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Background: Combination therapy with the administration of GW5074 and sorafenib significantly induced necrotic death in various cancer cells in vivo, as well as prolonging the survival of an animal disease model due to significant suppression of the primary and metastatic lesions. We sought to determine the safety, tolerability, pharmacokinetics, and anti-tumor activity of this co-administration therapy in patients with refractory advanced solid cancers. Methods: Twelve patients were enrolled. Eligible subjects received different dosages of GW5074 in one of the three dose cohorts (Cohort 1: 750 mg daily, Cohort 2: 1500 mg daily, Cohort 3: 750 mg twice daily) plus 200 mg of sorafenib daily to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) at phase 1. Furthermore, the expression level of phosphorylated DAPKS308 in primary tumor, metastatic tumor, and circulating tumor cells (CTC) were evaluated to investigate the relationship between biomarker and the efficacy profile. Results: Among the 12 enrolled patients in this phase 1 trial, most adverse effects (AE) were grade 1, with two being grade 3. The most frequent AE of all grades were weight loss and hypertension, occurring in 16.7% of participants. Eight patients (66.7%) had the disease controlled by receiving co-administration therapy of GW5074 and sorafenib. GW5074 was found to have poor absorption, as increasing the dosage did not result in a significant increase in the bioavailability of GW5074 in subjects. Furthermore, the expression level of phosphorylated DAPKS308 in tumor and CTCs were correlated with the disease control rate (DCR) and duration of response (DOR). Conclusions: Co-administration therapy of GW5074 and sorafenib demonstrated a favorable safety profile and showed anti-tumor activity in a variety of tumor types. However, the solubility of GW5074 is not satisfactory. A future phase 2a trial will be carried out using the new salted form that has been proven to be more effective.

Background Bone marrow aspiration and biopsy remain the gold standard for the diagnosis of hematological diseases despite the development of flow cytometry (FCM) and molecular and gene analyses. However, the interpretation of the results is laborious and operator dependent. Furthermore, the obtained results exhibit inter- and intravariations among specialists. Therefore, it is important to develop a more objective and automated analysis system. Several deep learning models have been developed and applied in medical image analysis but not in the field of hematological histology, especially for bone marrow smear applications. Objective The aim of this study was to develop a deep learning model (BMSNet) for assisting hematologists in the interpretation of bone marrow smears for faster diagnosis and disease monitoring. Methods From January 1, 2016, to December 31, 2018, 122 bone marrow smears were photographed and divided into a development cohort (N=42), a validation cohort (N=70), and a competition cohort (N=10). The development cohort included 17,319 annotated cells from 291 high-resolution photos. In total, 20 photos were taken for each patient in the validation cohort and the competition cohort. This study included eight annotation categories: erythroid, blasts, myeloid, lymphoid, plasma cells, monocyte, megakaryocyte, and unable to identify. BMSNet is a convolutional neural network with the YOLO v3 architecture, which detects and classifies single cells in a single model. Six visiting staff members participated in a human-machine competition, and the results from the FCM were regarded as the ground truth. Results In the development cohort, according to 6-fold cross-validation, the average precision of the bounding box prediction without consideration of the classification is 67.4%. After removing the bounding box prediction error, the precision and recall of BMSNet were similar to those of the hematologists in most categories. In detecting more than 5% of blasts in the validation cohort, the area under the curve (AUC) of BMSNet (0.948) was higher than the AUC of the hematologists (0.929) but lower than the AUC of the pathologists (0.985). In detecting more than 20% of blasts, the AUCs of the hematologists (0.981) and pathologists (0.980) were similar and were higher than the AUC of BMSNet (0.942). Further analysis showed that the performance difference could be attributed to the myelodysplastic syndrome cases. In the competition cohort, the mean value of the correlations between BMSNet and FCM was 0.960, and the mean values of the correlations between the visiting staff and FCM ranged between 0.952 and 0.990. Conclusions Our deep learning model can assist hematologists in interpreting bone marrow smears by facilitating and accelerating the detection of hematopoietic cells. However, a detailed morphological interpretation still requires trained hematologists.

Transposable element (TE)-derived sequences comprise more than half of the human genome, and their presence has been documented to alter gene expression in a number of different ways, including the generation of alternatively spliced transcript isoforms. Alternative splicing has been associated with tumorigenesis for a number of different cancers. The objective of this study was to broadly characterize the role of human TEs in generating alternatively spliced transcript isoforms in cancer. To do so, we screened for the presence of TE-derived sequences co-located with alternative splice sites that are differentially used in normal versus cancer tissues. We analysed a comprehensive set of alternative splice variants characterized for 614 matched normal-tumour tissue pairs across 13 cancer types, resulting in the discovery of 4820 TE-generated alternative splice events distributed among 723 cancer-associated genes. Short interspersed nuclear elements (Alu) and long interspersed nuclear elements (L1) were found to contribute the majority of TE-generated alternative splice sites in cancer genes. A number of cancer-associated genes, including MYH11 , WHSC1 and CANT1 , were shown to have overexpressed TE-derived isoforms across a range of cancer types. TE-derived isoforms were also linked to cancer-specific fusion transcripts, suggesting a novel mechanism for the generation of transcriptome diversity via trans -splicing mediated by dispersed TE repeats. This article is part of a discussion meeting issue ‘Crossroads between transposons and gene regulation'.

// Cho-Hao Lee 1 , Chin Lin 2, 3 , Chieh-Yung Wang 4 , Tzu-Chuan Huang 1 , Yi-Ying Wu 1 , Wu-Chien Chien 2 and Jia-Hong Chen 1, 5 1 Division of Hematology and Oncology Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China 2 School of Public Health, National Defense Medical Center, Taipei, Taiwan, Republic of China 3 Department of Research and Development, National Defense Medical Center, Taipei, Taiwan, Republic of China 4 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China 5 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, Republic of China Correspondence to: Jia-Hong Chen, email: ndmc_tw.tw@yahoo.com.tw Keywords: overweight; small-cell lung cancer; prognostic factor; body mass index Received: September 29, 2017 Accepted: March 05, 2018 Published: May 15, 2018 ABSTRACT Numerous evidence has indicated that excess weight is associated with an increased risk of mortality in patients in several cancer types including breast, colorectal, pancreatic, endometrial, and prostate cancer However, with respect to non-small cell lung cancer and upper aero-digestive cancer, evidence suggests that low body mass index (BMI) may increase the risk of mortality of these cancers, but a definitive link between premorbid BMI and overall survival in small cell lung cancer patients has yet to be fully explored. To investigate this possibility, we conducted a retro-spective of 173 small-cell lung cancer patients. Multivariate Cox analysis indicated that pretreatment overweight (BM I ≥ 23) was an independent prognostic factor for overall survival (OS) (Hazard ratio, = 0.58, 95% CI = 0.39–0.87, p = 0.008). In addition, meta-regression revealed that per-formance status (≤ 2) marginally interacted with increased BMI ( p = 0.068). However, subgroup analysis showed that patients with a BMI ≥ 23 and performance status ≤ 2 had the best OS (Hazard ratio: 0.31, 95% CI: 0.16–0.61, p = 0.001). Premorbid BMI and performance status level are easy to measure and may provide physicians an additional measurement to predict a small-cell lung cancer patient’s survival. The data from the present study indicates that a, further large scale prospective study is warranted to better assess the association of pretreatment BMI and OS in small-cell lung cancer.

Cardiac complications caused by metastatic gastric cancer are rarely reported. Here, we report a 58-year old woman who presented with chronic cough and intermittent shortness of breath for weeks. Chest radiographs showed a cardiac silhouette sign and a small amount of pleural effusion. After serial examinations including biopsy of the pericardium, ovarian and stomach, metastatic strong HER2/neu expressive signet-ring cell carcinoma of the stomach was diagnosed. Despite aggressive management with best supportive care and intravenous administration of trastuzumab, the patient died of respiratory failure and refractory pleural effusion. Through this case, we demonstrate that HER2/neu positive metastatic gastric cancer can initially present with these unusual cardiac and systemic manifestations. Primary clinical physicians should be aware of this unusual manifestation of gastric cancer.

Appendiceal tumors, particularly those with patterns of advanced malignancy, are rare in clinical practice. This study describes a patient with a mucinous adenocarcinoma originating from the appendix, who also had disseminated peritoneal carcinomatosis and abundant mucinous ascites despite chemotherapy and targeted therapy. Salvage cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) resulted in nearly complete remission.

A 62-year-old Taiwanese man presented to our hospital with soft masses over his right shoulder and left elbow that had rapidly developed over the previous three months. Diagnostic biopsy showed abnormal lymphoplasmacytoid cells in the soft tissue and bone marrow. Serial studies including immunohistochemistry and flow cytometry showed that these abnormal cells strongly expressed cell surface markers such as IgM and CD-20, but not CD3, CD5, or CD10, leading to the diagnosis of Waldenstrom macroglobulinemia (WM). These soft tissue lesions and abnormal cells in the bone marrow decreased gradually after multiple rounds of chemotherapy with R-COP. This study presents a case of WM—a rare B-cell lymphoproliferative disorder—with initial extramedullary soft tissue presentation. Thus, physicians should be aware of this rare soft tissue clinical manifestation in patients.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effectiveness and safety of maintenance therapy in individuals with chronic lymphocytic leukaemia (CLL).

Most chronic lymphocytic leukemia patients experience a relapse or become refractory to treatment with conventional chemotherapeutic agents. The network meta-analysis assesses the relative efficacy of novel targeted agents for the treatment of a relapse or refractory chronic lymphocytic leukemia. A systematic literature search included seven phase III randomized controlled trials, including a total of 2512 patients treated with nine regimens. Data were extracted and evidence synthesized using network meta-analysis. All novel targeted therapies were significantly more effective than ofatumumab and demonstrated promising prolongation of progression free survival (PFS), with a hazard ratio (HR) ranging from 0.10 to 0.52. Two novel targeted agent regimens, venetoclax plus rituximab and ibrutinib monotherapy, resulted in greater overall survival (HR, 0.335 and 0.361, respectively). Venetoclax plus rituximab and ibrutinib monotherapy were most favorable based on (1) HR for PFS compared with ofatumumab (Ibrutinib: HR, 0.10, 95% CI, 0.07&ndash, 0.14, Venetoclax plus rituximab: HR, 0.10, 95% CI, 0.05&ndash, 0.21) and SUCRA value (probability of being best) (Ibrutinib SUCRA, 0.92, Venetoclax rituximab SUCRA, 0.90) (2) HR for overall survival compared with ofatumumab (Ibrutinib: HR, 0.361, 95% CI, 0.208&ndash, 0.627, Venetoclax rituximab: HR, 0.335, 95% CI, 0.112&ndash, 0.997) and SUCRA value (Ibrutinib SUCRA, 0.84, Venetoclax rituximab SUCRA, 0.85) Both treatments reduced the risk of progression or death by 90% versus conventional ofatumumab. Both ibrutinib monotherapy and venetoclax rituximab have a high probability of being the most effective treatments for a relapse or refractory chronic lymphocytic leukemia with respect to long-term progression-free survival and overall survival.

Supplementary Tables 1-2 and Supplementary Figures 1-7

Hepatic angiosarcoma is a rare condition that has been associated with exposure to colloidal solutions of thorium dioxide, vinyl chloride, arsenic and radiation. Therapeutic guidelines have not been definitively established due to the small number of cases of this disease. The present study reviewed 28 cases of hepatic angiosarcoma from studies that had been published between January 2000 and December 2012, in addition to 6 cases diagnosed at Tri-Service General Hospital (Taipei, Taiwan). Clinical staging was based on American Joint Committee on Cancer staging system for soft tissue sarcoma (2014). With a mean follow-up of 27.5 months (range, 0.27–102 months), 18% (6/34) of the patients survived. The 1-, 3- and 5-year survival rates were 68.0±9.3, 42.1±10.2 and 32.7±9.8% for patients with stage I disease (mean follow-up, 32.7 months), whilst the 1- and 3-year survival rates were 33.3±15.7 and 22.2±13.9% for patients with stage IV disease (mean follow-up, 13.0 months). Determining an appropriate therapeutic strategy for this patient group is necessary. New studies encompassing larger patient populations are required in order to analyze and define standard prognostic parameters and to standardize a treatment approach for this extremely rare neoplasm.

Transposable element (TE) derived sequences comprise more than half of the human genome, and their presence has been documented to alter gene expression in a number of different ways, including the generation of alternatively spliced transcript isoforms. Alternative splicing has been associated with tumorigenesis for a number of different cancers. The objective of this study was to broadly characterize the role of human TEs in generating alternatively spliced transcript isoforms in cancer. To do so, we screened for the presence of TE-derived sequences co-located with alternative splice sites that are differentially utilized in normal versus cancer tissues. We analyzed a comprehensive set of alternative splice variants characterized for 614 matched normal-tumor tissue pairs across 13 cancer types, resulting in the discovery of 4,820 TE-generated alternative splice events distributed among 723 cancer-associated genes. SINEs (Alu) and LINEs (L1) were found to contribute the majority of TE-generated alternative splice sites in cancer genes. A number of cancer-associated genes - including MYH11, WHSC1, and CANT1 - were shown to have overexpressed TE-derived isoforms across a range of cancer types. TE-derived isoforms were also linked to cancer-specific fusion transcripts, suggesting a novel mechanism for the generation of transcriptome diversity via trans-splicing mediated by dispersed TE repeats. Citation Format: Evan A. Clayton, Lavanya Rishishwar, Tzu-Chuan Huang, Saurabh Gulati, Dongjo Ban, John F. McDonald, I. King Jordan. An atlas of transposable element derived alternative splicing in cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2115.

BACKGROUND Recently, many endocrine therapies have become available for hormone receptor-positive, human epidermal growth factor receptor 2-negative, pretreated, advanced breast cancer. Direct comparisons of these novel treatments to assess their added value, however, are lacking METHODS:: Our aim was to synthesize available evidence to compare all current endocrine treatments for hormone receptor-positive / human epidermal growth factor receptor 2-negative advanced breast cancer. We performed a systematic review to identify available randomized controlled trial evidence. We searched Embase, MEDLINE, and the Cochrane Central Register of Controlled Clinical Trials. Two trials presented at international oncology congresses (American Society of Clinical Oncology [ASCO]) were added to include the most recent evidence. A frequent network meta-analysis was used, and the surface under cumulative ranking area (SUCRA) was calculated to determine the best treatment RESULTS:: In total, 32 trials and 12,726 patients were identified, including 27 arms. Compared with fulvestrant 500 mg alone, novel target inhibitors combined with fulvestrant or exemestane had significantly prolonged progression-free survival with hazard ratios ranging from 0.62 to 0.82. Fulvestrant 500 mg plus palbociclib 125 mg and exemestane 25 mg plus entinostat 5 mg similarly extended progression-free survival (hazard ratio: 0.64 and 0.62 with SUCRA values of 91% and 92%, respectively). The exemestane 25 mg plus everolimus 10 mg combination had the best clinical benefit rate (risk ratio: 1.84, SUCRA: 91%) and overall response rate (risk ratio: 6.05, SUCRA: 97%) CONCLUSIONS:: On the basis of this analysis, the 2 combinations of exemestane plus everolimus and fulvestrant plus palbociclib were the best treatment options.

BCR-ABL tyrosine-kinase inhibitors are the first-line therapy for the majority of patients with chronic myelogenous leukemia (CML). Up to 20% of patients who have imatinib-treated CML in blast crisis (BC) experience a relapse in the central nervous system (CNS) due to the poor penetration of the drug by the blood-brain barrier. The present case reports a successful experience of using dasatinib-based combination therapy to treat a 22-year-old female who presented with initial symptoms of intermittent fever and easy bruising under the diagnosis of CML in BC. Although the patient eventually succumbed to profound sepsis, the CNS involvement was treated successfully using dasatinib-based combination therapy (cranial radiation and de-escalated intrathecal chemotherapy). This case demonstrates that dasatinib may be a viable option for those who are not medically fit for or are otherwise unwilling to receive high-dose chemotherapy. It appears that dose intensity is essential for optimal efficacy and should be maintained at 150 mg daily as far as possible.

PurposeIn a retrospective cohort study, we report the current epidemiology of patients with multiple myeloma (MM) and analyze the real-world clinical outcomes of bortezomib-based therapy.Materials and methodsThis retrospective study was mainly designed to evaluate the characteristics, treatment outcomes, and prognostic factors of patients with MM who received bortezomib-based therapy. We identified 5,726 patients in Taiwan with MM newly diagnosed between 2007 and 2015. Confidential data from the National Health Insurance Research Database (NHIRD) was used under strict guidelines, as it was made available in an electronic format for research purposes. In addition, we analyzed 96 patients who have been diagnosed with MM and were treated at the Tri-Service General Hospital (TSGH) between January 1, 2002, and December 31, 2018.ResultsPatients receiving first-line treatment with bortezomib had longer overall survival (OS) compared to those who received non-first-line treatment (pConclusionsBortezomib as a first-line treatment extended the OS in four-year mortality tracking and lowered the mortality risk according to the NHIRD analysis. In the TSGH analysis, the results indicated that the initial conditions of patients with MM have a lower influence on the OS and PFS after bortezomib-based therapy was administered.

Malignant bowel obstruction (MBO) is a disease with a poor prognosis, particularly in patients with advanced bowel or gynecological cancers. Multimodality teatments may be used to relieve the symptoms in patients with MBO; however, there is currently no consensus regarding the optimal treatment and no strong evidence supporting the efficacy of any treatment in improving the quality of life (QOL) and prolonging survival. We conducted a search through our medical center database of cancer registries for MBO cases between January, 1995 and December, 2008 and analyzed the clinicopathological characteristics and association between treatments and prognosis or QOL. The primary type of cancer causing MBO was found to be adenocarcinoma of colon. The overall survival time was found to be significantly higher among patients presenting with MBO as the initial symptom and improved QOL was achieved in patients who received surgical treatment. The mean survival time and the functional status of colorectal cancer patients receiving targeted therapy and chemotherapy were more satisfactory compared with those receiving surgery alone or conservative treatment. Furthermore, for end-stage cancer patients with MBO, hospice care was effective in reducing pain scores and relieving the symptoms of the disease.

Urinary d-lactate is highly correlated to diabetic nephropathy – a progressive kidney disease in renal glomeruli. In this study, we used a C3H/3e mouse model to investigate the relationship between urinary d-lactate and aristolochic acid nephropathy where the glomerular structure is not affected. The nephropathy was induced using intravenous injections of aristolochic acid at a dosage of 10 mg/kg per day for 5 days and was characterized biochemically and histologically. The urinary excretions of proteins, N-acetyl-β-d-glucosaminidase and serum creatinine were determined and connected to histological conventional findings. Urinary d-lactate was analyzed using column-switching high-performance liquid chromatography with fluorescence detection. The results showed a remarkable increase of urinary markers, including of urinary proteins and N-acetyl-β-d-glucosaminidase, and the histological examination confirmed a diagnosis of acute tubule necrosis. The ratio of d-lactate to creatinine in the urine of aristolochic acid-treated mice was approximately 36 times greater than that of the mice in the control group (p

In response to the introduction of new generation technology into rehabilitation therapy, new methods and effective management approaches specifically for rehabilitation therapy are in urgent need presently. Our lab has developed a 3D virtual game environment for training which mainly integrates 3D images, active touch, and other related information. Mainly consisting of a motor rehabilitation system and a series of 3D simulated flight games, the system aims to achieve rehabilitation of pronation and supination of the arms through the patient’s control and continuous exercise. In this study, social psychological variables are used to evaluate the human-computer interaction process.

Prior studies show that self-motions early after a fracture surgery can effectively reduce the tissue viscosity. However, due to the postoperative pain and unawareness of the postoperative limitations, a patient prefers to take medication to alleviate pain while complicated rehabilitation exercises can only be implemented under the limited intervention of a therapist, resulting in the patient's lack of interactive feedback on a daily basis and a failure of self-motions to miss the timing of rehabilitation. Additionally, an assessment for the patient's amount of movements is usually carried out by questioning a caregiver by the medical staff during a clinical interview to organize the patient's self-report because an oral statement is more subjective and difficult to quantify the patient's amount and quality of movements, which may lead to the compiling results that can not be compared or referenced to, and may become a blind spot in the record in the current health care system. This study is intended to develop a lower limb fracture postoperative-guided interactive rehabilitation training system for the hip, knee and ankle joints, and establish a method of motion analysis and a method of motion performance assessment in conjunction with the wireless sensor technology and animation techniques, providing an objective assessment from the caregiver and learning the patient's rehabilitation status with a simple and easy recording means. Additionally, with the design of interactive feedback, the improved postoperative rehabilitations are tried to increase the participant’s interest in self-management of health and facilitate to keep tracking the rehabilitation information. The medical evidences show that a guided rehabilitation system can enhance the patient's motive and willingness to be committed to a rehabilitation training as well as increase Quality and Amount of the exercise activity during the training process.

This study describes an exercise training case after stroke that can be remotely controlled by a therapiest, and the pilot clinical test result of rehabilitation platform. We have developed a set of training mission with graual difficulty in the virtual environment game, and the process includes delicate hand action and entire upper limb action, meanwhile, the operation patient and the therapist will stay at different room for the training. In the study, social psychology variable is used to assess the process of human machine interaction, thue result shows that after using this rehabilitation system, the negative feeling is significantly reduced (Confused feeking, t(13)=2.54, p

There are numerous causes of lower back pain. In the oncological setting, spine metastasis from a solid tumor is the most common. However, hematological disorders should also be taken into consideration. The current study presents a case of chronic myelomonocytic leukemia with the initial presentation of chronic lower back pain, followed by symptoms that included urinary retention, stool incontinence and left gum swelling, in a patient who was eventually diagnosed with granulocytic sarcoma (GS) over the sacral region. GS is a rare presentation of a tumor consisting of extramedullary leukemic infiltrations, which develop at different sites and cause different symptoms. Prompt and correct diagnosis of this type of disease may be crucial to improve the survival outcome by the early initiation of adequate treatment.

Objective Trastuzumab-containing treatment regimens have been shown to improve survival outcomes in HER2-positive breast cancer (BC). It is much easier to infuse a fixed one-vial dose to every patient on a regular schedule in the general clinical setting. The aims of this study were evaluating the efficacy of a 440 mg fixed-dose of trastuzumab administered on a monthly infusion schedule, and the risk factors for cardiac events. Patients and methods We retrospectively reviewed data from 300 HER2-positive BC patients in our institute: 208 were early-stage BC patients undergoing adjuvant trastuzumab treatment, and 92 were metastatic BC patients treated with trastuzumab infusions until disease progression. There were 181 patients receiving regular trastuzumab infusions every 3 weeks (Q3W; 8 mg/kg loading dose followed by 6 mg/kg every 3 weeks), and the other 119 patients were treated monthly with a fixed 440 mg dose (QM; fixed 440 mg every 4 weeks). Results The medians of progression-free survival (PFS) and overall survival (OS) in the adjuvant setting were not reached in both treatment groups. In the metastatic setting, there was no significant difference between groups in PFS or OS. The median time to significant cardiovascular (CV) dysfunction was 4.54 months. The incidence of congestive heart failure requiring medication in our cohort was 3.4%. Conclusion In our study, we found that fixed-dose monthly trastuzumab was feasible and effective. In addition, the CV risk was not higher with the fixed-dose protocol. This treatment modality could lower the cost and was easier to implement in clinical practice. Larger prospective randomized studies with longer-term follow up are needed to confirm our results.