Few Therapeutic Options For Patients Research Articles

O070 / #895 DURABILITY OF 10KHZ SPINAL CORD STIMULATION FOR TREATING NON-SURGICAL REFRACTORY BACK PAIN: 18-MONTH OUTCOMES: TRACK 3: NEUROSTIMULATION FOR BACK AND LEG PAIN

There are few therapeutic options for patients with chronic refractory back pain who have had no prior spine surgery and are not acceptable candidates for spine surgery. In the large proportion of these patients who do not meet therapeutic goals with conventional medical management (CMM), 10 kHz SCS is a therapy that has shown promise in a feasibility study (1). But inconsistent health care payer reimbursement provides an impetus for providing stronger evidence for SCS treating this condition that we have termed “Non-Surgical Refractory Back Pain” (NSRBP).

Mechanistic Rationales Guiding Combination Hepatocellular Carcinoma Therapies Involving Immune Checkpoint Inhibitors.

Hepatocellular carcinoma (HCC) is one of the deadliest cancers because of late symptom manifestation leading to delayed diagnosis, which limits patients with HCC in terms of receiving curative surgical treatment. There are only a few therapeutic options for patients with advanced HCC. The emergence of immune checkpoint inhibitors (ICIs) brings HCC treatment to a stage at which nivolumab, an anti-programmed cell death protein 1 monoclonal antibody, achieves a 20% response rate. However, the large proportion of unresponsive patients drives the exploration of therapeutic strategies to improve ICIs' efficacy. Recent preclinical and clinical studies have suggested that ICIs, when used in combinations or when used with other cancer therapies, might elicit synergistic antitumor effects. However, the mechanistic rationales guiding different drug combinations to maximize this synergy remain largely ambiguous. In this review, we discuss different drug combinations used in HCC and the underlying mechanistic rationales, aiming to enhance the understanding of how these treatments can achieve synergy. This knowledge sets the foundation for the development of more effective and promising combination therapies for HCC.

NMRK2 Gene Is Upregulated in Dilated Cardiomyopathy and Required for Cardiac Function and NAD Levels during Aging.

Dilated cardiomyopathy (DCM) is a disease of multifactorial etiologies, the risk of which is increased by male sex and age. There are few therapeutic options for patients with DCM who would benefit from identification of common targetable pathways. We used bioinformatics to identify the Nmrk2 gene involved in nicotinamide adenine dinucleotde (NAD) coenzyme biosynthesis as activated in different mouse models and in hearts of human patients with DCM while the Nampt gene controlling a parallel pathway is repressed. A short NMRK2 protein isoform is also known as muscle integrin binding protein (MIBP) binding the α7β1 integrin complex. We investigated the cardiac phenotype of Nmrk2-KO mice to establish its role in cardiac remodeling and function. Young Nmrk2-KO mice developed an eccentric type of cardiac hypertrophy in response to pressure overload rather than the concentric hypertrophy observed in controls. Nmrk2-KO mice developed a progressive DCM-like phenotype with aging, associating eccentric remodeling of the left ventricle and a decline in ejection fraction and showed a reduction in myocardial NAD levels at 24 months. In agreement with involvement of NMRK2 in integrin signaling, we observed a defect in laminin deposition in the basal lamina of cardiomyocytes leading to increased fibrosis at middle age. The α7 integrin was repressed at both transcript and protein level at 24 months. Nmrk2 gene is required to preserve cardiac structure and function, and becomes an important component of the NAD biosynthetic pathways during aging. Molecular characterization of compounds modulating this pathway may have therapeutic potential.

Metabolic pathways as possible therapeutic targets for progressive multiple sclerosis.

Unlike relapsing remitting multiple sclerosis, there are very few therapeutic options for patients with progressive forms of multiple sclerosis. While immune mechanisms are key participants in the pathogenesis of relapsing remitting multiple sclerosis, the mechanisms underlying the development of progressive multiple sclerosis are less well understood. Putative mechanisms behind progressive multiple sclerosis have been put forth: insufficient energy production via mitochondrial dysfunction, activated microglia, iron accumulation, oxidative stress, activated astrocytes, Wallerian degeneration, apoptosis, etc. Furthermore, repair processes such as remyelination are incomplete. Experimental therapies that strive to improve metabolism within neurons and glia, e.g., oligodendrocytes, could act to counter inadequate energy supplies and/or support remyelination. Most experimental approaches have been examined as standalone interventions; however, it is apparent that the biochemical steps being targeted are part of larger pathways, which are further intertwined with other metabolic pathways. Thus, the potential benefits of a tested intervention, or of an established therapy, e.g., ocrelizumab, could be undermined by constraints on upstream and/or downstream steps. If correct, then this argues for a more comprehensive, multifaceted approach to therapy. Here we review experimental approaches to support neuronal and glial metabolism, and/or promote remyelination, which may have potential to lessen or delay progressive multiple sclerosis.

Effects of ginsenoside compound K combined with cisplatin on the proliferation, apoptosis and epithelial mesenchymal transition in MCF-7 cells of human breast cancer

Context: Breast cancer seriously harms the health of women and there are currently few therapeutic options for patients with breast cancer.Objective: Effects of ginsenoside compound K (CK) in combination with cisplatin (DDP) on the proliferation, apoptosis, and epithelial mesenchymal transition (EMT) of MCF-7 cells were studied.Materials and methods: MCF-7 cells were divided into CK (50 μmol/L) group, DDP (10 mg/L) group, CK (50 μmol/L) +DDP (10 mg/L) group, and control (CON) group. The cells in the CON group were not treated with any drugs. Proliferation, apoptosis, expression of E-cadherin, N-cadherin, vimentin, protein kinase B (Akt), phosphorylated Akt (p-Akt), and level of fibronectin (FN) in MCF-7 cells were detected by methyl thiazolyl tetrazolium (MTT), flow cytometry, western blotting, and enzyme-linked immuno sorbent assay (ELISA), respectively.Results: The proliferation inhibition rates in CK, DDP, and CK + DDP groups at 48 h were 19.18 ± 2.25, 21.34 ± 2.84, and 43.37 ± 5.62, respectively. The apoptosis rates were 2.85 ± 0.56, 13.37 ± 2.28, 20.04 ± 2.92, and 30.78 ± 4.64 at 24 h and 3.14 ± 0.72, 20.36 ± 3.28, 27.58 ± 4.09, and 41.62 ± 5.83 at 48 h in CON, CK, DDP, and CK + DDP groups, respectively. CK or DDP alone and their combination all could reduce the levels of N-cadherin, vimentin, p-Akt/Akt, and FN and elevate level of E-cadherin.Discussion and conclusion: Both CK and DDP can inhibit the proliferation, EMT, and induce the apoptosis in MCF-7 cells, which may be related to the PI3K/Akt pathway. In addition, the combination of CK with DDP can produce a better effect.

Pathophysiology, Causes and Treatment of Chronic Cough in Adults: Literature Review

Received September 1, 2014 Accepted June 23, 2015 Address for correspondence Myung-Whun Sung, MD, PhD Department of Otorhinolaryngology, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea Tel +82-2-2072-3830 Fax +82-2-745-2387 E-mail mwsung@snu.ac.kr Chronic cough is a common symptom and the etiology of which can be challenging to diagnose. The key to successful management is to establish a diagnosis and to treat the cause of cough. Asthma, gastro-esophageal reflux, and postnasal drip syndrome have been thought to be most common causes of chronic cough. Various causes such as lung diseases (sarcoidosis, pertussis), obstructive sleep apnea, drug (angiotensin-converting enzyme inhibitor), and psychological status can induce chronic cough. However, many chronic cough patients do not have an identifiable cause. We need to understand the mechanisms underlying central and peripheral sensitization, how they interact with cough triggers and their relationship with the sensations that drive the urge to cough, and the subsequent motor cough response in chronic cough. Heightened cough reflex sensitivity is persistent and their cough is unexplained in many patients. In most patients who visited otorhinolaryngoloy clinics, it is possible to manage a majority of chronic cough patients successfully using a protocol based on presenting symptoms and therapeutic trials for the common causes of cough. However, there are few therapeutic options for patients with unexplained chronic cough. There is a pressing need to understand the physiological basis of unexplained chronic cough and to develop novel antitussive drugs that down regulate cough reflex sensitivity. Korean J Otorhinolaryngol-Head Neck Surg 2015;58(11):744-53

Nimotuzumab suppresses epithelial-mesenchymal transition and enhances apoptosis in low-dose UV-C treated salivary adenoid cystic carcinoma cell lines in vitro.

Salivary adenoid cystic carcinoma (SACC), which is one of the most common malignant tumors of the salivary glands, is associated with a poor long-term outcome. There are currently few therapeutic options for patients with SACC. Recent studies have shown the potential of the application of ultraviolet-C (UV-C) irradiation for the treatment of human cancer. In the present study, we investigated the effects of UV-C in the SACC cell lines SACC-83 and SACC-LM. High-dose UV-C (200 J/m) induced apoptosis and inhibited colony formation significantly. However, low-dose UV-C (10 J/m), which had little effect on apoptosis and colony formation, increased the ability of migration in SACC cells accompanied by a decrease in E-cadherin and an increase in vimentin, suggesting the occurrence of epithelial-mesenchymal transition (EMT). Low-dose UV-C (10 J/m) also resulted in upregulation of the phosphorylated forms of epidermal growth factor receptor (EGFR) and Akt (p-EGFR and p-Akt, respectively). Pretreatment with Nimotuzumab, an anti-EGFR monoclonal antibody, reversed the EMT as well as upregulation of p-EGFR/p-Akt induced by UV-C. Moreover, Nimotuzumab enhanced UV-C induced apoptosis and inhibition of colony formation. Our results indicate that EMT exerts a protective effect against apoptosis induced by low-dose UV-C. Thus, the combined application of Nimotuzumab and low-dose UV-C in vitro has an advantageous antitumor effect in SACC compared with the application of UV-C alone.

P13.05 * SECOND RADIOTHERAPY TREATMENT IN RECURRENT BRAIN TUMORS

BACKGROUND: Radiotherapy for recurrent irradiated brain tumors is limited by toxicity. The purpose of this study is to determine whether second radiotherapy treatment is beneficial or not for patients with recurrent brain tumors. PATIENTS AND METHODS: In a prospective study, 11 patients who recurred after primary brain tumors, first treated between 2005-2012, were analyzed for second radiotherapy treatment. Tumor histologic types are: glioblastoma multiforme (7), grade 2 astrocytoma (2), grade 3 oligodendroglioma (1) and grade 3 oligoastrocytoma (1). First radiotherapy (RT1) was performed with TD= 50-60Gy, 2Gy/ fraction for 8 patients and TD = 30 GY, 3Gy/ fraction in one patient. DFS (disease free survival) until the recurrence was 5.3-90.6 months. Second radiotherapy treatment (RT2) was associated with surgery and chemotherapy in 8 patients, with surgery or chemotherapy 2 patients; radiotherapy alone was performed in one patient. Karnofsky Index (KI) at RT2 was >70 for 9 patients and <70 for 2 patients. RT2 was delivered with: TD = 44-10 Gy, 2 Gy/fraction, 8 patients; TD = 30-44 Gy, 2,66-3 Gy/ fraction, 3 patients. Site of recurrence, isodose distributions, PTV1 (RT1) and PTV2 (RT2), KI at the beginning and at the end of radiotherapy were compared. RESULTS: The sites of recurrences were: central and marginal, 7 patients, at distance 4 patients. The same volume was second irradiated in 4 patients. PTV2 was greater than PTV1 only for 3 patients. KI was unchanged at the end of RT2 for 10 patients. Deterioration was observed in one patient. The median follow-up was 9,22 months (5,8-20,6 months). Six patients are alive, and 5 are dead. The median follow-up was 9.22 months. CONCLUSION: There are few therapeutic options for patients with recurrent brain tumors. Regardless of histology, second radiotherapy could be one of these options alone or with other treatment methods for patients with good KI, surgery at time of recurrence and longer DFS from first treatment.

Activity of the mTOR inhibitor RAD001, the dual mTOR and PI3‐kinase inhibitor BEZ235 and the PI3‐kinase inhibitor BKM120 in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most deadly cancers worldwide with only few therapeutic options for patients with advanced disease. There is growing evidence indicating that activation of the PI3K/Akt/mTOR pathway plays an important role in HCC and therefore represents a promising target for novel therapeutic approaches. The aim of this study was to evaluate and compare the antitumour activity of the mTOR inhibitor RAD001, the dual mTOR and PI3-kinase inhibitor BEZ235 and the PI3-kinase inhibitor BKM120 in vitro and in vivo. The antitumour effects of RAD001, BEZ235 and BKM120 were analysed in seven hepatoma cell lines as mono and combination therapy with Doxorubicin, Cisplatin, Irinotecan or 5-Flourouracil in vitro and in xenografts. Cell-cycle progression, apoptosis, and autophagy were analysed. Furthermore, effects on mitochondrial respiration and glycolysis were assessed. Treatment with RAD001, BEZ235 and BKM120 markedly reduced tumour cell viability. Combination of PI3K inhibitors with chemotherapy was most effective. RAD001, BEZ235 and BKM120 reduced tumour growth mainly by inhibiting cell-cycle progression rather than by inducing apoptosis. Interestingly, the antitumour effects were strongly associated with a reduction of mitochondrial respiration. BKM120, which exhibited the strongest antiproliferative effect, most strongly impaired oxidative phosphorylation compared with the other drugs. In this study, BKM120 showed the strongest antitumour activity. Our findings suggest impairment of mitochondrial function as a relevant mechanism of BKM120. Moreover, combination of PI3K and mTOR inhibitors with cytotoxic agents could be promising option for non-cirrhotic HCC patients.

Addition of an Immunomodulator to Infliximab Therapy Eliminates Antidrug Antibodies in Serum and Restores Clinical Response of Patients With Inflammatory Bowel Disease

There are few therapeutic options for patients with inflammatory bowel disease who lose response to infliximab because they produced antibodies against the drug. We performed a retrospective analysis to investigate whether administration of immune modulators to 5 patients who developed antibodies to infliximab (ATI) restored response to this drug; 3 patients were given azathioprine/6-mercaptopurine and 2 patients were given methotrexate. Concentrations of infliximab and ATIs, and antitumor necrosis factor (TNF) activity, were analyzed using enzyme-linked immunosorbent assay-based competition assays of serum samples collected before and after patients were given the immunomodulator. In all patients, levels of ATIs gradually decreased and trough levels of infliximab increased; clinical responses were restored to all patients. In competition assays, immunomodulator-induced elimination of ATIs was associated with increased anti-TNF activity in serum. The addition of immunomodulators to therapy might be helpful to patients who have lost response to anti-TNF agents owing to formation of antidrug antibodies.

Controversies in the Evaluation and Management of Chronic Cough

Chronic cough that cannot be explained after basic evaluation is a common reason for patients to be referred to respiratory outpatient clinics. Asthma, gastroesophageal reflux, and upper airway disorders frequently coexist with chronic cough. There is some controversy as to whether these conditions are causes or aggravants of cough. Heightened cough reflex sensitivity is an important feature in most patients. There is good evidence that it is reversible when associated with upper respiratory tract infection, angiotensin-converting enzyme inhibitor medications, and chronic cough associated with eosinophilic airway inflammation. In many patients, heightened cough reflex sensitivity is persistent and their cough is unexplained. There are few therapeutic options for patients with unexplained chronic cough. There is a pressing need to understand the genetic, molecular, and physiological basis of unexplained chronic cough and to develop novel antitussive drugs that down-regulate cough reflex sensitivity.

Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses

There are currently few therapeutic options for patients with pancreatic cancer, and new insights into the pathogenesis of this lethal disease are urgently needed. Toward this end, we performed a comprehensive genetic analysis of 24 pancreatic cancers. We first determined the sequences of 23,219 transcripts, representing 20,661 protein-coding genes, in these samples. Then, we searched for homozygous deletions and amplifications in the tumor DNA by using microarrays containing probes for approximately 10(6) single-nucleotide polymorphisms. We found that pancreatic cancers contain an average of 63 genetic alterations, the majority of which are point mutations. These alterations defined a core set of 12 cellular signaling pathways and processes that were each genetically altered in 67 to 100% of the tumors. Analysis of these tumors' transcriptomes with next-generation sequencing-by-synthesis technologies provided independent evidence for the importance of these pathways and processes. Our data indicate that genetically altered core pathways and regulatory processes only become evident once the coding regions of the genome are analyzed in depth. Dysregulation of these core pathways and processes through mutation can explain the major features of pancreatic tumorigenesis.

19-nor-1α,25-Dihydroxyvitamin D2 (Paricalcitol) inhibits the proliferation of human pancreatic cancer cells in vitro and in vivo

1,25-dihydroxyvitamin D3, (1,25(OH)2D3; calcitriol), the hormonal form of vitamin D, exerts growth-inhibitory, pro-apoptotic and anti-metastatic effects on tumor cells in vitro and in vivo but its clinical use is limited by its calcemic effects. Previous studies have shown that the antiproliferative effects of the less calcemic calcitriol analog 19-nor-1,25-(OH)2D2 (paricalcitol) on prostate tumor cell lines are indistinguishable from those of 1,25(OH)2D3. We therefore investigated the anti-proliferative effects of paricalcitol on the growth of pancreatic tumor cell lines in vitro and in vivo. Both 1,25(OH)2D3 and paricalcitol inhibited the growth of BxPC-3, Hs700T and AsPC-1 lines in a dose-dependent manner. This antiproliferative activity correlated with upregulation of the cell-cycle inhibitors p21 (Waf1/CIP1) and p27(Kip1). A fourth pancreatic cell line, Hs766T was unresponsive to both paricalcitol and calcitriol. Hs766T cells also failed to upregulate p21/Waf-1/Cip1 or p27/KiP in response to treatments with these agents. Paricalcitol, given three times per week inhibited the growth of AsPC-1 pancreatic tumor cell xenografts in nude mice at a dose that did not cause hypercalcaemia. Tumor inhibition was accompanied by in vivo upregulation of p21 and p27 expression. Given the few therapeutic options for patients with pancreatic cancer, further exploration of paricalcitol, an F.D.A. approved medication, is warranted.