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Background Robotic distal pancreatectomy has been accepted to be safe and effective for pancreatic tail lesion. Whether spleen preservation by preserving the splenic vessels with robot assistance is feasible and beneficial remains controversial. Here we would like to compare the operative outcomes of robotic distal pancreatectomy and splenectomy (DPS) with robotic spleen preserving distal pancreatectomy by means of splenic vessel preservation (SVP). Methods Between March 2011 and September 2019, 56 consecutive patients undergoing robotic distal pancreatectomy were identified, with 28 patients in each group. Patient demographics, histopathology findings and operative outcomes were prospectively collected and compared between the two groups. A subgroup analysis was made after excluding malignant and pancreatic lesions >6 cm in the DPS group. Results The two groups had similar conversion rate, blood loss, morbidity and pancreatic fistula rate. There was no operative mortality. The SVP group had shorter median operative time (245 vs 303.5 min, P = 0.019) and shorter median hospital stay (5 vs 6 days, P = 0.019) than the DPS group. However, all malignant lesions occurred in the DPS group and lesion size in DPS group was significantly larger. After matching, there were 28 SVP and 15 DPS. The histopathology findings and lesion size became comparable. The SVP group still had shorter operative time (245 vs 290 min, P = 0.022) and shorter hospital stay (5 vs 7 days, P = 0.014) than the DPS group. Conclusion Apart from avoiding risk of overwhelming postsplenectomy sepsis, robotic SVP had additional advantage of shorter operative time and shorter hospital stay than robotic DPS.

Hepatocellular carcinoma is one of the commonest cancer in the world. Despite curative resection, recurrence remains the largest challenge. Many risk factors were identified for predicting recurrence, including liver fibrosis and cirrhosis. Transient elastography (Fibroscan) is an accurate tool in measuring liver fibrosis. This study aimed to evaluate the use of preoperative liver stiffness measurement (LSM), with Fibroscan in predicting long-term recurrence of hepatocellular carcinoma (HCC) after curative resection.A prospective cohort study was conducted from February 2010 - June 2017 in Prince of Wales hospital. All consecutive patients with HCC undergone hepatectomy were included. Demographic factors, preoperative LSM, tumor characteristics and operative details were assessed. Primary outcome and secondary outcome were overall survival and disease free survival at 1 year, 3 year and 5 year respectively.A total of 401 cases were included. Patients with LSM ≥12kPa had significantly lower 5-year overall survival rate (75.1% vs 57.3%, p 0.001) and disease free survival rate (45.8% vs. 26.7%, p 0.001). On multivariate analysis, pre-operative creatinine and vascular invasion of tumor were significant factors in predicting early recurrence (p = 0.012 and p = 0.004). LSM ≥12kPa were the only significant factor in predicting late recurrence (p = 0.048).Pre-operative liver stiffness measurement could predict the late recurrence of hepatocellular carcinoma after curative resection.

PURPOSE To compare the survival outcomes of patients treated with transarterial ethanol ablation (TEA) with those treated with liver resection (LR) for solitary HCC less than 5 cm in diameter, in patients stratified according to liver function using ALBI grade. MATERIALS AND METHODS This retrospective study approved by the Institutional Committee included all treatment-naive patients with solitary HCC (≤ 5 cm) and Child-Pugh score 5, and who had received TEA (33 patients) or LR (192 patients) between 2004 and 2012. Treatment outcomes were compared between patients treated with TEA and LR after a period of at least 7 years of follow-up. Comparison was repeated for those patients with ALBI grade 2 or 3. RESULTS Both overall survival (OS, months) and recurrence-free survival (RFS months) were significantly longer in the LR group (OS: LR 129.7[119.5, 140], TEA 69.1[55.9, 82.3], P

Since Singapore became an independent nation in 1965, the development of its health-care system has been underpinned by an emphasis on personal responsibility for health, and active government intervention to ensure access and affordability through targeted subsidies and to reduce unnecessary costs. Singapore is achieving good health outcomes, with a total health expenditure of 4·47% of gross domestic product in 2016. However, the health-care system is contending with increased stress, as reflected in so-called pain points that have led to public concern, including shortages in acute hospital beds and intermediate and long-term care (ILTC) services, and high out-of-pocket payments. The main drivers of these challenges are the rising prevalence of non-communicable diseases and rapid population ageing, limitations in the delivery and organisation of primary care and ILTC, and financial incentives that might inadvertently impede care integration. To address these challenges, Singapore's Ministry of Health implemented a comprehensive set of reforms in 2012 under its Healthcare 2020 Masterplan. These reforms substantially increased the capacity of public hospital beds and ILTC services in the community, expanded subsidies for primary care and long-term care, and introduced a series of financing health-care reforms to strengthen financial protection and coverage. However, it became clear that these measures alone would not address the underlying drivers of system stress in the long term. Instead, the system requires, and is making, much more fundamental changes to its approach. In 2016, the Ministry of Health encapsulated the required shifts in terms of the so-called Three Beyonds-namely, beyond health care to health, beyond hospital to community, and beyond quality to value.

Purpose To describe the initial experience with the Assia Pupil Expander 200 (APX-200, APX Ophthalmology) in eyes that underwent phacoemulsification or intraocular lens repositioning surgery that required mechanical pupil expansion. Setting Department of Ophthalmology, Meir Medical Center, Kfar-Saba, and Ein-Tal Eye Center, Tel Aviv, Israel. Design Retrospective case series. Methods The APX-200 is a single-use device, intended for mechanical expansion of the pupil during intraocular surgery. Two devices are inserted through 2 opposite 19-gauge incisions using designated forceps. The surgical course and early postoperative follow-up was recorded in 50 eyes. Results The study included 50 consecutive eyes, with mean preoperative pupil diameter was 3.7 mm. The APX effectively dilated the pupils in all cases. No complication related to the use of the APX such as hyphema, iridodialysis, or Descemet membrane detachment were noted in this series. A central and round pupil was restored in all eyes at 1-month postoperatively, with 14 eyes (28%) having mild sphincter tears. Pupilloplasty was not required in any of the cases. Conclusions The APX-200 was an effective and safe device for pupil expansion during intraocular surgery.

Summary Background PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. Methods KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov , number NCT02853305 . Findings Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. Interpretation The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Funding Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

Background The only classification of Muller-Weiss disease (MWD) is based primarily on Meary’s talo-first metatarsal angle. It describes increasing sag of the medial longitudinal arch with greater degrees of compression and fragmentation of the navicular. Purportedly, the talar head pushes the subtalar joint into varus and drives the medial pole of the navicular medially, as it protrudes inferiorly and laterally. Its authors stipulated heel varus as a pre-requisite, coining the term ‘paradoxical pes planus varus’ to define heel varus and flatfoot as hallmark deformities of the condition. Methods We measured Meary’s and Kite’s talocalcaneal angles, heel offset, anteroposterior thickness of the navicular at each naviculocuneiform (NC) joint, medial extrusion of the navicular and calculated percentage compression at each NC joint in 68 consecutive feet presenting with MWD. Morphology and activity at the various peri-navicular joints were studied using SPECT-CT in 45 feet. Results Inverse relationships between Meary’s angle and degree of navicular compression reach statistical significance at NC2 but not at NC3. Strong correlation exists between medial extrusion and percentage compression at NC2 and NC3. Medial extrusion is significantly greater on the affected side in unilateral cases and on the more compressed side in bilateral cases. Significant inverse relationships exist between Kite’s angle and percentage compression at both NC2 and NC3 and degree of medial extrusion of the navicular. No correlation was detected between Kite’s angle and either heel offset or Meary’s angle. Varus heel offset was present in only 33% of cases. The combination of heel varus and negative Meary’s angle was present in just 26% of cases, the commonest combination being heel valgus with sagging at 56%. Conclusion Our findings confirm part of Maceira’s hypothesized pathomechanism of MWD. Reductions in Kite’s talocalcaneal angle confirm that lateral and inferior protrusion of the talar head causes increasing compression and medial extrusion of the navicular. However, such shift of the talar head does not always lead to heel varus. As such, we caution against universal advocacy of lateral displacement calcaneal osteotomy, as the heel is not always in varus in MWD.

Background Medulloblastomas with chromothripsis developing in children with Li-Fraumeni Syndrome (germline TP53 mutations) are highly aggressive brain tumors with dismal prognosis. Conventional photon radiotherapy and DNA-damaging chemotherapy are not successful for these patients and raise the risk of secondary malignancies. We hypothesized that the pronounced homologous recombination deficiency in these tumors might offer vulnerabilities that can be therapeutically utilized in combination with high linear energy transfer carbon ion radiotherapy. Methods We tested high-precision particle therapy with carbon ions and protons as well as topotecan with or without PARP inhibitor in orthotopic primary and matched relapsed patient-derived xenograft models. Tumor and normal tissue underwent longitudinal morphological MRI, cellular (markers of neurogenesis and DNA damage-repair), and molecular characterization (whole-genome sequencing). Results In the primary medulloblastoma model, carbon ions led to complete response in 79% of animals irrespective of PARP inhibitor within a follow-up period of 300 days postirradiation, as detected by MRI and histology. No sign of neurologic symptoms, impairment of neurogenesis or in-field carcinogenesis was detected in repair-deficient host mice. PARP inhibitors further enhanced the effect of proton irradiation. In the postradiotherapy relapsed tumor model, median survival was significantly increased after carbon ions (96 days) versus control (43 days, P < .0001). No major change in the clonal composition was detected in the relapsed model. Conclusion The high efficacy and favorable toxicity profile of carbon ions warrants further investigation in primary medulloblastomas with chromothripsis. Postradiotherapy relapsed medulloblastomas exhibit relative resistance compared to treatment-naïve tumors, calling for exploration of multimodal strategies.

Background Liver resection is an established treatment of choice for colorectal liver metastasis (CLM). However, the role of hepatectomy for non-colorectal liver metastasis (NCLM) is less clear. Patients and method From 2004 to 2017, 264 patients received curative hepatectomy for NCLM (n = 28) and CLM (n = 236). Propensity score (PS) matching was performed between two groups, with respect to the significant confounding factors. Short-term and long-term outcomes were compared between PS matched groups. Univariate analysis was performed to identify prognostic factors affecting overall and recurrence-free survival. Results After PS matching, there were 28 patients in NCLM group and 56 patients in CLM group. With a median follow-up of 34 months, there was no significant difference in 5-year overall survival rate between NCLM and CLM groups (62% vs. 39%) (P = 0.370). The 5-year recurrence-free survival rate was also comparable between NCLM and CLM groups (23% vs. 22%) (P = 0.707). Use of pre-operative systemic therapy (hazard ratio: 2.335, CI 1.157–4.712), multifocal tumors (hazard ratio: 1.777, CI 1.010–3.127), tumor size (hazard ratio: 1.135, CI 1.012–1.273), R1 resection (hazard ratio: 2.484, CI 1.194–5.169) and severe complications (hazard ratio: 6.507, CI 1.454–29.124), but not tumor type (NCLM vs. CLM), were associated with poor overall survival. Conclusion Hepatectomy for NCLM can achieve similar oncological outcomes in selected patients as those with CLM. Significant prognostic factors were identified associating with worse overall survival.

Minimally invasive approach has been increasingly applied in liver resection. However, laparoscopic major hepatectomy is technically demanding and is practiced only in expert centers around the world. Conversely, use of robot may help to overcome the difficulty and facilitate major hepatectomy. Between September 2010 and March 2019, 151 patients received robotic hepatectomy for various indications in our center. 36 patients received robotic hemihepatectomy: 26 left hepatectomy and 10 right hepatectomy. During the same period, 737 patients received open hepatectomy and out of these, 173 patients received open hemihepatectomy. A propensity score-matched analysis was performed in a 1:1 ratio. After matching, there were 36 patients each in the robotic and open group. The two groups were comparable in demographic data, type of hemihepatectomy, underlying pathology, size of tumor, and background cirrhosis. Conversion was needed in 3 patients (8.3%) in the robotic group. There was no operative mortality. The operative blood loss and resection margin were similar. Though not significantly different, there was a higher rate of complications in the robotic group (36.1% vs. 22.2%) and this difference was mostly driven by higher intra-abdominal collection (16.7% vs. 5.6%) and bile leak (5.6% vs. 2.8%). Operative time was significantly longer (400.8 ± 136.1 min vs 255.4 ± 74.4 min, P

The undeniable benefit of mentorship by experience senior mentors can meaningfully increase the breadth of their experience and contributions to society as well as address the dire inequality in global health. This model captures wisdom lost to retirement, enables opportunities for purposeful lifespan, underpins sustainable health care systems, and has the potential for building multinational partnerships., Key Messages Capturing the acquired wisdom and experience of mentors in global health offers a capstone for their careers and provides a purposeful healthspan for these professionals to continue to be engaged in meaningful work while leveraging their expertise to solve challenging health care problems.Senior professionals can mentor early career leaders to help them balance their professional commitments, interest in global health, and development of needed skills, such as understanding the nuances of cultural competence and adapting solutions to different environments.Institutional leaders, particularly in academic medical centers, recognize the importance of global engagement vis-à-vis their educational mission and for recruiting and retaining faculty and can benefit economically and programmatically from supporting experienced senior faculty or retirees to support these efforts.Program builders should include the opportunity for altruistic human service as an integral part of a career and highlight that they can access senior mentors and retirees who provide world-class expertise and mentorship at “volunteer prices.”

Background Microwave (MWA) and radiofrequency ablation are the commonly used local ablation for hepatocellular carcinoma (HCC). Studies comparing both techniques are scarce. The aim of this study was to compare the efficacy of MWA versus RFA as a treatment for HCC. Methods Patients with HCC who were suitable for local ablation were randomized into MWA or RFA. All patients were followed up regularly with contrast-enhanced computed tomography (CT) performed at 1, 3, 6 and 12 months after ablation. Both patients and the radiologists who interpreted the post-procedure CT scans were blinded to the treatment allocation. Treatment-related morbidity, overall and disease-free survivals were analyzed. Results A total of 93 patients were recruited. Among them, 47 and 46 patients were randomized to MWA and RFA respectively. Patients in two groups were comparable in baseline demographics and tumor characteristics. With a median follow-up of around 30 months, there were no significant difference in the treatment-related morbidity, overall and disease-free survivals. MWA had a significantly shorter overall ablation time when compared with RFA (12 min vs 24 min, p Conclusions MWA is no different to RFA with respect to completeness of ablation and survivals. It is, however, as safe and effective as RFA in treating small HCC.

Background Fundamental Research in Oncology and Thrombosis (FRONTLINE) is a global survey of physicians' perceptions and practice in the management of venous thromboembolism (VTE) in patients with cancer. Materials and Methods The present survey, FRONTLINE 2, follows the original FRONTLINE survey (published in The Oncologist in 2003) and provides insights into how physicians perceive risk of VTE in cancer and approach its prophylaxis and treatment. Results Between November 2015 and February 2016, 5,233 respondents participated, representing cancer physicians and surgeons. Most believed that less than one in five patients with any cancer might be at risk of VTE, with a slightly higher risk in patients with brain, pancreatic, and lung tumors. The most frequently reported reasons for giving prophylaxis were prior history of VTE (74.6%), abnormal platelet count (62.0%), and obesity (59.5%). In surgical and medical cancer patients, low‐molecular‐weight heparin (LMWH) was the most popular prophylactic measure, used by 74.2% and 80.6%, respectively. Oral anticoagulants (OACs) were given in less than one fifth of cases. In surgical patients, prophylaxis was usually provided for 1 month postoperatively. Following a diagnosis of VTE, patients initially received treatment with LMWH and were maintained long term on OACs, primarily warfarin, dabigatran, and rivaroxaban. Most surgical and medical cancer patients underwent treatment of VTE for 3–6 months. Conclusion Compared with the original FRONTLINE survey, FRONTLINE 2 reveals some differences in the management of VTE in patients with cancer. Newer anticoagulants such as fondaparinux, dabigatran, and rivaroxaban are being incorporated into the contemporary management of VTE in patients with cancer. Implications for Practice This globally conducted survey of more than 5,000 cancer clinicians revealed a number of insights into the perceived risk for venous thromboembolism as well as contemporary approaches to its prevention and treatment. Although guidelines have consistently recommended anticoagulant medications for prevention and treatment of cancer‐associated thrombosis, clinicians report substantial variation in their practice., Improvements in molecular analysis hold promise for improved identification and treatment of cancers of unknown primary. This article presents the case of a patient with a cancer of unknown primary and metastases in the brain and lung, detailing the genomic profiling performed to establish targeted therapy options.

Photovoltaic (PV) panels must be equipped with a cooling system to increase their electrical output generation. Despite numerous publications on the fabrication of form-stable phase change material (FSPCM) for thermal energy storage application, studies on the usage of FSPCM for PV cooling are incredibly limited. In this work, the cooling performance of myristic acid FSPCM encapsulated with cross-linked nitrile rubber (NBR) was investigated. A fin heat sink (FHS) was employed to hold the FSPCM. The thermal performance of the FHS embedded with FSPCM (FHS-FSPCM) was preliminarily tested in an indoor setup. Results show that the FHS-FSPCM has a lower temperature distribution curve than the bare FHS, highlighting the increase in cooling capability of fabricated FSPCM. Field-testing of PV panels integrated with an FHS-FSPCM displayed that FSPCM manages to reduce the operating temperature of the panel by 4 to 15 °C and increase power output generation by 38.61%.

Background Bacterial meningitis is the commonest cause of acquired deafness (Fortnum, 1992) resulting in permanent sensorineural hearing loss (SNHL). Therefore, early audiological assessment is essential (Rahko et al, 1984). Currently, Streptococcus pneumoniae and Neisseria meningitidis are the most common organisms responsible for bacterial meningitis (Kutz et al, 2006). Labyrinthine ossification, a significant and rapid otological emergency, is more common after infection with Streptococcus pneumoniae (Douglas et al, 2008). Objectives The primary objective was to determine the post-meningitis auditory complications. The secondary objectives were to determine the pathogen, neuro-radiological changes and to ascertain the relationship with the auditory deficit. Methods This was a retrospective case-note audit of children who had at least 1 audiological assessment in a tertiary children’s hospital in UK following referral to the Audiovestibular Department with suspected or confirmed meningitis and/or septicaemia. Referrals made within 24-months (1st January 2018 to 31st December 2019) were considered. Patients that did not have an audiological assessment (e.g. child returned home and out of catchment area) were excluded. The audiological results (degree, type and laterality of deafness), microbiological details, radiological changes and audiological intervention were recorded. Results During the 24-months, 44 children had at least one audiological assessment following suspected or confirmed meningitis and/or sepsis. The majority were in-patient ward referrals (n=38, 86%) and others were from various referral sources (General Paediatric clinic, Newborn Hearing Screening Programme, Speech Therapist and Health Visitor). The age on admission ranged from 2days (2 children) to 16 years. 9 (20%) babies were As per British Society of Audiology guidelines, 39 children (89%) had satisfactory hearing on soundfield or ear-specific tests. 2 children had bilateral severe-to-profound SNHL. Further 2 had unilateral SNHL. One had unilateral conductive hearing loss due to underlying otitis media with effusion. Of the two with bilateral SNHL, one had Neisseria meningitides and bilateral significant labyrinthine ossification on neuro-radiology. The other had Streptococcus parasanguinis and intracranial fluid collections over the left cerebellar hemisphere and right frontal lobe. They both eventually underwent cochlear implantation for hearing rehabilitation. The microbiological profile of the cohort included Neisseria meningitides (including the above child) (n=15, 34%), Enterovirus (n=8, 18%), Streptococcus agalactiae (n=6, 14%), Streptococcus pneumoniae and E. coli (4 each), culture negative but neutrophilia in cerebrospinal fluid samples (n=3) and 1 each with Haemophilus influenzae, Streptococcus parasanguinous (above bilateral SNHL), Streptococcus gallalyticus and unknown organism. Post-meningitis neuro-radiological changes were noted in about 30% of children. These included bilateral labyrinthine ossification (n=1, above child), non-cystic focal lesions (n=5), significant intracranial fluid collections (including hydrocephalus) (n=4), subdural effusions (n=2) and gliosis (n=1). Conclusions The most prevalent organism in our cohort was Neisseria meningitides and 1 child had significant rapid cochlear ossification needing urgent cochlear implantation. Pneumococcal meningitis can result in unilateral SNHL (2 children). 30% of children had labyrinthine and intra-cranial radiological changes. Therefore, it is vital to consider the micro-organism, radiological findings and correlate these with the audiological findings to ascertain the audiological risk and prognosis after meningitis in children.

Background: International experiences have shown that trauma system development significantly reduces preventable deaths and disabilities. During the 8-year study, the aim was to find solutions for trauma system development in Shenzhen, China, so as to reduce trauma mortality and morbidity. Methods: Introducing the ATLS® program to mainland China was started in 2013. A geospatial analysis of traumatic incidents was conducted in 2014. A regional trauma center was illustrated as an example to be used as a reference. The trauma audit meeting was introduced as an approach to continuous trauma quality improvement. The Shenzhen Trauma Surgery Committee was established to finalize the plan for designation of trauma care hospitals. The American College of Surgeons Trauma System Development Guidelines were translated into Chinese. Results: ATLS® provider course was held in Shenzhen and totally 205 doctors received training. A regional trauma center where adopted ATLS® principles as the standard for trauma resuscitation and early trauma care, with results showing significant improvements in trauma team organization, trauma resuscitation, definitive trauma care and a significant reduction in mortality among major trauma patients. The trauma audit meeting was introduced to 8 hospitals. A new trauma system plan for Shenzhen was set up and a consensus was reached on trauma center designation. The American College of Surgeons' “Resources for Optimal Care of the Injured Patient” was translated into Chinese and published in November 2020. Conclusion: The critical steps in establishing the framework for the Shenzhen trauma system included: geospatial analysis of traumatic incidents, trauma care training for providers, trauma center development, regional trauma center designation and development of trauma quality improvement programs. This practical approach can be replicated in other countries seeking to establish a trauma system. We are now working toward extension of this approach to other regions of mainland China.

Several meta-analyses have been conducted to evaluate the weight loss effect of sodium-glucose cotransporter 2 (SGLT-2) inhibitors in patients with type 2 diabetes, whereas pooled analysis focusing on individuals without diabetes is lacking. The objective of this systematic review and meta-analysis is to evaluate the effect of SGLT-2 inhibitor monotherapy on weight change and cardiometabolic profiles. Multiple databases were searched for randomized controlled trials reporting weight change effect of SGLT-2 inhibitor treatment compared with placebo for more than 12 weeks among individuals with overweight or obesity and without diabetes. A total of eight randomized controlled trials with 750 subjects were identified. SGLT-2 monotherapy was associated with significant reduction in body weight of -2.32 kg, compared to -1.01 kg for placebo, giving a mean difference of -1.31 kg. Significant reductions in body mass index and fasting blood glucose were observed, but not for the changes in waist circumference, fat mass, blood pressure, and lipid profile compared with placebo. SGLT-2 inhibitor monotherapy for 12 weeks or more can result in modest weight loss among people with overweight or obesity and without diabetes. Depending on pre-existing comorbidities or risk factors, SGLT-2 inhibitors can be considered adjuncts in the treatment of obesity.

PURPOSE We explore the potential use of radar technology for fiducial marker tracking for monitoring of respiratory tumor motion during radiotherapy. Historically microwave radar technology has been widely deployed in various military and civil aviation applications to provide detection, position, and tracking of single or multiples objects from far away and even through barriers. Recently, due to many advantages of the microwave technology, it has been successfully demonstrated to detect breast tumor, and to monitor vital signs in real time such as breathing signals or heart rates. We demonstrate a proof-of-concept for radar-based fiducial marker tracking through the synthetic human tissue phantom. METHODS We performed a series of experiments with the vector network analyzer (VNA) and wideband directional horn antenna. We considered the frequency range from 2.0 to 6.0 GHz, with a maximum power of 3 dBm. A horn antenna, transmitting and receiving radar pulses, was connected to the vector network analyzer to probe a gold fiducial marker through a customized synthetic human tissue phantom, consisting of 1-mm thickness of skin, 5-mm fat, and 25-mm muscle layers. A 1.2 × 10-mm gold fiducial marker was exploited as a motion surrogate, which was placed behind the phantom and statically positioned with an increment of 12.7 mm to simulate different marker displacements. The returned signals from the marker were acquired and analyzed to evaluate the localization accuracy as a function of the marker position. RESULTS The fiducial marker was successfully localized at various measurement positions through a simplified phantom study. The averaged localization accuracy across measurements was 3.5 ± 1.3 mm, with a minimum error of 1.9 mm at the closest measurement location and a maximum error of 4.9 mm at the largest measurement location. CONCLUSIONS We demonstrated that the 2-6 GHz radar can penetrate through the attenuating tissues and localize a fiducial marker. This successful feasibility study establishes a foundation for further investigation of radar technology as a non-ionizing tumor localization device for radiotherapy.

ObjectivesWe aimed to harness IDentif.AI 2.0, a clinically actionable AI platform to rapidly pinpoint and prioritize optimal combination therapy regimens against COVID-19.MethodsA pool of starting candidate therapies was developed in collaboration with a community of infectious disease clinicians and included EIDD-1931 (metabolite of EIDD-2801), baricitinib, ebselen, selinexor, masitinib, nafamostat mesylate, telaprevir (VX-950), SN-38 (metabolite of irinotecan), imatinib mesylate, remdesivir, lopinavir, and ritonavir. Following the initial drug pool assessment, a focused, 6-drug pool was interrogated at 3 dosing levels per drug representing nearly 10,000 possible combination regimens. IDentif.AI 2.0 paired prospective, experimental validation of multi-drug efficacy on a SARS-CoV-2 live virus (propagated, original strain, B.1.351 and B.1.617.2 variants) and Vero E6 assay with a quadratic optimization workflow.ResultsWithin 3 weeks, IDentif.AI 2.0 realized a list of combination regimens, ranked by efficacy, for clinical go/no-go regimen recommendations. IDentif.AI 2.0 revealed EIDD-1931 to be a strong candidate upon which multiple drug combinations can be derived.ConclusionsIDentif.AI 2.0 rapidly revealed promising drug combinations for clinical translation. It pinpointed dose-dependent drug synergy behavior to play a role in trial design and realizing positive treatment outcomes. IDentif.AI 2.0 represents an actionable path towards rapidly optimizing combination therapy following pandemic emergence.Graphical AbstractHighlights-When novel pathogens emerge, the immediate strategy is to repurpose drugs.-Good drugs delivered together in suboptimal combinations and doses can yield low or no efficacy, leading to misperception that the drugs are ineffective.-IDentif.AI 2.0 does not use in silico modeling or pre-existing data.-IDentif.AI 2.0 pairs optimization with prospectively acquired experimental data using a SARS-CoV-2/Vero E6 assay.-IDentif.AI 2.0 pinpoints EIDD-1931 as a foundation for optimized anti-SARS-CoV-2 combination therapies.

Introduction With the COVID-19 vaccine rollout is well underway now beginning in children ages 12 and over, it is unknown what percent of parents plan to vaccinate their children against COVID-19. Method The purpose of this descriptive correlational study was to examine parents’ attitudes, beliefs, and behaviors in administering a COVID-19 vaccine. Results Only 21.93% of the subjects reported overall VH. Half of parents (49.45%) say they want the COVID vaccine for their child, and 44.17% plan to vaccinate against COVID once the vaccine becomes available to them. Concern for vaccine side effects (61.5%) and vaccine safety (48.96%) were significant factors that increased VH. In addition, there was a significant correlation between parents who were planning to vaccinate their child against the flu and being less VH about a COVID-19 vaccine for their child. Discussion This is the first known study to describe parental perceptions’ of COVID-19 VH and identify factors that increase VH for parents.

Purpose: Stereotactic ablative radiation therapy (SABR) for oligometastatic prostate cancer (OMPC) may improve clinical outcomes, but current challenges in intrafraction tracking of multiple small targets limits treatment accuracy. A biology-guided radiation therapy (BgRT) delivery system incorporating positron emission tomography (PET) detectors is being developed to use radiotracer uptake as a biologic fiducial for intrafraction tumor tracking to improve geometric accuracy. This study simulates prostate-specific membrane antigen (PSMA)-directed BgRT using a cohort from our phase II randomized trial of SABR in men with recurrent hormone sensitive OMPC and compares dose distributions to clinical SABR (CSABR). Methods and Materials: A research treatment planning system (RTPS) was used to replan 15 patients imaged with PSMA-targeted 18F-DCFPyL PET/computed tomography and previously treated with CSABR using conventional linear accelerators (linacs). The RTPS models a prototype ring-mounted linac incorporating PET and kilo-voltage computed tomography imaging subsystems and can be used to optimize BgRT plans, as well as research SABR (RSABR) plans, which use the prototype linac without radiotracer guidance. CSABR, RSABR, and BgRT plans were compared in terms of maximum planning target volume (PTV) dose (Dmax), mean dose to proximal organs at risk (DOAR), conformity index, as well as voxel-wise correlation of dose with PET specific uptake values to investigate possible dose-painting effects. Results: RSABR and BgRT plans resulted in mean ± standard deviation increases in Dmax of 4 ± 11% (P = .21) and 18 ± 15% (P < .001) and reductions in DOAR of –20 ± 19% (P

ObjectiveHepatocellular carcinoma (HCC), mostly developed in fibrotic/cirrhotic liver, exhibits relatively low responsiveness to immune checkpoint blockade (ICB) therapy. As myeloid-derived suppressor cell (MDSC) is pivotal for immunosuppression, we investigated its role and regulation in the fibrotic microenvironment with an aim of developing mechanism-based combination immunotherapy.DesignFunctional significance of MDSCs was evaluated by flow cytometry using two orthotopic HCC models in fibrotic liver setting via carbon tetrachloride or high-fat high-carbohydrate diet and verified by clinical specimens. Mechanistic studies were conducted in human hepatic stellate cell (HSC)-peripheral blood mononuclear cell culture systems and fibrotic-HCC patient-derived MDSCs. The efficacy of single or combined therapy with anti-programmed death-1-ligand-1 (anti-PD-L1) and a clinically trialled BET bromodomain inhibitor i-BET762 was determined.ResultsAccumulation of monocytic MDSCs (M-MDSCs), but not polymorphonuclear MDSCs, in fibrotic livers significantly correlated with reduced tumour-infiltrating lymphocytes (TILs) and increased tumorigenicity in both mouse models. In human HCCs, the tumour-surrounding fibrotic livers were markedly enriched with M-MDSC, with its surrogate marker CD33 significantly associated with aggressive tumour phenotypes and poor survival rates. Mechanistically, activated HSCs induced monocyte-intrinsic p38 MAPK signalling to trigger enhancer reprogramming for M-MDSC development and immunosuppression. Treatment with p38 MAPK inhibitor abrogated HSC-M-MDSC crosstalk to prevent HCC growth. Concomitant with patient-derived M-MDSC suppression by i-BET762, combined treatment with anti-PD-L1 synergistically enhanced TILs, resulting in tumour eradication and prolonged survival in the fibrotic-HCC mouse model.ConclusionOur results signify how non-tumour-intrinsic properties in the desmoplastic microenvironment can be exploited to reinstate immunosurveillance, providing readily translatable combination strategies to empower HCC immunotherapy.

Modern medicine, including the care of the cancer patient, has significantly advanced, with the evidence-based medicine paradigm serving to guide clinical care decisions. Yet we now also recognize the tremendous heterogeneity not only of disease states but of the patient and his or her environment as it influences treatment outcomes and toxicities. These reasons and many others have led to a reevaluation of the generalizability of randomized trials and growing interest in accounting for this heterogeneity under the rubric of precision medicine as it relates to personalizing clinical care predictions, decisions, and therapy for the disease state. For the cancer patient treated with radiation therapy, characterizing the spatial treatment heterogeneity has been a fundamental tenet of routine clinical care facilitated by established database and imaging platforms. Leveraging these platforms to further characterize and collate all clinically relevant sources of heterogeneity that affect the longitudinal health outcomes of the irradiated cancer patient provides an opportunity to generate a critical informatics infrastructure on which precision radiation therapy may be realized. In doing so, data science-driven insight discoveries, personalized clinical decisions, and the potential to accelerate translational efforts may be realized ideally within a network of institutions with locally developed yet coordinated informatics infrastructures. The path toward realizing these goals has many needs and challenges, which we summarize, with many still to be realized and understood. Early efforts by our group have identified the feasibility of this approach using routine clinical data sets and offer promise that this transformation can be successfully realized in radiation oncology.

Background Newborns affected with congenital pulmonary airway malformations (CPAMs) may present with severe respiratory distress or remain asymptomatic. While surgical resection is the definitive treatment for symptomatic CPAMs, prophylactic elective surgery may be recommended for asymptomatic CPAMs owing to the risk of tumour development. However, the implementation of prophylactic surgery is quite controversial on the grounds that more evidence linking CPAMs and cancer is needed. The large gap in knowledge of CPAM pathogenesis results in uncertainties and controversies in disease management. As developmental genes control postnatal cell growth and contribute to cancer development, we hypothesised that CPAMs may be underlain by germline mutations in genes governing airways development. Methods Sequencing of the exome of 19 patients and their unaffected parents. Results A more than expected number of mutations in cancer genes (false discovery rate q-value, Congenital pulmonary airway malformation (CPAM) patients have more than expected numbers of damaging variants in genes involved in lung carcinoma; this may provide evidence for clinicians choosing to adopt prophylactic excision in CPAM http://ow.ly/h1AE30n4DIe

Purpose/Objective(s) Flash radiotherapy, the delivery of high radiation dose (> 10 Gy) at ultrahigh dose rates (> 37 Gy/s), has been shown to reduce significantly normal tissue toxicity compared to conventional irradiation, while maintaining tumor control probability at similar level. Great excitement has since ensued about the transformative potential of FLASH radiotherapy. At present, important FLASH research employs complex accelerator technologies of limited accessibilities. Here, we study the feasibility of a novel self-shielded x-ray irradiation cabinet system, as an enabling technology to enhance the preclinical research capabilities of the radiation research community. Materials/Methods The proposed system employs two commercially available high capacity 150 kVp fluoroscopy x-ray sources, RAD-44 or G-1592 tubes, with rotating anode technology in a parallel-opposed arrangement. Simulation was performed using a simulation toolkit. Simulated dosimetric properties of the x-ray beam for both FLASH and conventional dose-rate irradiations were characterized in terms of output, uniformity and symmetry as a function of SSD, beam current, exposure time, and external filters. Dose and dose rate from a single kV x-ray fluoroscopy source at various depths in solid water phantom were verified with measurements using radiographic films. Results The parallel-opposed x-ray sources can deliver doses up to 67 Gy to a 20-mm thick water equivalent medium at FLASH dose-rates of 40 – 240 Gy/s. A uniform depth dose rate within ± 5% deviation is achieved over 8-12 mm in central region of the phantom. Conventional dose-rate irradiation (≤ 0.1 Gy/s) can also be achieved by reducing the tube current and increasing the distance between the phantom and tubes. Either the RAD-44 or G-1592 x-ray source can be used to deliver FLASH and conventional dose-rate irradiations with the field larger than 25 mm and up to 200 mm in length, respectively. These field dimensions are well suitable for small animal and cell culture irradiations. For FLASH irradiation using parallel-opposed source arrangement, entrance and exit doses can be increased by 30% compared to the dose at the phantom center. Beam angling can be employed to reduce the high surface doses by minimizing the beams overlap at the phantom surfaces. For a 10 × 10 mm2 field, for example, 26degree beam angle from vertical axis reduces the entrance dose by 39%, while maintaining FLASH dose rate of 118 Gy/s spanning in 8 mm thickness. Conclusion It is feasible to achieve FLASH dose rate irradiation with kV x-rays using rotating anode x-ray sources in the parallel-opposed arrangement. The system is amendable to self-shielding and readily deployable. Availability of both FLASH and conventional dose rate irradiations in the same platform enables effective comparative research. A cabinet FLASH irradiation system will greatly enhance research in the regular laboratory setting to elucidate the important biological mechanism of the FLASH effect.

Purpose/objective(s) The developing radio-immunotherapy has cast the use of radiation therapy (RT) into a pivotal role in the management of pancreatic cancer. There is a need to study pancreatic cancer in pre-clinical setting to advance our understanding of the role of RT. The challenge to study abdominal malignancy in vivo is lack of proper imaging guidance. Bioluminescence with its strong imaging contrast has been widely used to monitor tumor growth. We innovated 3D bioluminescence tomography (BLT) to guide irradiation for an orthotopic pancreatic ductal adenocarcinoma (PDAC), and monitor its growth and treatment response. Materials/methods To establish the orthotopic PDAC model, we implanted a fraction of BxPc3-Red-FLuc tumor into the pancreas of a nude mouse. For BLT, mice were subject to multi-spectral and multi-projection bioluminescence imaging (BLI), followed by small animal radiation research platform (SARRP) CBCT imaging. CBCT image was acquired to generate anatomical mesh for BLT reconstruction. We inserted a titanium wire to the center of tumor as the marker to validate the BLT localization accuracy. We will also quantify the accuracy of BLT reconstructed volume with MRI and ex vivo method. Volume-averaged bioluminescent power (BP), related to tumor viability, will also be assessed in comparing with surface BLI and ex vivo method, to determine if it is a proper metric for tumor monitoring and assessment. We will further irradiate the in vivo PDAC volume guided by BLT and demonstrate the application of BLT to longitudinally assess the change of PDAC volume/power in response to treatment. Results Our initial result shows 3D BLT can retrieve the orthotopic PDAC location within 1.5 mm accuracy at depth from 3-5 mm, common depth observed in pancreatic study. The BP is observed linearly by 12-fold along the tumor growth 4 weeks after tumor implantation. With BLT, we are able to reconstruct the 3D bioluminescent tumor volume using multiple-projection imaging. Conclusion The quantitative BLT system offers unique opportunities for researchers to study important pancreatic tumor in orthotopic setting to quantify its location, growth and response to therapeutic intervention.

Purpose Widely used cone beam computed tomography (CBCT)-guided irradiators in preclinical radiation research are limited to localize soft tissue target because of low imaging contrast. Knowledge of target volume is a fundamental need for radiation therapy (RT). Without such information to guide radiation, normal tissue can be overirradiated, introducing experimental uncertainties. This led us to develop high-contrast quantitative bioluminescence tomography (QBLT) for guidance. The use of a 3-dimensional bioluminescence signal, related to cell viability, for preclinical radiation research is one step toward biology-guided RT. Methods and Materials Our QBLT system enables multiprojection and multispectral bioluminescence imaging to maximize input data for the tomographic reconstruction. Accurate quantification of spectrum and dynamic change of in vivo signal were also accounted for the QBLT. A spectral-derivative method was implemented to eliminate the modeling of the light propagation from animal surface to detector. We demonstrated the QBLT capability of guiding conformal RT using a bioluminescent glioblastoma (GBM) model in vivo. A threshold was determined to delineate QBLT reconstructed gross target volume (GTVQBLT), which provides the best overlap between the GTVQBLT and CBCT contrast labeled GBM (GTV), used as the ground truth for GBM volume. To account for the uncertainty of GTVQBLT in target positioning and volume delineation, a margin was determined and added to the GTVQBLT to form a QBLT planning target volume (PTVQBLT) for guidance. Results The QBLT can reconstruct in vivo GBM with localization accuracy within 1 mm. A 0.5-mm margin was determined and added to GTVQBLT to form PTVQBLT, largely improving tumor coverage from 75.0% (0 mm margin) to 97.9% in average, while minimizing normal tissue toxicity. With the goal of prescribed dose 5 Gy covering 95% of PTVQBLT, QBLT-guided 7-field conformal RT can effectively irradiate 99.4 ± 1.0% of GTV. Conclusions The QBLT provides a unique opportunity for investigators to use biologic information for target delineation, guiding conformal irradiation, and reducing normal tissue involvement, which is expected to increase reproducibility of scientific discovery.

PURPOSE: Severe and long-lasting lymphopenia occurs in 40% of patients with malignant gliomas and is associated with inferior survival. Inadvertent irradiation of circulating lymphocytes is a major contributor to this lymphopenia. Fingolimod causes striking but reversible lymphopenia by sequestering circulating lymphocytes in lymphoid tissues. Fingolimod could potentially reduce iatrogenic immunosuppression by decreasing the number of lymphocytes in circulation during radiation. However, combining radiation with fingolimod should result in severe lymphopenia. These pilot studies were conducted to determine the safety of this approach in mice and humans. METHODS: Ten BALB/c mice received focal brain irradiation (4Gy x 10 fractions). Half of the mice received intraperitoneal fingolimod (3mg/kg) before and during the two weeks of radiation. Five patients with newly diagnosed glioblastoma were given fingolimod one week prior to and during the six weeks of concurrent radiation and temozolomide. RESULTS: Mice treated with fingolimod and radiation had more severe lymphopenia than those treated with radiation alone. However, lymphocyte counts and weight loss recovered similarly in both treatment cohorts and no added toxicities were noted. Humans receiving fingolimod developed severe lymphopenia which deepened when radiation and temozolomide were initiated. This was well tolerated and no grade III-IV opportunistic infections were noted. CONCLUSIONS: These pilot studies demonstrate the feasibility and safety of combining fingolimod with radiation in mice and humans. This novel approach to reducing the number of circulating lymphocytes exposed to radiation deserves further study given the importance of the host immune system on cancer survival and response to immunologic interventions.

We developed genetic-epigenetic tissue mapping (GETMap) to determine the tissue composition of plasma DNA carrying genetic variants not present in the constitutional genome through comparing their methylation profiles with relevant tissues. We validated this approach by showing that, in pregnant women, circulating DNA carrying fetal-specific alleles was entirely placenta-derived. In lung transplant recipients, we showed that, at 72 hr after transplantation, the lung contributed only a median of 17% to the plasma DNA carrying donor-specific alleles, and hematopoietic cells contributed a median of 78%. In hepatocellular cancer patients, the liver was identified as the predominant source of plasma DNA carrying tumor-specific mutations. In a pregnant woman with lymphoma, plasma DNA molecules carrying cancer mutations and fetal-specific alleles were accurately shown to be derived from the lymphocytes and placenta, respectively. Analysis of tissue origin for plasma DNA carrying genetic variants is potentially useful for noninvasive prenatal testing, transplantation monitoring, and cancer screening.

Tumor invasion into the inferior vena cava (IVC) and hepatic vein (HV) is challenging in cancer surgery with curative intent. Appropriate techniques for venous reconstruction are essential. We have described in detail a novel technique of fashioning an interposition tube graft using the falciform ligament to reconstruct the IVC and HV. The falciform ligament maintains all the benefits of an autologous tissue graft, with the added advantage of its flexibility in customizing graft dimensions. Its use in IVC and HV reconstruction has rarely been reported. The short-term outcomes with this tube graft are promising.

Genetically engineered mouse model(GEMM) that develops pancreatic ductal adenocarcinoma(PDAC) offers an experimental system to advance our understanding of radiotherapy(RT) for pancreatic cancer. Cone beam CT(CBCT)-guided small animal radiation research platform(SARRP) has been developed to mimic the RT used for human. However, we recognized that CBCT is inadequate to localize the PDAC growing in low image contrast environment. We innovated bioluminescence tomography(BLT) to guide SARRP irradiation for in vivo PDAC. Before working on the complex PDAC-GEMM, we first validated our BLT target localization using subcutaneous and orthotopic pancreatic tumor models. Our BLT process involves the animal transport between the BLT system and SARRP. We inserted a titanium wire into the orthotopic tumor as the fiducial marker to track the tumor location and to validate the BLT reconstruction accuracy. Our data shows that with careful animal handling, minimum disturbance for target position was introduced during our BLT imaging procedure(

Background The insufficient T cell infiltration into non-inflamed tumors such as hepatocellular carcinoma (HCC) restricts the effectiveness of immune-checkpoint blockade (ICB) to a minority of patients. Epigenetic therapy provides new opportunities to rewire cancer transcriptional programs, but whether and how selective epigenetic inhibition counteracts the immune-excluded phenotype to sensitize ICB therapy remain incompletely defined. Here, we aimed to investigate the therapeutic efficacy and mechanistic basis of histone deacetylase 8 (HDAC8), a histone H3 lysine 27 (H3K27)-specific isoform, in HCC development and ICB responsiveness. Methods The immune-modulatory and anti-tumor effects of HDAC8 inhibition via a HDAC8-selective inhibitor, PCI34051, were determined in orthotopic HCC mouse models. Molecular mechanisms and functional significance of HDAC8 inhibition were conducted by genome-wide H3K27ac ChIP-seq and RNAseq in HCC patient specimens, cancer cell lines, NOD-SCID and humanized mouse models. The efficacy of single or combined therapy with anti-programmed death-1-ligand-1 (anti-PD-L1) and PCI34051 was determined in orthotopic and spontaneous HCC mouse models. Results Pharmacological inhibition of HDAC8 thwarted HCC tumorigenicity in immunocompetent but not immunodeficient mice. The tumor-suppressive effect of PCI34051 was abrogated by CD8+T cell depletion or regulatory T cell adoptive transfer. Chromatin profiling of human HDAC8-expressing HCCs revealed genome-wide H3K27 deacetylation in 1,251 silenced enhancer-target gene pairs that were enriched in metabolic and immune regulators. Mechanistically, down-regulation of HDAC8 increased global and enhancer levels of H3K27 acetylation to reactivate T cell-trafficking chemokine production from HCC cells, thus relieving T cell exclusion in both NOD-SCID and humanized mouse models. In the HCC preclinical model, selective HDAC8 inhibition significantly increased tumor-infiltrating CD8+T cells and potentiated eradication of established hepatoma by anti-PD-L1 therapy without a sign of toxicity. Importantly, mice treated with HDAC8/PD-L1 co-blockade were protected against subsequent tumor re-challenge with the induction of memory T cells and remained tumor-free for ≥15 months. Conclusions Our study demonstrates that selective HDAC8 inhibition elicits effective and durable ICB responses by co-opting adaptive immunity via enhancer reprogramming, thereby providing a new strategy for effective combined epigenetic immunotherapy.

The liver is an immunologically tolerant organ and a common metastatic site of multiple cancer types. Although a role for cancer cell invasion programs has been well characterized, whether and how liver-intrinsic factors drive metastatic spread is incompletely understood. Here, we show that aberrantly activated hepatocyte-intrinsic cell cycle-related kinase (CCRK) signaling in chronic liver diseases is critical for cancer metastasis by reprogramming an immunosuppressive microenvironment. Using an inducible liver-specific transgenic model, we found that CCRK overexpression dramatically increased both B16F10 melanoma and MC38 colorectal cancer (CRC) metastasis to the liver, which was highly infiltrated by polymorphonuclear-myeloid-derived suppressor cells (PMN-MDSCs) and lacking natural killer T (NKT) cells. Depletion of PMN-MDSCs in CCRK transgenic mice restored NKT cell levels and their interferon gamma production and reduced liver metastasis to 2.7% and 0.7% (metastatic tumor weights) in the melanoma and CRC models, respectively. Mechanistically, CCRK activated nuclear factor-kappa B (NF-κB) signaling to increase the PMN-MDSC-trafficking chemokine C-X-C motif ligand 1 (CXCL1), which was positively correlated with liver-infiltrating PMN-MDSC levels in CCRK transgenic mice. Accordingly, CRC liver metastasis patients exhibited hyperactivation of hepatic CCRK/NF-κB/CXCL1 signaling, which was associated with accumulation of PMN-MDSCs and paucity of NKT cells compared to healthy liver transplantation donors. In summary, this study demonstrates that immunosuppressive reprogramming by hepatic CCRK signaling undermines antimetastatic immunosurveillance. Our findings offer new mechanistic insights and therapeutic targets for liver metastasis intervention.

Although hepatectomy is a curative treatment modality for hepatocellular carcinoma (HCC), the associated 10-year long-term actual survival are rarely reported. This study aims to develop and validate a predictive nomogram for 10-year actual survivors with HCC.From 2004 to 2009, 753 patients with curative hepatectomy for HCC (development set, n = 325; validation set, n = 428) were included. In development set, comparison of clinic-pathological data was made between patients surviving ≥10 years and those surviving10 years. Good independent prognostic factors identified by multivariate analysis were involved in a nomogram development, which was validated internally and externally using validation set.On multivariate analysis, five independent good prognostic factors for 10-year survival were identified, including young age (OR = 0.943), good ASA status (≤2) (OR = 2.794), higher albumin level (OR = 1.116), solitary tumor (OR = 2.531) and absence of microvascular invasion (OR = 3.367). A novel nomogram was constructed with C-index of 0.801 (95% CI 0.762-0.864). A cut-off point of 167.5 had a sensitivity of 0.794 and specificity of 0.730. Internal validation using bootstrap sampling and external validation using validation set revealed C-index of 0.792 (95% CI, 0.741-0.853) and 0.761 (95% CI, 0.718-0.817).A novel nomogram for 10-year HCC survivor using age, ASA status, preoperative albumin, tumor number and presence of microvascular tumor invasion was developed and validated with high accuracy.

COVID-19, the disease caused by SARS-CoV-2 (1), was declared a pandemic by the World Health Organization (WHO) in March 2020 (2). While awaiting a vaccine, several antivirals are being used to manage the disease with limited success (3, 4). To expand this arsenal, we screened 4 compound libraries: a United States Food and Drug Administration (FDA) approved drug library, an angiotensin converting enzyme-2 (ACE2) targeted compound library, a flavonoid compound library as well as a natural product library. Of the 121 compounds identified with activity against SARS-CoV-2, 7 were shortlisted for validation. We show for the first time that the active form of Vitamin D, calcitriol, exhibits significant potent activity against SARS-CoV-2. This finding paves the way for consideration of host-directed therapies for ring prophylaxis of contacts of SARS-CoV-2 patients.

Introduction: We describe a technique of intraoperative fundus visualization during anterior segment surgery using an anterior chamber air bubble. Methods: An air bubble that occupies one-half to two-thirds of the anterior chamber is injected via existing corneal incisions at any time during surgery. By focusing downwards and looking through the air bubble, an upright image of the posterior pole of the fundus is seen. The technique is demonstrated in a series of cases in the form of photos and supplementary video files. Results: Visualization of the fundus can be safely and effectively performed regardless of the lens status (phakic/pseudophakic/aphakic) of the eye. This technique allows the posterior pole and up to mid-peripheral fundus to be quickly inspected at any stage of surgery. Conclusion: This technique may help surgeons to briefly inspect the fundus in cases of unusual light reflex or following complicated surgery without any additional instrumentation.

We proposed to build a mobile fluorescence tomography (mFT) system as an image-guided platform for pre-clinical radiotherapy research. The mFT system is expected to localize functional target/tumor, guide irradiation, and provide longitudinal treatment assessment.

Chemokine receptor CXCR4 was involved in the progression of breast cancer to a metastatic phenotype, leading to the major cause of death in patients. A more in-depth understanding of signaling mechanism underlying CXCR4 is critical to develop effective therapies toward metastasis. Recently, the role of antimicrobial peptide LL-37 in contributing to the metastasis of breast cancer cells was observed. Clinical analysis of data herein demonstrated for the first time that overexpression of LL-37 and CXCR4 co-existed in human primary breast tumors with lymph node metastases. Further study disclosed that forced expression of CXCR4 led to the enhancement of pro-migratory signaling and migration rate induced by LL-37 in breast cancer cells. Moreover, LL-37 affected tumor microenvironment including induction of migration of mesenchymal stem cells and CXCR4-dependent capillary-like tubule formation. Functional analysis showed that LL-37 induced the internalization of CXCR4 through approaching Glu268, the residue of CXCR4, independent of the binding pocket (Asp171, Asp262, and Glu288) for CXCR4 inhibitor AMD3100, signifying that LL-37 is a distinct agonist of CXCR4. These results suggest the reciprocal roles of LL-37 and CXCR4 in promoting breast cancer cell migration and provide new insight into the design of CXCR4 inhibitor for intervention of metastatic breast cancer.

Purpose: In the proper context, radiotherapy can promote antitumor immunity. It is unknown if elective nodal irradiation (ENI), a strategy that irradiates tumor-associated draining lymph nodes (DLN), affects adaptive immune responses and combinatorial efficacy of radiotherapy with immune checkpoint blockade (ICB). Experimental Design: We developed a preclinical model to compare stereotactic radiotherapy (Tumor RT) with or without ENI to examine immunologic differences between radiotherapy techniques that spare or irradiate the DLN. Results: Tumor RT was associated with upregulation of an intratumoral T-cell chemoattractant chemokine signature (CXCR3, CCR5-related) that resulted in robust infiltration of antigen-specific CD8+ effector T cells as well as FoxP3+ regulatory T cells (Tregs). The addition of ENI attenuated chemokine expression, restrained immune infiltration, and adversely affected survival when combined with ICB, especially with anti-CLTA4 therapy. The combination of stereotactic radiotherapy and ICB led to long-term survival in a subset of mice and was associated with favorable CD8 effector-to-Treg ratios and increased intratumoral density of antigen-specific CD8+ T cells. Although radiotherapy technique (Tumor RT vs. ENI) affected initial tumor control and survival, the ability to reject tumor upon rechallenge was partially dependent upon the mechanism of action of ICB; as radiotherapy/anti-CTLA4 was superior to radiotherapy/anti-PD-1. Conclusions: Our results highlight that irradiation of the DLN restrains adaptive immune responses through altered chemokine expression and CD8+ T-cell trafficking. These data have implications for combining radiotherapy and ICB, long-term survival, and induction of immunologic memory. Clinically, the immunomodulatory effect of the radiotherapy strategy should be considered when combining stereotactic radiotherapy with immunotherapy. Clin Cancer Res; 24(20); 5058–71. ©2018 AACR.

Background This study analyzes position of the peroneal tendons and status of the superior peroneal retinaculum (SPR) whenever a lateral malleolar bony flake fracture occurs. Methods Twenty-four patients had a lateral malleolar bony fleck on anteroposterior ankle radiographs, either in isolation or associated with other hindfoot injuries. We studied size of the bony flecks, presence or absence of peroneal tendon dislocation and pathoanatomy on CT scans. Results In 11 patients, a small bony fleck lies within the superior peroneal retinaculum and contiguous periosteum, which are stripped off the lateral fibula (Class II lesions). Tendons dislocate into the subperiosteal pouch thus formed, resembling Class I lesions without associated bony avulsion. Treatment for Class II is same as for Class I injuries. In 8 patients with a big bony fleck, tendons dislocate into the fracture site and SPR is intact (Class III lesions). In Class IV lesions, observed in 5 patients with 2-part calcaneal fracture/dislocation, SPR remains intact and peroneal tendons are not dislocated. The invariably large fleck results from the displacing lateral calcaneal fragment abutting against the fibula, whereas the dislocating tendons cause the bony avulsions in Classes II and III. Conclusions Due to pathoanatomical differences, surgical approach and natural history of neglected lesions differ depending on size of the bony fleck. The SPR must not be incised in case of big Class III flecks.

Objective We explore whether a knowledge–discovery approach building a Classification and Regression Tree (CART) prediction model for weight loss (WL) in head and neck cancer (HNC) patients treated with radiation therapy (RT) is feasible. Methods and materials HNC patients from 2007 to 2015 were identified from a prospectively collected database Oncospace. Two prediction models at different time points were developed to predict weight loss ≥5 kg at 3 months post-RT by CART algorithm: (1) during RT planning using patient demographic, delineated dose data, planning target volume–organs at risk shape relationships data and (2) at the end of treatment (EOT) using additional on-treatment toxicities and quality of life data. Results Among 391 patients identified, WL predictors during RT planning were International Classification of Diseases diagnosis; dose to masticatory and superior constrictor muscles, larynx, and parotid; and age. At EOT, patient-reported oral intake, diagnosis, N stage, nausea, pain, dose to larynx, parotid, and low-dose planning target volume–larynx distance were significant predictive factors. The area under the curve during RT and EOT was 0.773 and 0.821, respectively. Conclusions We demonstrate the feasibility and potential value of an informatics infrastructure that has facilitated insight into the prediction of WL using the CART algorithm. The prediction accuracy significantly improved with the inclusion of additional treatment-related data and has the potential to be leveraged as a strategy to develop a learning health system.

Big clinical data analytics as a primary component of precision medicine is discussed, identifying where these emerging tools fit in the spectrum of genomics and radiomics research. A learning health system (LHS) is conceptualized that uses clinically acquired data with machine learning to advance the initiatives of precision medicine. The LHS is comprehensive and can be used for clinical decision support, discovery, and hypothesis derivation. These developing uses can positively impact the ultimate management and therapeutic course for patients. The conceptual model for each use of clinical data, however, is different, and an overview of the implications is discussed. With advancements in technologies and culture to improve the efficiency, accuracy, and breadth of measurements of the patient condition, the concept of an LHS may be realized in precision radiation therapy.