Twelve Asian patients with sarcoma received interval-compressed (ic-) chemotherapy scheduled every 14 days with a regimen of vincristine (2 mg/m2), doxorubicin (75 mg/m2), and cyclophosphamide (1200-2200 mg/m2) (VDC) alternating with a regimen of ifosfamide (9000 mg/m2) and etoposide (500 mg/m2) (IE), with filgrastim (5-10 mcg/kg/day) between cycles. Carboplatin (800 mg/m2) was added for CIC-rearranged sarcoma. The patients were treated with 129 cycles of ic-VDC/IE with a median interval of 19 days (interquartile range [IQR], 15-24 days. Median nadirs (IQR) were neutrophil count, 134 (30-396) × 106/L at day 11 (10-12), recovery by day 15 (14-17) and platelet count, 35 (23-83) × 109/L at day 11 (10-13), recovery by day 17 (14-21). Fever and bacteremia were observed in 36% and 8% of cycles, respectively. The diagnoses were Ewing sarcoma (6), rhabdomyosarcoma (3), myoepithelial carcinoma (1), malignant peripheral nerve sheath tumor (1), and CIC-DUX4 Sarcoma (1). Seven of the nine patients with measurable tumors responded (one CR and six PR). Interval-compressed chemotherapy is feasible in the treatment of Asian children and young adults with sarcomas.

BACKGROUND/AIM:Stem cell therapy and regenerative medicine are promising for treating Parkinson's disease (PD) not only for the potential for cell replacement but also for the paracrine effect of stem cell secretion, especially proteins and nucleotide-enriched exosomes. This study investigated the neuroprotective effect of exosomes secreted from human adipocyte-derived stem cells (hADSCs) on PD.MATERIALS AND METHODS:hADSCs were isolated from the visceral fat tissue of individuals without PD who underwent bariatric surgery and were validated using surface markers and differentiation ability. Exosomes were isolated from the culture medium of hADSCs through serial ultracentrifugation and validated. Condensed exosomes were administered intravenously to 12-week-old MitoPark mice, transgenic parkinsonism mouse model with conditional knockout of mitochondrial transcription factor A in dopaminergic neurons, monthly for 3 months. Motor function, gait, and memory were assessed monthly, and immunohistochemical analysis of neuronal and inflammatory markers was performed at the end of the experiments.RESULTS:The hADSC-derived exosome-treated mice exhibited better motor function in beam walking and gait analyses than did the untreated mice. In the novel object recognition tests, the exosome-treated mice retained better memory function. Immunohistochemical analysis revealed that although exosome treatment did not prevent the loss of dopaminergic neurons in the substantia nigra of mice, it down-regulated microglial activation and neuroinflammation in the midbrain.CONCLUSION:hADSC-derived exosomes were neuroprotective in this in vivo mouse model of PD, likely because of their anti-inflammatory effect. Use of hADSC-derived exosomes may offer several beneficial effects in stem cell therapy. Since they can also be produced at an industrial level, they are a promising treatment option for PD and other neurodegenerative diseases.

Cancer is one of the major causes of mortality worldwide, therefore it is considered a major health concern. Breast cancer is the most frequent type of cancer which affects women on a global scale. Various current treatment strategies have been implicated for breast cancer therapy that includes surgical removal, radiation therapy, hormonal therapy, chemotherapy, and targeted biological therapy. However, constant effort is being made to introduce novel therapies with minimal toxicity. Gene therapy is one of the promising tools, to rectify defective genes and cure various cancers. In recent years, a novel genome engineering technology, namely the clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein-9 (Cas9) has emerged as a gene-editing tool and transformed genome-editing techniques in a wide range of biological domains including human cancer research and gene therapy. This could be attributed to its versatile characteristics such as high specificity, precision, time-saving and cost-effective methodologies with minimal risk. In the present review, we highlight the role of CRISPR/Cas9 as a targeted therapy to tackle drug resistance, improve immunotherapy for breast cancer.

Breast cancer (BRCA) malignancy causes major fatalities amongst women worldwide. SCF (Skp1-cullin-F-box proteins) E3 ubiquitin ligases are the most well-known members of the ubiquitination–proteasome system (UPS), which promotes cancer initiation and progression. Recently, we demonstrated that FBXL8, a novel F-box protein (SCFF-boxes) of SCF E3 ligase, accelerates BRCA advancement and metastasis. Since SCFF-boxes is a key component of E3 ligases, we hypothesized that other SCFF-boxes besides FBXL8 probably collaborate in regulating breast carcinogenesis. In this study, we retrospectively profiled the transcriptome of BRCA tissues and found a notable upregulation of four SCFF-box E3 ligases (FBXL8, FBXO43, FBXO15, and CCNF) in the carcinoma tissues. Similar to FBXL8, the knockdown of FBXO43 reduced cancer cell viability and proliferation, suggesting its pro-tumorigenic role. The overexpression of CCNF inhibited cancer cell progression, indicating its anti-tumorigenic role. Unexpectedly, CCNF protein was markedly downregulated in BRCA tissues, although its mRNA level was high. We showed that both E3 ligases, FBXL8 and FZR1, pulled down CCNF. Double knockdown of FBXL8 and FZR1 caused CCNF accumulation. On the other hand, CCNF itself pulled down a tumorigenic factor, RRM2, and CCNF overexpression reduced RRM2. Altogether, we propose a signature network of E3 ligases that collaboratively modulates CCNF anti-cancer activity. There is potential to target BRCA through modulation of the partnership axes of (i) CCNF-FBXL8, (ii) CCNF-FZR1, and (iii) CCNF-RRM2, particularly, via CCNF overexpression and activation and FBXL8/FZR1 suppression.

The initiation and progression of breast cancer (BRCA) is associated with inflammation and immune-overactivation, which is critically modulated by the E3 ubiquitin ligase. However, the underlying mechanisms and key factors involved in BRCA formation and disease advancement remains under-explored. By retrospective studies of BRCA patient tissues; and gene knockdown and gain/loss-of-function studies, we uncovered a novel E3 ligase, FBXL8, in BRCA. A signature expression profile of F-box factors that specifically target and degrade proteins involved in cell death/survival, was identified. FBXL8 emerged as a prominent member of the F-box factors. Ex vivo analysis of 1349 matched BRCA tissues indicated that FBXL8 promotes cell survival and tumorigenesis, and its level escalates with BRCA progression. Knockdown of FBXL8 caused: (i) intrinsic apoptosis, (ii) inhibition of cell migration and invasion, (iii) accumulation of two tumor-suppressors, CCND2 and IRF5, and (iv) downregulation of cancer-promoting cytokines/chemokines; all of which curtailed the tumor microenvironment and displayed potential to suppress cancer progression. Co-IP study suggests that two tumor-suppressors, CCND2 and IRF5 are part of the immune-complex of FBXL8. The protein levels of CCND2 and IRF5 inversely correlated with FBXL8 expression, implying that FBXL8 E3 ligase was associated with the degradation of CCND2 and IRF5. Altogether, we propose the exploitation of the ubiquitin signaling axis of FBXL8-CCND2-IRF5 for anti-cancer strategies and potential therapeutics.

The initiation and progression of breast cancer (BRCA) is associated with inflammation and immune-overactivation. The E3 ubiquitin ligase is known to subtly balance immune-overactivation and pro-tumorigenesis. Here, by global transcriptional profiling of BRCA patient tissues, we identified a signature expression profile of F-box factors, of which FBXL8 emerged as a novel key component of E3 ligase. Our ex vivo studies (n=1349) indicate that FBXL8 promotes tumorigenesis and its level escalates with BRCA advancement. Knockdown of FBXL8 caused: (i) accumulation of two tumorsuppressors, CCND2 and IRF5, suggesting their collaborative regulation of BRCA status, (ii) intrinsic apoptosis in BRCA, (iii) inhibition of cell migration and invasion and (iv) downregulation of cancer-promoting cytokines/ chemokines; all of these effects curtailed the tumor microenvironment and suppressed cancer progression. Our findings highlight the translational impact of exploiting FBXL8 and its interaction partners (CCND2 and IRF5) for developing anti-cancer strategies and potential therapeutics to limit BRCA progression.

OBJECTIVE: Peer-assisted learning has been regarded as an adjunct to teaching modalities. It remains inconclusive regarding the benefits of peer observation in skills learning. Hence, we investigated whether the active engagement (AE) of peer observation in addition to expert demonstration would facilitate the performance in the virtual reality (VR) tasks. SETTING/DESIGN: The programs involved 4 VR tasks including basic (camera targeting), intermediate (energy dissection and energy switching), and advanced (suture sponge) tasks in the da Vinci Skills Simulators, which were set up in the operating room at Taipei Medical University Hospital. Fifty medical students participated in the study. The AE of the participants was defined as the total number of peer observations in addition to expert observation before their performance. We assessed the correlations between AE and surgical task performance using Pearson correlation and the concept of learning analytics. PARTICIPANTS: Medical students (sixth-year students in Taiwan, equivalent to fourth-year students in the US system) from Taipei Medical University were recruited. RESULTS: AE was correlated with the energy dissection task (r = 0.329, p = 0.02) and marginally associated with the energy switching task (r = 0.271, p = 0.057). However, AE was not correlated with either task scores for camera targeting (r = 0.096, p = 0.509) or task scores for suture sponge (r = 0.091, p = 0.529). CONCLUSIONS: Our findings suggest that AE of peer observation may facilitate learning energy dissection task, which is an intermediate-level task, but not in other basic or advanced tasks in a VR context. The study highlights the potential effect of AE of peer observation on surgical learning based on a distinct level of tasks. Tasks that fit the learners' level are recommended. Nevertheless, the effectiveness of peer observation on surgical training still has to be explored to ensure favorable results and optimal learning outcomes. ((C) 2019 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Rectal neoplasm is one of the most common malignancies worldwide. Screening programs for rectal neoplasm result in early diagnosis and a decrease in disease-related mortality and morbidity. In selected patients, early rectal cancer may be treated with local excision. Owing to poor exposure during conventional transanal excision, transanal minimally invasive surgery (TAMIS) was developed, and TAMIS is feasible for the local excision of selected rectal neoplasms. However, the limited range of motion is a major disadvantage of this operation. Therefore, robotic TAMIS was developed to resolve this issue. This paper describes the surgical outcomes of robotic TAMIS for selected rectal tumors. Methods: The eligibility criteria for robotic TAMIS were as follows: benign neoplasms, early malignancy, complete remission after concurrent chemoradiotherapy, lesions located in the middle or lower rectum, and a lesion size of less than 5 cm. To gain access to the anal canal, a transanal access platform was used, and the da Vinci robotic system was mounted for surgery. Patient characteristics and surgical outcomes were recoded. Results: A total of 23 patients were included, and the median tumor size was 2.5 cm (range: 1.1-4.5 cm) on average. The median tumor location was 5 cm (range: 2-8 cm) from the anal verge. The median length of hospital stay was 3 days (range: 1-10 days). No intraoperative complications were reported, and no patient readmission occurred. The median follow-up period was 9.6 months. No recurrent lesion was found in the follow-up period. Conclusion: Based on the short-term results, robotic TAMIS is a feasible and safe technique for the local excision of selected rectal neoplasms. (C) 2019 Asian Surgical Association and Taiwan Robotic Surgery Association. Publishing services by Elsevier B.V.

OBJECTIVE: To evaluate the effectiveness of a simulation-based flipped classroom in gaining the laparoscopic skills in medical students.& para;& para;DESIGN: An intervention trial.& para;& para;SETTING: Taipei Medical University Hospital, an academic teaching hospital.& para;& para;PARTICIPANTS AND METHODS: Fifty-nine medical students participating in a 1-hour laparoscopic skill training session were randomly assigned to a conventional classroom (n = 29) or a flipped classroom approach (n = 30) based on their registered order. At the end of the session, instructors assessed participants' performance in laparoscopic suturing and intracorporeal knot-tying using the assessment checklist based on a modified Objective Structured Assessment of Technical Skills tool.& para;& para;RESULTS: Students in the flipped group completed more numbers of stitches (mean [M] = 0.47; standard deviation [SD] = 0.507) than those in the conventional group (M= 0.10; SD = 0.310) (mean difference: 0.37; 95% CI: 0.114-582; p = 0.002). Moreover, students in the flipped group also had higher stitch quality scores (M = 7.17; SD = 2.730) than those in the conventional group (M = 5.14; SD = 1.767) (mean difference = 2.03; 95% CI: 0.83-3.228; p = 0.001). Meanwhile, students in the flipped group had higher pass rates for the second throw (p < 0.001), third throw (p = 0.002), appropriate tissue reapproximation without loosening or strangulation (p < 0.001), needle cut from suture under direct visualization (p = 0.004), and needle safely removed under direct visualization (p = 0.018) than those in the conventional group.& para;& para;CONCLUSIONS: Comparing with traditional approach, a simulation-based flipped classroom approach may improve laparoscopic intracorporeal knot-tying skill acquisition in medical students. (C) 2017 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.

Background Chronic groin pain after inguinal hernia repair, a serious problem, is caused by entrapment of the ilioinguinal nerve either by mesh or development of fibrosis. Division of the ilioinguinal nerve during hernioplasty has been found to reduce the incidence of chronic groin pain. However, the traditional approach favors preservation of the ilioinguinal nerve during open hernia repair.Methods We conducted a systematic review and meta-analysis of randomized controlled trials that compared the outcomes of preservation versus division of the ilioinguinal nerve during open mesh repair of inguinal hernia. The primary outcome was the incidence of groin pain; secondary outcomes were numbness and sensory loss.Results We reviewed six trials with 1,286 patients. We found no difference between the groups for the incidence of groin pain or numbness at 1, 6, and 12 months after open mesh inguinal repair. The incidence of sensory loss or change was significantly higher in the division group than in the preservation group at 6 months [risk ratio (RR) 1.25; 95 % confidence interval (CI) 1.02-1.53] and at 12 months (RR 1.55; 95 % CI 1.01-2.37) postoperatively. No significant differences between the groups were noted at any other points in time.Conclusions Preservation of the ilioinguinal nerve during open mesh repair of inguinal hernia is associated with a decreased incidence of sensory loss at 6 and 12 months postoperatively compared with that of the division technique. No significant differences were found between the groups for chronic groin pain or numbness.

We describe a 71-year-old male patient who suffered from flash bloody stool and small-caliber stool for 6 months. Obstructive symptoms progressed, and he came to our Department of Surgery for help. A colonoscopy and double-contrast barium study showed a typical apple-core lesion in his rectum. A low anterior resection was performed, and rectal cancer was confirmed. Multiple ova in the rectum with inflammatory cell aggregation were noted, both in the adenocarcinoma and normal areas. The species Schistosomiasis japonicum was confirmed. Identification of a higher incidence of altered p53 expression in the schistosomal colitis-associated colorectal cancer group raised the possibility that schistosomiasis is capable of producing a specific alteration in the function of this protein which could lead to colon cancer development.

An incarcerated hernia through a suprapubic catheterization site is rare. Attention is required for such hernias as they may become obstructed due to the narrow neck. We report an 83yearold male patient without a history of a laparotomy. The patient had received transurethral resection of the prostate (TURP) with insertion of a suprapubic catheter 10 years previous. A rare presentation of an obstructed incisional hernia through the suprapubic catheterization site in this elderly gentleman was noted, which could not be reduced. Segmental resection of the incarcerated small bowel and repair of the hernia were successfully performed.

We describe a 21-year-old female who suffered from voiding difficulty, incomplete voiding sensation and a small-caliber urinary stream for 6 months. She had menarche at 12 years of age, and denied any history of trauma, sexual abuse, intercourse or genital tract infection. Her uterus and both ovaries were anatomically normal as evidenced by abdominal sonography. Intravenous pyelography showed a normal urinary system. Uroflowmetry showed a flattened curve with 2 ml/sec of maximum flow rate (Qmax). While attempting to catheterize her bladder for urodynamic study, severe labial fusion with a pinpoint opening was mistaken for urethral orifice. She received two weeks of local premarin cream application but the symptoms persisted. After labial reconstruction, she has had no more voiding dysfunction.