Abstract

• Delayed-onset seizures after deep brain stimulation (DBS) surgery were seldom reported in previous studies. We studied 341 PD patients who underwent STN-DBS surgery from 2006 to 2021 in our department retrospectively.

• Five patients experienced seizures after DBS surgery with an incidence of 1.47 %. All 5 seizures cases were characterized as delayed-onset with an average time of 12 days postoperatively, which was different from the previous studies. In the further risk factors analysis of seizures, we found that the average diameter of peri-electrode edema of patients with seizures was larger than the average diameter of patients without seizures, which indicated that peri-electrode edema was risk factor for delayed-onset seizures after DBS surgery.

• Further multivariate analysis confirmed the result. Our study is the first report focusing on clinical characteristics and risk factors of delayed-onset seizures after DBS surgery based on a case series.

• Although DBS related seizure is uncommon complication, patients who experienced seizures are still exposed in risks of trauma and damage to the implanted simulator. We believe that these findings were useful for prevention and management of seizures associated with DBS surgery.

Introduction

Deep brain stimulation (DBS) is a well-established surgical therapy for some movement and psychiatric disorders. Patients are exposed in risks of trauma and implanted simulator damage when seizures occur, though seizures are not common postoperative adverse event of deep brain stimulation surgery. Previous studies indicated that the risk factors for seizures related to DBS included hemorrhage, peri-electrode edema, and increased age [1, 2, 3]. Most of the seizures occurred during electrode implantation procedures or within 48 h after DBS surgery [1, 2, 3], and delayed-onset seizures were seldom reported. However, this seizures incidence time-point presents quite different from those reports when retrospectively screening those PD patients who underwent subthalamic nucleus (STN) DBS in our center. We found that the seizures after DBS surgery were mainly delayed-onset (1–2 weeks after surgery). Therefore, this study summarized the clinical characteristics of delayed-onset seizures after DBS surgery and analyzed related risk factors.

Conclusions

Delayed-onset seizure after STN-DBS treating PD patients was uncommon with an incidence of 1.47 %. The seizures were transient and self-limiting, not easily developing into chronic epilepsy. Peri-electrode edema was a risk factor for delayed-onset seizures after DBS surgery. Patients with an average peri-electrode edema diameter > 2.70 cm had a higher risk to develop seizures.

Abstract

Keywords

Introduction

Methods

Results

Discussion

Conclusions

Other information

Declarations

Acknowledgements

References

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Abstract

Background
Poor treatment adherence among leprosy patients contribute to relapse, development of antimicrobial resistance, and the eventual plateauing of the prevalence and incidence of leprosy not just in the Philippines, but also worldwide. For this reason, we aimed to identify the patterns and determinants affecting treatment completion and default among multibacillary leprosy patients.

Methods
We conducted a retrospective cohort study involving three large hospitals in Metro Manila, Philippines. Patients who started the World Health Organization – Multiple Drug Therapy for multibacillary leprosy between January 1, 2007 and December 31, 2013 were included in the study. Selected socio-demographic and clinical data were abstracted from the patient treatment records. Survival analysis and proportional hazards regression were used to analyze the data.

Results
Records of 1,034 patients with a total follow-up time of 12,287 person-months were included in the analysis. Most patients were male, younger than 45 years old, had an initial bacterial index between 1 and 4, and were residents of Metro Manila. Less than 20% had their treatment duration extended to more than 12 months. Treatment adherence of the patients was poor with less than 60% completing treatment. Most patients complete their treatment within 12 months, but treatment duration may be extended for up to three years. Patients who default from treatment usually do so a few months after initiating it. After adjusting for other variables, hospital, initial bacterial index, and non-extended treatment duration were associated with treatment completion. These factors, in addition to age, were also found to be associated with treatment default.

Conclusion
This study provides quantitative evidence that there might be marked variations in how doctors in particular hospitals manage their patients, and these findings underscore the need to revisit and re-evaluate clinical practice guidelines to improve treatment outcomes and adherence

1. Introduction

Poor treatment adherence among leprosy patients is associated with relapse and the occurrence of antimicrobial resistance [[1]]. It has also been reported to contribute to the plateauing incidence and prevalence of leprosy in the Philippines [[2]], and worldwide [[3], [4], [5], [6]]. A perceived reason for poor treatment adherence is the long duration of the World Health Organization (WHO) multiple drug therapy (MDT) regimen, lasting a year for multibacillary leprosy patients [[7], [8]], which could even be extended for up to three years [[9], [10]]. In addition to the long duration of treatment, a host of psychosocial, economic, medical and health service, as well as personal factors were found to affect treatment adherence [[11]]. Two earlier reviews reported the following factors to be associated with poor treatment adherence: socio-economic status; educational attainment; gender; alcohol consumption; knowledge about leprosy; stigma associated with the disease; cultural factors; transportation costs; remoteness of residence; financial concerns; adverse effects of MDT; source of MDT; MDT drug shortages; poor relationship between patient and healthcare provider; and occurrence of leprosy reactions [[1], [12]]

1- Introduction

2- pH-responsive polymeric nanocarriers

3- Temperature-responsive polymeric nanocarriers

4- Redox potential-responsive polymeric nanocarriers

5- Enzyme-responsive polymeric nanocarriers

6- Light-responsive polymeric nanocarriers

7- Dual-responsive polymeric nanocarriers

8- Future perspectives

9- Conclusions

References

Abstract

In the last decade, considerable attention has been devoted to the use of biodegradable polymeric materials as potential drug delivery carriers. However, bioavailability and drug release at the disease site remain uncontrollable even with the use of polymeric nanocarriers. To address this issue, successful methodologies have been developed to synthesize polymeric nanocarriers incorporated with regions exhibiting a response to stimuli such as redox potential, temperature, pH, and light. The resultant stimuli-responsive polymeric nanocarriers have shown tremendous promise in drug delivery applications, owing to their ability to enhance the bioavailability of drugs at the disease site. In such systems, drug release is controlled in response to specific stimuli, either exogenous or endogenous. This review reports recent advances in the design of stimuli-responsive nanocarriers for drug delivery in cancer therapy. In particular, the synthetic methodologies investigated to date to introduce different types of stimuli-responsive elements within the biomaterials are described. The sufficient understanding of these stimuli-responsive nanocarriers will allow the development of a better drug delivery system that will allow us to solve the challenges encountered in targeted cancer therapy.

Conclusions

In this review, it was focused on the most recent advances in the development of stimuli-responsive nanocarriers for drug delivery in cancer therapy. These smart drug delivery systems respond to the distinct changes in cancer cells, such as changes in pH gradient and elevated secretion of certain enzymes, rather than the conditions in normal cells. Targeting tumors with stimuliresponsive nanocarriers could not only increase the therapeutic benefit and minimize associated toxicity, but could also enhance the curative effect by specifically releasing the anti-cancer drug in a powerful precise mode, both temporally and spatially. The different approaches adopted to incorporate stimuli responsive elements within the polymeric nanocarriers were discussed, with a particular focus on polymeric materials with stimuliresponsive mechanisms in response to pH, redox potential, enzymes, temperature, and light. Despite the tremendous progress that has been made regarding the engineering of new stimuli-responsive materials, several challenges still remain to be addressed with respect to nanomedicine applications. For example, their biodegradability and biocompatibility profiles should be critically investigated prior to utilization in human clinical trials. Many of these systems have only been reported as an in vitro proof-of-concept and follow-up work in vivo preclinical models has been described for only a few. However, the translation of these stimuli-responsive delivery systems from the bench to the bedside might be facilitated, to some extent, if the regulatory requirements for human clinical trials are considered in light of the key features that render a biopolymer suitable for biomedical application, such as biocompatibility, biodegradability, high drug loading capability, programmable release, excellent in vivo stability, non-cytotoxicity, and ability to support effective targeting. Given the ongoing developments in the field of bionanotechnology along with the wide knowledge accumulated over recent years, it is convinced that the collaborative efforts of chemists, biologists, and medicinal and pharmaceutical scientists will revolutionize the design of responsive polymeric materials for cancer therapy to significantly improve both the quality and duration of the lives of patients with cancer.

1- Introduction

2- Materials and methods

3- Results

4- Discussion

References

Abstract

Drug resistance is a big problem in cancer treatment and one of the most prominent mechanisms underlain is overexpression of ATP-binding cassette (ABC) transporters, particularly ABCB1, ABCC1 and ABCG2. Inhibition of ABC transporters is an important approach to overcome drug resistance. The inositol-requiring enzyme 1α (IRE1α), an arm of unfolded protein response (UPR), splices XBP1 mRNA to generate an active transcription factor XBP1s. UPR is implicated in drug resistance. However, the underlying mechanism is unclear. We found that the anticancer drugs such as 5-fluorouracil (5-FU) activated the IRE1α-XBP1 pathway to induce the expression of ABCB1, ABCC1 and ABCG2 in colon cancer cells. Inhibition of IRE1α RNase activity with small molecule 4μ8c suppressed the drug-induced expression of these ABC transporters and sensitized 5-FU-resistant colon cancer cells to drug treatment. In vivo xenograft assay indicates that administration of 4μ8C substantially enhanced the efficacy of 5-FU chemotherapy on 5-FU-resistant colon cancer cells. These results suggest that IRE1α-targeting might be a strategy to cope with drug resistance of colon cancer.

Introduction

Cancers have the ability to develop resistance to chemotherapy, and the increasing prevalence of these drug resistant cancers necessitates further research and treatment development. Multidrug resistance is a phenomenon by which, after exposure to a chemotherapeutic agent, cancer cells develop resistance, and simultaneous cross-resistance, to a wide range of functionally and structurally unrelated chemotherapeutic drugs (1, 2). Intrinsic or acquired multidrug resistance is one of the main reasons for chemotherapy failure, leading to the recurrence of malignant tumors and ultimately, patient relapse or death (3). A variety of mechanisms have been attributed to multidrug resistance, such as enhanced drug efflux, increased DNA damage repair, reduced apoptosis, elevated autophagy, and/or altered drug metabolism (4-6). Previous studies have confirmed that multidrug resistance both in cancer cell lines and human tumor tissues is most often associated with the overexpression of the ATP-binding cassette (ABC) transporters (4, 7, 8). These ABC transporters are efflux pumps that transport various structurally unrelated and potentially dangerous substances out of the cells. They hydrolyze ATP for energy and actively pump drug components out of cells, leading to drug resistance. In these transporters, ABCB1 (also known as MDR1 or P-gp), ABCC1 (MRP1) and ABCG2 (BCRP1) play an important role in drug resistance in vivo (4, 7). Developing inhibitors of ABC transporters is an important approach to overcoming drug resistance. Extensive efforts have been made to develop inhibitors targeting ABC transporters, particularly ABCB1. However, no such agents have been developed successfully as was initially hoped.

1- Introduction

2- DDS for targeted BC treatment

3- Conclusion and outlook

References

Abstract

Bladder cancer is a severe disease that threatens human health. The high recurrence rate and severe side-effects of traditional bladder cancer therapy require more efficient and higher targeting treatment. Drug delivery systems especially being endowed with the targeting property may provide a feasible means to solve such problems. Herein, we have reviewed the recent progress of the drug delivery systems aiming at bladder cancer therapy especially focusing on their targeting strategies. Additionally, we give some outlook of the design on targeting strategy for more effective anti-cancer applications.

Introduction

Cancer is a category of disease originating from unregulated cell growth and such abnormal cells are able to spread or invade other parts of our body. It is a major public health problem and becomes the second leading cause of death worldwide. Among them, bladder cancer (BC) tops the list of the estimated new cases and deaths [1]. In Europe, BC is the 5th most common cancer type for both sexes affecting rather men than women [2]. In US, BC ranks the 4th most common caner and the 8th in mortality in men [1]. In principle, BC is a rather heterogeneous disease, resulting in a challenge in classification, staging and grading. Generally, 70% of bladder urothelial cell carcinomas represent a superficial disease called nonmuscle-invasive BC, while the other 30% develop a muscle-invasive disease bearing the risk of metastatic spread of the tumor [3]. The standard scheme for superficial BC treatment is surgical transurethal resection with an 80% early success rate. Unfortunately, among them, 70% of those patients develop tumor recurrence within 5 years after surgical transurethal resection [4]. Therefore, chemotherapy still plays an important role in the prevention of tumor recurrence and progression. Although systemic or intravesical chemotherapy using the first-line chemotherapeutic agents (cisplatin, taxanes, gemcitabine, etc.) enables long-term survival in some patients, the high recurrence rate and severe side-effects still hinder BC therapy. Thus, more efficient and higher targeting treatment is in urgent need to improve the quality of the BC patients’ lives.

Introduction

Materials and methods

Results

Discussion

References

Abstract

Purpose: Questionnaire survey among the members of the German Spine Society (Deutsche Wirbels€ aulen-Gesellschaft, DWG) to objectify oncological infrastructure and current standard of care in spinal tumor treatment in Germany. Methods: All DWG-members were contacted via the society’s e-mail and asked to respond in anonymized form to a related questionnaire. Questions were asked regarding surgical specialty, type of institution involved, numbers of spinal procedures, as well as questions on treatment for primary tumors, whether the respondent belonged to a tumor center, decision-making procedures for surgery, and the type of procedure. Results: 84 centers providing surgical treatment for spinal tumors in their departments were identified. 52.6% were carrying out more than 500 spinal procedures per year. There was a significant association (P
0.05) between the numbers of spinal surgeries, the number of treated tumor patients per year, the organisation in a tumor center and the treatment of primary tumors. 76% are part of a local tumor center for interdisciplinary decision making (i.e.surgical treatment and adjuvant therapy). 74% of the institutions stated that conventional postoperative radiotherapy is standardly administered in the case of secondary lesions, with 24% of them referring patients to external services for radiotherapy. Conclusion: In spite of often large numbers of spinal operations, the centers perform relatively small numbers of tumor operations, particularly for primary tumors. A nearly three-quarter majority of the departments are integrated into interdisciplinary tumor care. However, there is a marked number that do not belong to an interdisciplinary organisation. Further advances in multidisciplinarity and oncology training are a continuous issue to increase treatment quality in spinal tumor patients.

Introduction

The diagnosis of a tumor on the spine is a severe and momentous event for those affected and represents an equally great challenge for the specialist disciplines treating these lesions. There is controversy regarding the value, necessity, options and extent of surgical interventions and on whether they are lastingly effective [1]. Oncological treatment is now primarily based on and guided by the biology of the underlying tumors, and currently a paradigm shift in surgical therapy is observed. Among the involved disciplines, the spinal surgeon is usually the first who is contacted either by the symptomatic patient or diagnostic radiologist. However, to provide the complete range of treatment, other disciplines as radiooncology, pathology, pain therapy, internal oncology etc. as well as the necessary infrastructure also have to be available locally to consecutively guarantee the patient a oncological treatment in accordance with the latest standards and guidelines. The treatments are mainly palliative in nature due to secondary lesions developing in 10e20% of all cancer patients [2]. Surgical procedures are aimed at relieving neurological complications, severe pain or restoring spinal integrity and vertebral stability in order to ensure an acceptable quality of life for the period remaining. With regard to primary tumors or so called „solitary“ metastases in definded constellations, the current data in the literature show that radical resection combined with adjuvant therapy is markedly superior to intralesional procedures [3e5].

1- Introduction

2- Feature extraction

3- Epileptic seizure detection

4- Methods for feature evaluation

5- Experimental results

6- Conclusions

References

Abstract

Since the manual detection of electrographic seizures in continuous electroencephalogram (EEG) monitoring is very time-consuming and requires a trained expert, attempts to develop automatic seizure detection are diverse and ongoing. Machine learning approaches are intensely being applied to this problem due to their ability to classify seizure conditions from a large amount of data, and provide pre-screened results for neurologists. Several features, data transformations, and classifiers have been explored to analyze and classify seizures via EEG signals. In the literature, some jointly-applied features used in the classification may have shared similar contributions, making them redundant in the learning process. Therefore, this paper aims to comprehensively summarize feature descriptions and their interpretations in characterizing epileptic seizures using EEG signals, as well as to review classification performance metrics. To provide meaningful information of feature selection, we conducted an experiment to examine the quality of each feature independently. The Bayesian error and non-parametric probability distribution estimation were employed to determine the significance of the individual features. Moreover, a redundancy analysis using a correlation-based feature selection was applied. The results showed that the following features – variance, energy, nonlinear energy, and Shannon entropy computed on a raw EEG signal, as well as variance, energy, kurtosis, and line length calculated on wavelet coefficients – were able to significantly capture the seizures. When compared with a baseline method of classifying all epochs as normal, an improvement of 4.77–13.51% in the Bayesian error was obtained.

Introduction

An epileptic seizure, as defined by the International League Against Epilepsy [1], is a temporary event of symptoms due to synchronization of abnormally excessive activities of neurons in the brain. It has been estimated that approximately 65 million people around the world are affected by epilepsy [2]. Nevertheless, it is still a time-consuming process for neurologists to review continuous electroencephalograms (EEGs) to monitor epileptic patients. Therefore, several researchers have developed differenttechniques that help neurologists to identify an epilepsy occurrence [3–5]. The whole process of automated epileptic seizure analysis primarily consists of data acquisition, signal pre-processing, feature extraction, feature or channel selection, and classification. This paper focuses on a selection of features commonly used in the literature, including statistical parameters (mean, variance, skewness, and kurtosis), amplitude-related parameters (energy, nonlinear energy, line length, maximum and minimum values) and entropyrelated measures. These features can be categorized based on their interpretation or the domain from which the features are calculated. While some studies have considered a particular group of features applicable to their proposed classification method [6–8], others have applied various groups of features extracted from the time, frequency, and time-frequency domains. For example, 55 features were used with a support vector machine (SVM) and postprocessing for neonatal seizure detection, which provided a good detectionrate of 89.2% withone false detectionperhour [9]. Feature redundancy and relevance analysis were applied to 132 features to reduce the vector dimension [10]. Fast correlation based-filter proposed in [11], correlation-based selection (CFS) [12], and ReliefF established in [13], were utilized to select non-redundant features and the filtered features were classified by an artificial neural network (ANN). It turned out that 30-optimal selected features by ReliefF achieved the best result with 91% sensitivity and 95% specificity. These studies showed thatthere is the need to review feature selection as relevant features are directly related to the seizure classification performance.

1- Introduction

2- Noncoding RNAs and sirtuins function in cancer drug resistance

3- Future prospective and conclusion

References

Abstract

Cancer is a rising and major health issue around the world. The acquisition of resistance to chemotherapeutic drugs is a great obstacle for the effective treatment of nearly all cancers. Drug resistance is regulated by multiple factors and mechanisms including genetic mutations, abnormal expression of some cellular transporters such as multidrug resistance (MDR) transporters, changes in apoptotic pathways, cancer stem cells, tumor microenvironment, and noncoding RNAs (ncRNAs). Evidence clearly indicates a key role for sirtuins in several characteristics of cancer drug resistance. Recent studies demonstrated the crucial impact of some ncRNAs on sirtuins expression leading to modulation of chemotherapy resistance in cancers. In this review, we will focus on the current findings about the impacts of ncRNAs on the sirtuins pathway and their role in drug resistance of cancer.

Introduction

Cancer is considered a complex disease associated with some genetic mutations, deletions, epigenetic alterations and chromosomal translocations that are involved in cancer initiation, promotion, metastasis and drug resistance (Bach and Lee, 2018). Chemotherapy is one of the most widely used therapies for the treatment of cancer and improves the lifespan of patients. However, prolonged utilization of chemotherapeutic drugs. may lead to drug resistance which is a major issue in cancer treatment (Szakacs et al., 2006). Based on statistical reports, over than 90% of deaths in patients with different types of cancer are associated with chemotherapeutic drug resistance (Li et al., 2008; Longley and Johnston, 2005). Cancer cells apply many different mechanisms to impede drug treatment, including the genetic mutations, cell cycle alterations, apoptosis induction, drug metabolism, efflux alterations and DNA methylation (Balch et al., 2004; Gillet and Gottesman, 2010; Xia and Hui, 2014). NcRNAs have been reported to play an essential role in determining drug sensitivity or restoring drug sensitivity in resistant cells in many cancers. (Kapranov et al., 2010). NcRNAs are RNA molecules that do not code any protein. However, they exert an important impact on the expression of more than 60% of human genes. They are classified into two main groups including the most studied microRNAs (miRNAs) and the long non-coding RNAs (lncRNA) (Kapranov et al., 2010). MiRNAs are single-stranded RNAs, 19-23bp in length and account for approximately 30% of gene expression regulation. MiRNAs can bind to the 3′ untranslated regions (UTRs) of their target mRNAs and regulate gene expression. The most important function of miRNAs is the suppression of gene expression (Omidkhoda et al., 2019; Szulwach et al., 2010). lncRNAs are transcripts with 200 nt to ~100 kb in length. They do not have any significant open reading frames. lncRNAs are poly-adenylated and located within the cell nucleus or cytosol. They can regulate the expression of genes by cis-acting or trans-acting regulation. Cis-acting lncRNAs affect the expression of neighboring genes by acting at the site of transcription, while trans-acting lncRNAs affect the expression of genes by acting away from the site of synthesis (Barangi et al., 2019; Batista and Chang, 2013).

1- Introduction

2- Common lethal cancers

3- Investigating miRNA profiling in cancers

4- MiR candidates for early phase group detection

5- Conclusion

References

Abstract

Cancer is considered as a challenging lethal agent around the world and its detection at early stages would help prevention of the high mortality. Among the widely used biomarkers in clinical diagnosis of cancer, extracellular non-coding RNAs as ribonucleic acid biomarkers serve as state-of-the-art candidates for molecular diagnosis. In that regard, microRNAs are of great priority mainly because of high variety and stability in body fluids. Accordingly, common miRNAs among most prevalent cancers could help us (pre)diagnose cancer with high accuracy in target samples. In this study, common lethal cancers to humans were investigated in case of miRNA profiles to determine the possible common correlation between miRNA up-regulation or down-regulation (as a ribonucleic acid biomarker) and developing the cancers. It was shown that among the investigated miRNAs, five typical extracellular miRNAs (miR-18a, miR-21, miR-155, miR-221, and miR-375) dysregulation are predominant in most cancer varieties comprising breast, colon, lung, prostate, pancreas, gastric, ovarian, esophagus and liver. This could serve as an appropriate target site for developing point-of-care approaches for cancer detection e.g. designing diagnostic biosensor-based microarrays or kits for both quantification and qualification of the biomarkers. Besides, the miRNA candidates could be efficiently applied to cancer therapeutic approaches.

Introduction

Cancer keeps on being a remarkable cause of worldwide mortality in spite of many years of effort and cost. Deadliest types of cancers to human includes pancreas, liver, lung and bronchus, prostate/breast, colon, rectum and ovary [1–3]. Most of cancers do not induce clinical symptoms until in the later stages when the therapeutic treatment is no longer an option. However, detection of cancer at first stages, regardless of its origin, greatly increases the chance of effective treatments. In spite of much research in cancer biomarkers, only a few are considered for early diagnosis of common cancers. In addition, there is not a general biomarker for population screening in order to detect both asymptomatic cancers and early-staged cancers. Hence, investigating more sensitive and non-invasive biomarkers is still a promising challenge in cancer diagnosis and prognosis [4]. Accessing circulating cancer biomarkers through biological fluids using liquid biopsy seems to propose a promising cost-effective and non-invasive solution. Literally, cf-miRNAs are considered as ideal circulating cancer biomarkers due to their ease of access and quantification, besides integration with other macromolecules e.g. proteins, and high stability in plasma [5, 6]. MiRNAs are endogenous, small (18–24 nt), non-coding (nc) RNA molecules that play important regulatory roles in cell proliferation, apoptosis, metastasis and angiogenesis [7]. Dysregulated miRNA(s) have both oncogenic and tumor-suppressing effects depending on their corresponding targets. The increase or decrease of miRNAs is related to the role of their target genes in cancer progression or regression. MiRNAs are mainly categorized in two groups: 1) OncomiRs that are up-regulated in cancers to target protein-coding transcripts in tumor suppressive pathways, and consequently increase cell proliferation, invasion and metastasis. 2) Tumor-suppressor miRNAs that repress the oncogenic genes and their down-regulation in cancer increases the oncogenic activity [8]. MiRNAs show various expression patterns in tissue and blood of many cancers in comparison with normal samples. Furthermore, miRNA profiles in cancers with various tissue origins are distinct from each other [9].

1- Acute leukemias — Novel therapeutics are urgently required

2- cAMP-dependent pathway – A meaningful target in hematological malignancies

3- Targeting cAMP transporters/efflux – an unexplored approach to modulation of the cyclic nucleotide pathway

4- Conclusions

References

Abstract

While current treatment regimens for acute leukemia can dramatically improve patient survival, there remains room for improvement. Due to its roles in cell differentiation, cell survival, and apoptotic signaling, modulation of the cyclic AMP (cAMP) pathway has provided a meaningful target in hematological malignancies. Several studies have demonstrated that gene expression profiles associated with increased pro-survival cAMP activity or downregulation of various pro-apoptotic factors associated with the cAMP pathway are apparent in acute leukemia patients. Previous work to increase leukemia cell intracellular cAMP focused on the use of cAMP analogs, stimulating cAMP production via transmembrane-associated adenylyl cyclases, or decreasing cAMP degradation by inhibiting phosphodiesterase activity. However, targeting cyclic nucleotide efflux by ATP-binding cassette (ABC) transporters represents an unexplored approach for modulation of intracellular cyclic nucleotide levels. Preliminary studies have shown that inhibition of cAMP efflux can stimulate leukemia cell differentiation, cell growth arrest, and apoptosis, indicating that targeting cAMP efflux may show promise for future therapeutic development. Furthermore, inhibition of cyclic nucleotide transporter activity may also contribute multiple anticancer benefits by reducing extracellular pro-survival signaling in malignant cells. Hence, several opportunities for drug repurposing may exist for targeting cyclic nucleotide transporters.

Biology and etiology of acute leukemias

While not the most prevalent malignancy in the United States, acute leukemia ranks among the top ten cancers in terms of both morbidity and mortality [1]. These hematological malignancies involve aberrant proliferation of blood cells with immature phenotypes. Acute leukemias are typically identified by the presence of > 20% blast cells in the peripheral blood or bone marrow [2]. Due to inherent characteristics related to a reduced differentiation state, and the ability to rapidly propagate, acute leukemias may have worse prognoses than chronic leukemias. Acute myelogenous leukemia (AML) is most prominent in elderly adults over 65 years of age. Annually, 21,450 cases are diagnosed in the United States, and 10,920 cases succumb to the disease [1]. The five year overall survival for this disease is a disheartening 28.3% for adults [1] and about 60% for children [3]. T-cell lineage and B-cell precursor acute lymphoblastic leukemia (T-ALL and B-ALL) primarily affects children, adolescents and young adults, with about 6,000 new cases diagnosed and 1,500 deaths each year [4, 5]. This disease is considered > 80% curable, however there is much room for improvement, specifically for high-risk subtypes such as Ph-like ALL, leukemias harboring rearrangements of KMT2A gene at 11q23 or BCR-ABL1 translocations, etc. [6-8] Therefore, there is a strong need for the development of novel approaches to treat these malignancies and improve patient outcome. The primary classification of acute leukemia is based on the presence of chromosomal abnormalities and translocations along with immunophenotyping. For example, 25-30% of B-ALL have hyperdiploidy [9], while a surprising 40-50% of AML are cytogenetically normal [2]. An analysis of primary AML samples determined an average of 13 mutated genes per sample [10]. It has also been reported that > 80% of B-ALL cases contain deletions within genes related to B cell development [11]. De novo B-ALL genomes also contain 10-20 gene coding mutations [12]. Most commonly, the etiology of acute leukemias is attributed to the combination of mutations that govern pro-survival signaling and reduce tumor suppressor genes [13]. Many factors are potentially implicated in leukemogenesis, and most include aberrancies that increase cell proliferation and induce differential arrest. Due to potential mutations, rapid growth, and deviant signaling, leukemia cells have the capacity to overcome normal mechanisms that would typically result in cell death.

Introduction

Methods

Results

Discussion

References

Abstract

Background: In some Dutch pancreatic surgery centers, patients who underwent pancreatoduodenectomy (PD) for ampullary cancer undergo surveillance for colorectal cancer (CRC), since an association is suggested in contemporary literature. This study aimed to examine the CRC incidence after PD for ampullary cancer in four pancreatic surgery centers and a Dutch nationwide cohort. Methods: All patients who underwent resection of ampullary cancer from 2005 through 2017 at four centers were included. All colonoscopies and CRC diagnoses in these patients were recorded. In addition all PDs for ampullary cancer in the Dutch Pathology Registry (2000-2017) were recorded along with the CRC diagnoses and compared with an age, sex, and year-matched cohort. Results: Out of 287 included patients by the four centers, 11% underwent a colonoscopy within one year after PD. Eight (2.7%) were diagnosed with CRC before PD and two (0.7%), at 14 and 72 months after PD. In the nationwide cohort comparison, the CRC incidence was similar before (2.6% versus 1.9%, P = 0.424) and after surgery (2.1% versus 3.1%, P = 0.237). Within one year after PD, the incidence was 0.3% compared to 0.6% in the matched controls (P = 0.726) Conclusions: The current study could not find an increased risk of CRC in patients with resected ampullary cancer. Therefore, there is insufficient justification to screen for CRC in patients with resected ampullary cancer.

Introduction

Ampullary cancer is a rare malignancy that accounts for approximately 0.2% of all gastrointestinal cancers.[1] Due to its origin distal to the bile and pancreatic duct confluence at the duodenal outflow, the onset of symptoms (e.g. biliary obstruction) is early compared to most other periampullary and pancreatic tumors. As a consequence, resection rates of ampullary cancers reach up to 92%[2] and the reported 5-year survival rates range from 38 to 67%.[3-5] Several reports have suggested an increased incidence of colorectal polyps and malignancies in patients with ampullary cancer. Ampullary cancer in some patients is associated with hereditary colorectal cancer (CRC) syndromes, such as hereditary non-polyposis colorectal cancer (HNPCC) [6] and familial adenomatous polyposis (FAP).[7-9] However, in ampullary cancer patients without these syndromes, the CRC incidence is also reported to be higher than in age-adjusted control groups.[10, 11] This association has led to colorectal surveillance in patients who underwent pancreatoduodenectomy (PD) for ampullary cancer in some pancreatic cancer centers in the Netherlands. The yield of routine colonoscopy within one year after surgery is subject of debate.

The full impact of the Coronavirus Disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2 virus, on the field of hematopoietic cell transplantation (HCT) is unknown. This perspective paper reviews the following: current COVID-19 epidemiology, diagnosis and potential therapies; care considerations unique to HCT patients; and the concept of a learning network to assimilate emerging guidelines and best practices and to optimize patient outcomes through facilitating shared learning and experience across transplant centers.

Introduction

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel single strand (ss) RNA beta-coronavirus, has caused the current Coronavirus Disease 2019 (COVID-19) pandemic. As of April 13, 2020, the World Health Organization (WHO) reported 1,773,084 laboratory confirmed cases and 111,652 deaths globally. 1 What ultimate impact COVID-19 will have on the field of hematopoietic cell transplantation (HCT) is currently unknown. This perspectives paper anticipates the significant influence of COVID-19 on HCT patients given their immune compromise, presence of other medical co-morbidities, and concerns for higher infection-related severity and mortality and also reviews the substantial impact of COVID-19 on the HCT-related healthcare system. To address these challenges, novel care approaches and ways to assimilate and share information in the background of rapid change are critically needed. Therefore, the concept of learning networks as interactive platforms for effectively assimilating and distributing evolving information to transplant centers is introduced.

The novel coronavirus (2019-nCoV) is an emerging pathogen that was first described in late December 2019 and causes a severe respiratory infection in humans. Since the outbreak of COVID-19, international attention has raised to develop treatment and control options such as types of immunotherapies. The immunotherapy is an effective method for fighting against similar viral infections such as SARS-CoV, and MERS-CoV. These methods include several types of vaccines, monoclonal antibody candidates, and etc. This systematic review article was designed to evaluate the existing evidence and experience related to immunotherapy for 2019-nCoV. Web of Science (ISI), PubMed, and Scopus databases were used to search for suitable keywords such as 2019-nCoV, novel coronavirus, Immunotherapy, interleukin, vaccine and the related words for relevant publications up to 24.3.2020. The present systematic review was performed based on PRISMA protocol. Data extraction and quality valuation of articles were performed by two reviewers. 51 articles were the results of the search and based on the inclusions and exclusions criteria, 7 articles were included in the final review. As a conclusion of these studies demonstrated that although no serious research has been done on this subject at the time of writing this article, similar studies on the related viruses showed notable results. So immunotherapy for this virus can also be a suitable option.

Background

2019-nCoV a large enveloped virus with a positive sense, singlestranded RNA genome, is the third known coronavirus after SARS-CoV and MERS-CoV that was first identified in late December 2019 and causes severe respiratory illness and pneumonia-like infection in humans [1,2]. WHO has declared the pandemic outbreak of novel coronavirus (2019-nCoV) as a global health emergency. Immunotherapy is an efficient therapeutic option intervention against viral infections. Most immunotherapy attempts have been successful to fight against similar COVID-19 viruses such as SARS-CoV and MERS-CoV. The main methods in this regard include several vaccines and monoclonal antibody candidates. Furthermore, according to existing evidence in fighting against viral infections such as Ebola, influenza, SARS, and MERS plasma exchange can likely reduce the viral load and disease mortality [3,4]. In both SARS-CoV and SARS-CoV-2 viruses entry into the host cells is mediated by interaction of the receptor-binding domain (RBD) in S protein on virus outer-membrane and angiotensin-converting enzyme 2 (ACE2) on cell. So, these proteins can be the major potential targets for immunotherapy [1,5]. The increasing knowledge of MERS-CoV and SARS-CoV immunotherapies in recent years might increase the opportunities to design effective same therapeutics for novel coronavirus [3].