of hyperpigmented MF. Unfortunately, we did not examine the serum levels of SCF. However, the increasing numbers of mast cells suggest the existence of similar underlying mechanisms as reported by Yamamoto et al.1 Table 1 Mast cell counts in skin

Successful outcome of lamellar ichthyosis with oral retinoid therapy: A series of six cases

Lamellar ichthyosis (LI) is a rare skin disorder inherited as an autosomal recessive trait. Affected babies are born in a collodion membrane that sheds gradually revealing extensive scaling of the skin. The present communication is intended to provide the details of oral isotretinoin therapy in the management of LI in six children. The dose of oral isotretinoin which produced maximum clearing of the lesions with minimum side effects was found to vary from 0.6 mg/kg to 1 mg/kg body weight among these children and the duration of therapy lasted from 6 to 16 weeks. Therapeutic improvement varied from excellent in four and mild to satisfactory in two children and cheilitis of the lips was observed to be the main side effect.

DNA Methylation of Cellular Retinoic Acid-Binding Proteins in Cervical Cancer.

This study determined the methylation status of cellular retinoic acid-binding protein (CRABP) gene promoters and associated them with demographic characteristics, habits, and the presence of human papilloma virus (HPV) in patients with cervical cancer (CC), low and high squamous intraepithelial lesions, and no intraepithelial lesion. Women (n = 158) were selected from the Colposcopy Clinic of Sanitary Jurisdiction II in Ciudad Juarez, Chihuahua, Mexico. Demographic characteristics and habit information were collected. Cervical biopsy and endocervical scraping were used to determine methylation in promoter regions by methylation-specific polymerase chain reaction technique. We found hemi-methylation patterns in the promoter regions of CRABP1 and CRABP2; there was 28.5% hemi-methylation in CRABP1 and 7.0% in that of CRABP2. Methylation in CRABP1 was associated with age (≥35 years, P = 0.002), family history of cancer (P = 0.032), the presence of HPV-16 (P = 0.013), and no alcohol intake (P = 0.035). These epigenetic changes could be involved in the CC process, and CRABP1 has the potential to be a predictive molecular marker of retinoid therapy response.

Facial features in Harlequin ichthyosis: Clinical findings about 4 cases

We report 4 cases of Harlequin ichthyosis, which is a rare and severe congenital ichthyosis involving the face. Facial appearance consists in severe ectropion, conjonctival edema, eclabium, flattened ears, broadened nose and large, thick, plate-like skin scales. Recent advances in neonatal care have been made, such as retinoid therapy, and have led to an increased survival rate. Early surgical correction of ectropion may be required because of ocular complications.

Redox balance influences differentiation status of neuroblastoma in the presence of all-trans retinoic acid

Neuroblastoma is the most common extra-cranial solid tumor in childhood; and patients in stage IV of the disease have a high propensity for tumor recurrence. Retinoid therapy has been utilized as a means to induce differentiation of tumor cells and to inhibit relapse. In this study, the expression of a common neuronal differentiation marker [neurofilament M (NF-M)] in human SK-N-SH neuroblastoma cells treated with 10μM all-trans retinoic acid (ATRA) showed significantly increased expression in accordance with reduced cell number. This was accompanied by an increase in MitoSOX and DCFH2 oxidation that could be indicative of increased steady-state levels of reactive oxygen species (ROS) such as O2•− and H2O2, which correlated with increased levels of MnSOD activity and immuno-reactive protein. Furthermore PEG-catalase inhibited the DCFH2 oxidation signal to a greater extent in the ATRA-treated cells (relative to controls) at 96h indicating that as the cells became more differentiated, steady-state levels of H2O2 increased in the absence of increases in peroxide-scavenging antioxidants (i.e., glutathione, glutathione peroxidase, and catalase). In addition, ATRA-induced stimulation of NF-M at 48 and 72h was enhanced by decreasing SOD activity using siRNA directed at MnSOD. Finally, treatment with ATRA for 96h in the presence of MnSOD siRNA or PEG-catalase inhibited ATRA induced increases in NF-M expression. These results provide strong support for the hypothesis that changes in steady-state levels of O2•− and H2O2 significantly contribute to the process of ATRA-induced differentiation in neuroblastoma, and suggest that retinoid therapy for neuroblastoma could potentially be enhanced by redox-based manipulations of superoxide metabolism to improve patient outcome.

Acute Promyelocytic Leukemia: A Review and Discussion of Variant Translocations.

The majority of patients with acute promyelocytic leukemia (APL) manifest the t(15;17)(q24.1;q21.2) translocation; however, a minor but significant proportion of patients with APL harbor complex, cryptic, or variant translocations, which typically involve RARA. With the exception of ZBTB16/RARA, these variants have similar morphologic and immunophenotypic features as classic APL. Study of the variant forms of APL not only gives insight into the pathogenesis of APL but also allows us to understand the mechanism of retinoid therapy. It is important to identify these cryptic and variant translocations because certain variants, including ZBTB16/RARA and STAT5B/RARA, are resistant to treatment with all-trans retinoic acid, arsenic trioxide, and anthracyclines.

Up-regulation of steroid biosynthesis by retinoid signaling: Implications for aging

Retinoids (vitamin A and its derivatives) are critical for a spectrum of developmental and physiological processes, in which steroid hormones also play indispensable roles. The StAR protein predominantly regulates steroid biosynthesis in steroidogenic tissues. We have reported that regulation of retinoid, especially atRA and 9-cis RA, responsive StAR transcription is largely mediated by an LXR–RXR/RAR heterodimeric motif in the mouse StAR promoter. Herein we demonstrate that retinoids are capable of enhancing StAR protein, P-StAR, and steroid production in granulosa, adrenocortical, glial, and epidermal cells. Whereas transient expression of RARα and RXRα enhanced 9-cis RA induced StAR gene transcription, silencing of RXRα with siRNA, decreased StAR and steroid levels. An oligonucleotide probe encompassing an LXR–RXR/RAR motif bound to adrenocortical and epidermal keratinocyte nuclear proteins in EMSAs. ChIP studies revealed association of RARα and RXRα with the StAR proximal promoter. Further studies demonstrated that StAR mRNA levels decreased in diseased and elderly men and women skin tissues and that atRA could restore steroidogenesis in epidermal keratinocytes of aged individuals. These findings provide novel insights into the relevance of retinoid signaling in the up-regulation of steroid biosynthesis in various target tissues, and indicate that retinoid therapy may have important implications in age-related complications and diseases.

Abstract 3511: Targeted epigenetic reprogramming reverts tumor progression in triple-negative breast cancer models by the activation of retinoic acid receptor alpha

Abstract INTRODUCTION: Triple negative breast cancer (TNBC) is associated with aggressiveness, early recurrence and poor prognosis and no other therapeutic alternative besides chemotherapy. The silencing of genes associated with cell differentiation in cancer is required for tumor progression. In this process the epigenetic modifications induced by aberrant control of the chromatin remodeling machinery in transformed cells plays a key role. Therefore, finding a mechanism to restore the expression of these genes by reverting the abnormal epigenetic modifications is an important task in the fight against cancer. We showed previously that the selective interference of the Sin3's PAH2 domain with Sin3 interaction domain (SID) mimicking peptides restored expression of E-cadherin, estrogen receptor and RARa target genes such as RARb and CRBP1 leading to cell differentiation and anti-tumor effect in TNBC cells. Here we studied whether the re-expression of retinoic acid receptors (RARs) induced by the small molecule C16 (SID decoy) can make TNBC cells sensitive to selective retinoid therapies. EXPERIMENTAL APPROACH: Human and mouse cell models of TNBC as well as MMTV-Myc oncomice were used to test the effects of the SID decoys on the induction of RAR signaling, cell proliferation, induction of differentiation in 3D cultures, expansion of the cancer stem cell compartment, atypical ductal hyperplasia (ADH), ductal carcinola in situ (DCIS), tumor development and metastatic dissemination. RESULTS: Our data show that C16 induced a differential expression of RARs, ∼10 fold upregulation of RARa2, RARbeta1/2, ∼10 fold downregulation of RARg1 and ∼30% increased production of retinoic acid (RA). The combination of C16 plus RARa agonists, AM80 (tamibarotene) or AM580 induced 75% inhibition of cell proliferation in 2D cultures, induced immature acini in 3D and impaired cancer stem cell proliferation inhibiting tumorsphere formation (∼65%) in vitro. In vivo, the combination of C16 and AM580 reduced 90% tumor growth and metastasis. Interestingly, the treatment of MMTV-Myc oncomice with C16 alone or in combination with AM80 prevented mammary gland hyperplasia, DCIS and delayed tumor development (80% tumor free survival, Kaplan-Meier analysis). CONCLUSION: As a whole, the epigenetic reprogramming of the TNBC cells is promising for design of therapies based on the use of RARa agonists to induce differentiation of the tumor cells; giving these patients a chance of an alternative or complementary therapy to chemotherapy regimens. Citation Format: Nidhi Bansal, Almudena Bosch, Boris A. Leibovitch, Keely Pierzchalski, Zhou Ming-Ming, Maureen Kane, Samuel Waxman, Eduardo Farias. Targeted epigenetic reprogramming reverts tumor progression in triple-negative breast cancer models by the activation of retinoic acid receptor alpha. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3511. doi:10.1158/1538-7445.AM2015-3511

Regulation of retinoid mediated cholesterol efflux involves liver X receptor activation in mouse macrophages

Removal of cholesterol from macrophage-derived foam cells is a critical step to the prevention of atherosclerotic lesions. We have recently demonstrated the functional importance of retinoids in the regulation of the steroidogenic acute regulatory (StAR) protein that predominantly mediates the intramitochondrial transport of cholesterol in target tissues. In the present study, treatment of mouse macrophages with retinoids, particularly all-trans retinoic acid (atRA) and 9-cis RA, resulted in increases in cholesterol efflux to apolipoprotein AI (Apo-A1). Activation of the PKA pathway by a cAMP analog, (Bu)2cAMP, markedly augmented retinoid mediated cholesterol efflux. Macrophages overexpressing hormone-sensitive lipase increased the hydrolysis of cholesteryl esters and concomitantly enhanced the efficacy of retinoic acid receptor and liver X receptor (LXR) ligands on StAR and ATP-binding cassette transporter A1 (ABCA1) protein levels. RAs elevated StAR promoter activity in macrophages, and an increase in StAR levels augmented cholesterol efflux to Apo-A1, suggesting retinoid-mediated efflux of cholesterol involves enhanced oxysterol production. Further studies revealed that retinoids activate the LXR regulated genes, sterol receptor-element binding protein-1c and ABCA1. These findings provide insights into the regulatory events in which retinoid signaling effectively enhances macrophage cholesterol efflux and indicate that retinoid therapy may have important implications in limiting and/or regressing atherosclerotic cardiovascular disease.

Cutaneous Squamous Cell Carcinomas in Organ Transplant Recipients.

Non-melanoma skin cancers represent a major cause of morbidity after organ transplantation. Squamous cell carcinomas (SCC) are the most common cutaneous malignancies seen in this population, with a 65–100 fold greater incidence in organ transplant recipients compared to the general population. In recent years, human papillomaviruses (HPV) of the beta genus have been implicated in the pathogenesis of post-transplant SCCs. The underlying mechanism of carcinogenesis has been attributed to the E6 and E7 proteins of HPV. Specific immunosuppressive medications, such as the calcineurin inhibitors and azathioprine, are associated with a higher incidence of post-transplant SCCs compared to other immunosuppressive agents. Compared to other immunosuppressives, mTOR inhibitors and mycophenolate mofetil have been associated with a decreased risk of developing post-transplant non-melanoma skin cancers. As a result, they may represent ideal immunosuppressive medications in organ transplant recipients. Treatment options for post-transplant SCCs include surgical excision, Mohs micrographic surgery, systemic retinoid therapy, adjunct topical therapy, electrodessication and curettage, and radiation therapy. This review will discuss the epidemiology, risk factors, and management options of post-transplant SCCs. In addition, the underlying mechanisms of beta-HPV mediated carcinogenesis will be discussed.

Thymosin-β4 is a determinant of drug sensitivity for Fenretinide and Vorinostat combination therapy in neuroblastoma

Retinoids are an important component of neuroblastoma therapy at the stage of minimal residual disease, yet 40–50% of patients treated with 13-cis-retinoic acid (13-cis-RA) still relapse, indicating the need for more effective retinoid therapy. Vorinostat, or Suberoylanilide hydroxamic acid (SAHA), is a potent inhibitor of histone deacetylase (HDAC) classes I & II and has antitumor activity in vitro and in vivo. Fenretinide (4-HPR) is a synthetic retinoid which acts on cancer cells through both nuclear retinoid receptor and non-receptor mechanisms. In this study, we found that the combination of 4-HPR + SAHA exhibited potent cytotoxic effects on neuroblastoma cells, much more effective than 13-cis-RA + SAHA. The 4-HPR + SAHA combination induced caspase-dependent apoptosis through activation of caspase 3, reduced colony formation and cell migration in vitro, and tumorigenicity in vivo. The 4-HPR and SAHA combination significantly increased mRNA expression of thymosin-beta-4 (Tβ4) and decreased mRNA expression of retinoic acid receptor α (RARα). Importantly, the up-regulation of Tβ4 and down-regulation of RARα were both necessary for the 4-HPR + SAHA cytotoxic effect on neuroblastoma cells. Moreover, Tβ4 knockdown in neuroblastoma cells increased cell migration and blocked the effect of 4-HPR + SAHA on cell migration and focal adhesion formation. In primary human neuroblastoma tumor tissues, low expression of Tβ4 was associated with metastatic disease and predicted poor patient prognosis. Our findings demonstrate that Tβ4 is a novel therapeutic target in neuroblastoma, and that 4-HPR + SAHA is a potential therapy for the disease.

Retinoid Chemoprevention: Who Can Benefit?

Acute promyelocytic leukemia (APL) is a treatment success story. From a highly deadly disease it was turned into a highly curable disease by the introduction of differentiation-induction therapy with all-trans retinoic acid (ATRA) in the 1990's. During the last quarter of century, ATRA and other retinoids were used for the treatment and prevention of other cancers and even other diseases. The results were less spectacular, but nevertheless important. Progress has been made toward understanding the mechanism of action of retinoids in different physiological and pathological contexts. For some diseases, specific genetic backgrounds were found to confer responsiveness to retinoid therapy. Therapies that include retinoids and other modalities are very diverse and used both for combined targeting of multiple pathways and for diminishing toxicity.

Influence of oxidative injury and monitoring of blood plasma by DSC on patients with psoriasis

Oxidative stress induced by oxygen free radicals (OFRs) is a casual factor in psoriasis. Our aim was to detect the oxidative stress parameters and blood plasma changes with differential scanning calorimetry (DSC) in psoriatic patients. The study included untreated (n = 39) and treated (retinoids, methotrexate, biologic response modifiers; n = 33) white adult patients from both sex. To monitor oxidative stress concentration of malondialdehyde (MDA), reduced glutathione and sulfhydryl groups, production of OFRs, and activity of myeloperoxidase (MPO), superoxide dismutase, and catalase were measured. Denaturation of plasma components was detected in SETARAM Micro DSC-II calorimeter. Total production of OFRs and MPO activity, and the concentration of MDA were significantly increased both in untreated patients with moderate and severe symptoms and in all drug-treated groups compared with controls (p < 0.001). All of the scavengers and antioxidants were significantly decreased in untreated patients and better preserved after retinoid and biological therapy. DSC scans of blood plasma showed melting temperature a characteristic parameter to follow the severity of disease. The calorimetric enthalpy is exhibiting a moderate decrease with the progression of the inflammation. These findings suggest that an imbalance exists between pro-oxidants and antioxidants in untreated severe psoriatic patients. All drug therapy reduced the changes, mainly the biologic response modifiers. Similarly, DSC showed differences between untreated and conventional systemic drug treatment.

Duration of oral antibiotic therapy for the treatment of adult acne: A retrospective analysis investigating adherence to guideline recommendations and opportunities for cost-savings

The duration of oral antibiotic acne therapy for adolescents compared with guidelines was recently investigated; however it was uncertain if duration of antibiotics for adult acne therapy differed. This study aimed to evaluate duration of oral antibiotics for adult acne compared with guidelines and determine possible cost-savings. This was a retrospective cohort study of MarketScan Commercial Claims and Encounters database that incorporated claims data to determine duration and costs of antibiotic treatment among adults ages 21 years and older. Of 17,448 courses, 84.5% (14,737) aligned with duration guidelines, although 12,040 (69.0%) courses did not include concomitant topical retinoid therapy. Mean savings of $592.26 per person could result if prolonged courses met guidelines. Mean (median) costs of generic and branded formulations for the most frequent course duration (90-179 days) were $103.77 ($54.27) and $1421.61 ($1462.25), respectively. Actual patient prescription adherence is uncertain and database lacks information regarding acne severity, patient physical characteristics, and clinical outcomes. The majority of oral antibiotic course durations follow guidelines, although topical retinoids are underused. Costs of antibiotic therapy were lower for shorter courses and those using generic medications; the cost-effectiveness of these modifications has not been investigated.

Interferons in oral potentially malignant disorders, its effect and cure: A review

Potentially malignant lesion earlier known as a precancerous lesion is a morphologic alteration in the tissue which may progress into the development of malignancy. Similarly, a potentially malignant condition is associated with high risk of cancer. These lesions are commonly seen to occur after exposure to carcinogens, such as tobacco, areca nut, and alcohol, and they frequently progress to frank malignancy. Although, these lesions in the early stage (with hyperplasia and mild dysplasia) respond to retinoid therapy, advanced lesions (with moderate to severe dysplasia) are known to show resistance to the therapy. Bio-chemo-preventive therapy appears to be highly active in cases of advanced premalignant lesions, particularly those of the oral cavity. Interferons (IFNs) came into limelight with their use in hepatitis infections. It has been used in various cancer treatment modalities. IFNs and its uses have been less seeked in cases of head and neck cancers. This review will demonstrate the critical importance IFNs and its mode of action with a translational approach toward advancing our understanding of the pathobiologic basis of tumorigenesis and therapeutic outcome of IFNs in oral potentially malignant disorders.