bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and efficacy of surgical fixation of fibula fractures using an intramedullary nail: a retrospective observational cohort study in 30 patients
Authors: Boni Guilherme , Sanchez Gustavo T. , Arliani Gustavo , Zelle Boris A. , Pires Robinson E. , dos Reis Fernando B.
Published: October 2019

Background

Open reduction and internal fixation remains the standard treatment for displaced unstable ankle fractures. Plate fixation represents the most frequently used instrumentation option in fibula fractures and favourable outcomes have been reported. Recently, intramedullary nailing techniques have been suggested as a viable alternative resulting in less soft tissue disruption. The objectives of this study are to describe the surgical technique and to evaluate the safety and efficacy of using an intramedullary nail in patients undergoing surgical fixation of their fibula fracture.

Methods

A total of 30 skeletally mature patients with unstable ankle fracture who underwent intramedullary fixation of their fibula fractures from February 2016 to July 2017 were included in this retrospective study. Patients were evaluated using the Short Form-36 (SF-36) and the American Orthopaedic Foot and Ankle Society (AOFAS) at 18 months after surgery.

Results

All patients went on to fracture union. Two patients required a secondary surgical procedure. No patient included in this series developed any wound complications. The mean Physical Component Summary (PCS) of the SF-36 was 53.90 ± 13.3 and the mean Mental Component Summary Score (MCS) was 52.63 ± 11.12. The AOFAS subscale scores were 34.67 ± 1.03 for pain, 42.40 ± 0.2997 for function and 9.50 ± 0.2785 for alignment.

Conclusions

Our study demonstrates promising outcomes associated with intramedullary nail fixation of unstable fibula fractures. We recommend intramedullary nail fixation of fibula fractures to be a safe procedure with a low complication rate.

Level of evidence

Level 4 retrospective case series.
SEPATH: benchmarking the search for pathogens in human tissue whole genome sequence data leads to template pipelines
Authors: Gihawi Abraham , Rallapalli Ghanasyam , Hurst Rachel , Cooper Colin S. , Leggett Richard M. , Brewer Daniel S.
Published: October 2019

Background

Human tissue is increasingly being whole genome sequenced as we transition into an era of genomic medicine. With this arises the potential to detect sequences originating from microorganisms, including pathogens amid the plethora of human sequencing reads. In cancer research, the tumorigenic ability of pathogens is being recognized, for example, Helicobacter pylori and human papillomavirus in the cases of gastric non-cardia and cervical carcinomas, respectively. As of yet, no benchmark has been carried out on the performance of computational approaches for bacterial and viral detection within host-dominated sequence data.

Results

We present the results of benchmarking over 70 distinct combinations of tools and parameters on 100 simulated cancer datasets spiked with realistic proportions of bacteria. mOTUs2 and Kraken are the highest performing individual tools achieving median genus-level F1 scores of 0.90 and 0.91, respectively. mOTUs2 demonstrates a high performance in estimating bacterial proportions. Employing Kraken on unassembled sequencing reads produces a good but variable performance depending on post-classification filtering parameters. These approaches are investigated on a selection of cervical and gastric cancer whole genome sequences where Alphapapillomavirus and Helicobacter are detected in addition to a variety of other interesting genera.

Conclusions

We provide the top-performing pipelines from this benchmark in a unifying tool called SEPATH, which is amenable to high throughput sequencing studies across a range of high-performance computing clusters. SEPATH provides a benchmarked and convenient approach to detect pathogens in tissue sequence data helping to determine the relationship between metagenomics and disease.
Treatment of lumbar vertebra epithelioid hemangioma with radiation therapy: a case report
Authors: Siltumens Aldis P. , Smith Na L. , Sharain Rosalind F. , Haddock Michael G. , Hooten W. Michael
Published: October 2019

Background

Although epithelioid hemangiomas involving bone have been described in previous case reports and case series, the effects of radiation therapy on vertebral epithelioid hemangioma has not been fully reported. Here we provide a case report of tumor response to radiation therapy in a young adult with a large epithelioid hemangioma involving the fourth lumbar vertebrae.

Case presentation

A 27-year-old Latino man with a past medical history of type 1 diabetes and a 3-year history of low back pain presented to a hospital emergency department following acute worsening of back pain. On transfer to our tertiary medical center, he described the pain as “shock-like” which originated at the lateral aspect of his right hip and radiated down to his right knee. Paresthesia was also reported along the medial aspect of his lower right leg. Imaging included a computed tomography scan and magnetic resonance imaging which revealed fourth lumbar and right iliac lytic bone lesions. Image-guided biopsies of the lytic lesions were consistent with a diagnosis of epithelioid hemangioma and radiation therapy was recommended as the primary treatment. Our patient’s low back and leg pain were initially managed with acetaminophen, oxycodone, pregabalin, and lidocaine patch 5%. He noted improvement in pain after his third fraction of radiation. Pain intensity continued to decline and oxycodone was discontinued.

Conclusions

This case report demonstrates an unusual etiology of back and leg pain in a young man and elucidates the palliative effects of radiation therapy for epithelioid hemangioma involving the lumbar spine.
Recombinant expressing angiopep-2 fused anti-VEGF single chain Fab (scFab) could cross blood–brain barrier and target glioma
Authors: Ji Xuemei , Wang Hongyan , Chen Yue , Zhou Junfei , Liu Yu
Published: October 2019

In 2009, the FDA approved bevacizumab for the treatment of adult patients diagnosed with recurrent glioblastoma. However, the poor permeability of the macromolecules across the blood–brain barrier, determined by multifactorial anatomical and physiological milieu, restricts the clinical therapeutic effect of bevacizumab. The low-density lipoprotein receptor related protein 1 (LRP1) is highly expressed in the endothelial cells of the brain capillary and the glioma cells. Angiopep-2 (ANG) is a 19-aa oligopeptide that can bind to LRP1 and penetrate the blood–brain barrier by receptor-mediated transport. Therefore, ANG can be used as a dual-targeting drug delivery carrier into the brain and the glioma sites. In this study, ANG gene was fused with the C-terminal domain of single-chain antigen binding fragment (scFab) of the anti-VEGF antibody and recombinant scFab-ANG protein was expressed and purified using Rosatte (DE3) strain. We confirmed that ANG could carry anti-VEGF-scFab, penetrate a three-dimensional model of the brain tumor, and cross the hCMEC/D3 monolayer in the in vitro blood–brain barrier model. The animal experiments demonstrated that 3 h after the tail intravenous protein injection, the fluorescent signals in the brains of the mice in the scFab-ANG group were stronger than that in the scFab group. Furthermore, the study of the in situ rat glioma model shows that scFab-ANG could target glioma while anti-VEGF-scFab could not. These findings indicate that scFab-ANG had stronger transepithelial permeability and glioma targeting capacity. Thus, it can be a potential candidate drug for glioblastoma therapy.
Dietary fibre enrichment of supplemental feed modulates the development of the intestinal tract in suckling piglets
Authors: Van Hees H. M. J. , Davids M. , Maes D. , Millet S. , Possemiers S. , den Hartog L. A. , van Kempen T. A. T. G. , Janssens G. P. J.
Published: October 2019

Background

Commercial pre-weaning diets are formulated to be highly digestible and nutrient-dense and contain low levels of dietary fibre. In contrast, pigs in a natural setting are manipulating fibre-rich plant material from a young age. Moreover, dietary fibre affects gastrointestinal tract (GIT) development and health in older pigs. We hypothesised that supplemental diets that contain vegetal fibres are accelerating GIT development in suckling piglets in terms of size and functionality. From d 2 of life, sow-suckled piglets had access to a low fibre diet (CON), a diet with a fermentable long-chain arabinoxylan (lc-AXOS), a diet with a largely non-fermentable purified cellulose (CELL), or a diet containing both fibres. During the initial 2 weeks, the control diet was a high-density milk replacer, followed by a dry and highly digestible creep meal. Upon weaning at 25 d, 15 piglets from each treatment group, identified as eaters and originating from six or seven litters, were sacrificed for post-mortem examination of GIT morphology, small intestinal permeability and metabolic profile of the digesta. The microbiota composition of the mid-colon was evaluated in a sub-set of ten piglets.

Results

No major statistical interactions between the fibre sources were observed. Piglets consumed the fibre-containing milk supplements and creep diets well. Stomach size and small intestinal permeability was not affected. Large intestinal fill was increased with lc-AXOS only, while relative large intestinal weight was increased with both fibre sources (P < 0.050). Also, CELL decreased ileal pH and tended to increase ileal DM content compared to CON (P < 0.050). Moreover, the concentration of volatile fatty acids was increased in the caecum (P < 0.100) and mid-colon (P < 0.050) by addition of CELL. lc-AXOS only stimulated caecal propionate (P < 0.050). The microbiota composition showed a high individual variation and limited dietary impact. Nonetheless, CELL induced minor shifts in specific genera, with notable reductions of Escherichia-Shigella.

Conclusions

Adding dietary fibres to the supplemental diet of suckling piglets altered large intestinal morphology but not small intestinal permeability. Moreover, dietary fibre showed effects on fermentation and modest changes of microbial populations in the hindgut, with more prominent effects from the low-fermentable cellulose.
Survival data following phase 1/2 studies using precision tumor-targeted gene delivery to advanced chemotherapy-resistant malignancies.
Authors: Gordon Erlinda Maria , Chawla Sant P. , Hall Frederick L
Published: October 2019

101

Background: Targeted gene delivery in vivo has long been considered the “Holy Grail” of gene therapy. Methods: We reviewed long-term data of patients with advanced chemotherapy-resistant malignancies, previously-treated patients with two tumor-targeted retrovectors: (1) encoding cytotoxic dominant negative cyclin G1, DeltaRex-G (formerly Rexin-G), and (2) encoding cytokine GMCSF plus suicide gene HStk, DeltaVax (formerly Reximmune-C). Results: Ninety-nine patients received > 5,000 intravenous infusions of DeltaRex-G; another 16 patients received 288 intravenous infusions of DeltaRex-G + 96 infusions of DeltaVax followed by valacyclovir p.o. No therapy-related bone marrow suppression, organ dysfunction or delayed treatment related adverse events were observed. Survival analysis showed 5.0% 10-year overall survival rate for patients who received DeltaRex-G alone, and 18.8% for DeltaRex-G + DeltaVax. Conclusions: Data analysis indicates that tumor-targeted gene delivery in vivo, represented by cytocidal DeltaRex-G, with or without immuno-stimulatory DeltaVax, has induced prolonged ( > 10 years) sustained remissions in cancer patients presenting with advanced chemotherapy-resistant solid and hematologic malignancies—plausibly due to safety, selectivity, and immune modulation. While the curative potential of precision targeted genetic medicine necessarily remains an academic question; it is clear that these initial long-term, cancer-free ( > 10 year) survivors represent a major milestone in both cancer therapy and immunotherapy. Phase 2-3 clinical trials are planned for these hard-to treat malignancies.
Geriatric head and neck squamous carcinomas treated with modulated radiotherapy: Learning curve.
Authors: Basu Trinanjan , Karpe Ashay , Kendre Pradip , Nayek Deepika , Rao Satish , Ambulkar Indu B
Published: October 2019

107

Background: Geriatric head and neck squamous carcinomas (GHNC) treatment remains challenging due to multiple patient and treatment related factors. We analysed preliminary data for seventy HNC patients beyond 70 years of age treated by modulated radiotherapy (MRT). The objective was to realise the learning curve ahead. Methods: There were 70 patients (M:56,F:14) with median age of 78 years (70-96) treated by MRT at our centre. They were analysed for efficacy and acute side effects. Besides demographic and disease related parameters compliance to treatment, rate of hospitalisation, dependency of WHO ladder 3 analgesia and early clinico-radiological outcomes were analysed. Results: The median follow up was 12 months. 65% patients were locally advanced stage and 65% received radical MRT. For radical MRT the dose ranged between 66-70 Gy in 30-33 fractions and 5 patients received palliative MRT. 83% completed intended treatment with 30% had MRT interruptions. 48% patients required hospitalisation. 60% had comorbidities with 35% two or more types. 13 patients had concurrent chemotherapy and 48% had hospitalisation and 60% had feeding tubes.65% and 30% had post MRT endoscopic evaluation and imaging respectively. Among them 80% are loco-regionally controlled. 30% patients are long term (more than 3 months) tube dependent and morphine dependent. There were 5 deaths while on MRT both due to associated cardiac and pulmonary comorbidities. 40% and 65% of palliative and radical MRT patients respectively had complete response post MRT. All patients underwent psychological counselling and dietician evaluation. The median G8 screening score was 15. Conclusions: GHNC are a unique group with its own challenge. The learning curve was need of specialised setting and modern MRT for effective outcome. Non disease related concerns like alteration in daily quality of life, social engagement related issues, dementia and end of life care emerged as prominent issues beyond disease control.
Development of expert system that improve the decision-making process with an emphasis on health-related quality of life in elderly patients with a colon cancer.
Authors: Shilo Polina , Kanina Aleksandra
Published: October 2019

113

Background: Health-Related Quality of Life (HRQoL) is an important issue for elderly patients with colon cancer. We created the expert system which allows to predict low level of HRQoL and accessed it’s quality by using several simulation studies. Methods: We performed a systematic review to figure out the known factors associated with low level of HRQoL in elderly colon cancer patients. The searches were performed in PubMed. We accessed the possible impact of several factors affecting HRQoL, including symptoms, comorbidities and treatment toxicity. All relevant factors were included in prediction model. We assigned the different weights to different factors based on evaluation of clinical studies to develop the logistic regression and Markov stochastic model later. As we needed a binary dependent variable we performed the ROC analysis to figure out an optimal cutoff of HRQoL. Then we simulated a partly virtual dataset based on elderly colon cancer patients diagnosed in Davidovskiy Hospital to evaluate the prediction model quality. All statistical calculations were performed in RStudio. The simulation part was performed using simFrame R package. Results: Twenty two studies with a total number of 2516 patients were included in our systematic review. The 39 factors with different weights were included prediction model with different weights assigned. The weights range varied from 1 to 18.6. The adjusted proportion of summary score's variance (R2 ) varied from 0.09 to 0.47 in univariate analysis. The final logistic regression model quality was moderate: the Nagelkerke R-square coefficient was 57.9. However, the developed model showed a 76% sensitivity and 61% specificity in predicting of lower HRQoL level. Conclusions: Our prediction model allows to prospectively manage of elderly colon cancer patients, making the emphasis on HRQoL. However, the present study has some restrictions: simulation nature of internal validation, possible underestimating of the rare events impact. The long-term comprehensive approach with external validation using large real data analysis is needed to evaluate our prediction model.
Irreversible electroporation followed by chemotherapy vs. chemotherapy alone for locally advanced pancreatic cancer: A large cohort propensity score analysis.
Authors: He Chaobin , Li Shengping
Published: October 2019

117

Background: Locally advanced pancreatic cancer (LAPC) has a dismal prognosis with the standard chemotherapy and the local progression contributed to nearly one-third of deaths of these patients. Irreversible electroporation (IRE) is a local destructive method which is feasible for the treatment of LAPC. The aim of this study was to evaluate IRE combined with chemotherapy as a new treatment and compared its efficacy with that of chemotherapy alone for LAPC patients. Methods: Data of LAPC patients who received chemotherapy combined IRE or not were extracted from database of the Surveillance, Epidemiology, and End Results (SEER) and Sun Yat-sen University Cancer Center (SYSUCC). The efficacy of these two treatments was compared based on data analyzed with propensity score matching (PSM) analysis. Results: In all, 3515 LAPC patients from SEER database were included, including 3348 patients received chemotherapy and 167 patients received combination therapy of IRE and chemotherapy. Additionally, 36 patients who received IRE plus chemotherapy and another 96 patients who received chemotherapy from the SYSUCC were included. After PSM, survival rates were compared between two groups. Patients in combination group achieved better survival than those in chemotherapy group [SEER: overall survival (OS), 16.0 months (95% CI, 12.0-21.0) vs 9.0 months (95% CI, 7.2-11.6), P < 0.001; SYSUCC: OS, 21.6 months (95% CI, 17.8-25.3) vs 7.1 months (95% CI, 5.4-9.5), P = 0.006]. Moreover, similar better results in terms of cancer-specific survival (CSS) and progression-free survival (PFS) were observed in patients who received combination therapy compared with chemotherapy alone. IRE combined with chemotherapy was shown as a favorable factor for OS, CSS and PFS in LAPC patients. Conclusions: Patients with LAPC who received IRE combined with chemotherapy had better survival compared with those after chemotherapy treatment alone. This combination method may be a more suitable way of treatment for patients with LAPC.
Differences in prognosis by p53 expression after neoadjuvant chemotherapy in triple-negative breast cancer.
Authors: Jung Seung Pil , Bae Soo Youn , Lee Jeong Hyeon , Bae Joung Won
Published: October 2019

119

Background: Triple negative breast cancer (TNBC) exhibits a higher rate of early recurrence and more aggressive behavior. Despite unfavorable prognoses, TNBCs are known to be highly reactive to chemotherapy and show higher pathologic complete response rates after neoadjuvant chemotherapy. However, TNBC patients with residual cancer have significantly worse prognoses than patients with non-TNBC associated residual cancer. TP53 mutations are the most common genetic alterations in breast cancer and are highly linked to basal subtype carcinomas. Past studies have investigated if TP53 mutation can predict the response of cancer to chemotherapy or affect a difference in prognosis; however, the lack of consistent results has hampered clinical applications. Because immunostaining studies can be easily performed, those results may be more useful until Next generation sequencing results are clinically applicable. The aim of this study was to determine whether p53 expression in TNBC could predict the response to neoadjuvant chemotherapy and the resulting prognosis. Methods: From 2009 to 2017, TNBC patients who underwent neoadjuvant chemotherapy were reviewed, including a total of 31 TNBC patients who had clinical lymph node metastasis. The status of p53 expression in patients before and after chemotherapy was evaluated. Results: Two patients (22.2%, 2/9) achieved pCR in p53(+) TNBC and four patients (50%, 5/10) achieved pCR in p53(-) TNBC. There was no correlation between pCR rate and p53 expression ( P= 0.350). Based on pre-chemotherapy p53 expression, there was no significant difference in DFS between p53(+) TNBC and p53(-) TNBC ( P= 0.335) . However, after chemotherapy, p53(+) TNBC had shown higher DFS than p53(-) TBNC ( P= 0.099). Based on pre-chemotherapy p53 expression, p53(+) TNBC had better OS than p53(-) TNBC, but the difference was not statistically significant ( P= 0.082). After chemotherapy, p53(+) TNBC showed significantly better OS than p53(-) TNBC ( P = 0.018). Conclusions: Immunohistochemically detected p53 expression in TNBC could not predict the response to neoadjuvant chemotherapy. However, p53 (+) TNBC had a better OS than p53 (-) TNBC in patients who underwent neoadjuvant chemotherapy.
A SEER population analysis of stage IB resected gastric cancer: Who can benefit from adjuvant therapy?
Authors: Wang Yue
Published: October 2019

122

Background: The benefit of adjuvant therapy (AT) remains controversial in stage IB gastric cancer (GC). This study aimed to offer a reference for the rational indications of AT. Methods: We retrospectively included 1935 stage IB GC patients who experienced curative surgery from the SEER database between 2004 and 2015. These patients were allocated into two groups: Group AT and Group surgery alone (Group SA). Risk factors associated with AT were examined using univariate/multivariate analyses. A nomogram to project overall survival (OS) of AT was established and internally validated. Results: Five variables, which were significantly related with OS of AT, were incorporated in the nomogram. These variables were sex, age, examined lymph nodes, tumor site, and family income. The C-index of the model was 0.636 and the calibration curve showed that the anticipated values were in accordance with the actual values. The decision curve demonstrated that the optimal clinical impact was achieved when the threshold possibility was 0-47%. Then the entire cohort was separated into low-risk (≤107 points) as well as high-risk ( > 107 points) groups based on the projected 5-year OS. Group SA revealed a significantly poorer OS than Group AT for high-risk patients (P < 0.001); on the other hand, there was a comparable OS for low-risk patients (P = 0.067). Conclusions: We have developed an effective, intuitional and applied prognostic tool based on nomogram to clinical decision-making. For stage IB GC after surgical resection, AT was only recommended for high-risk patients. However, AT may be dispensable for low-risk patients.
Sensitization of immunotherapeutic efficiency in HCC by polyinosinic-polycytidylic acid-triggered CXCL10 secretion in liver sinusoidal endothelial cells.
Authors: Wen Liang , Liang Tingbo , Bai Xueli , Zhao Jianhui
Published: October 2019

126

Background: Nowadays, the efficiency of immune checkpoint blockades (ICBs) in the treatment of advanced hepatocellular carcinoma (HCC) was low. The previous study we published in Hepatology demonstrated that polyinosinic-polycytidylic acid (PolyIC), a TLR3 agonist, could trigger the accumulation, proliferation and activation of CTLs, which contributes to the enhanced anti-tumor efficiency of PD-L1 Ab in HCC. However, the mechanism remains unclear. Methods: The mouse HCC model was established by hydrodynamic transfection of combinational c-Myc/N-Ras oncogenes. PolyIC, CTLA-4 Ab, PD-L1 Ab, CD8 Ab and CXCR3 Ab were all intraperitoneal injected. Mice liver non-parenchymal cells (NPCs) were isolated after liver perfusion and multistep centrifugation. The proliferation, activation and cytotoxic function of CTLs were assessed by flow cytometry. Liver sinusoidal endothelial cells (LSECs) were isolated by magnetic cell sorting. Expressions of TLR3 and CXCL10 were quantitatively analyzed by qRT-PCR and ELISA. LSECs were cultured in vitro by using DMEM medium. Results: Combination of polyIC and PD-L1 Ab (or CTLA-4 Ab) had a synergistic anti-tumor effect on the treatment of mouse HCC. PolyIC induced the accumulation, proliferation, activation and cytotoxic function of CTLs in liver, which were further enhanced when combined ICBs. And CTLs depletion by CD8 Ab attenuated the synergistic anti-tumor effect of polyIC when combined with ICBs. TLR3 expression was much higher in NPCs than other cells in liver, especially in LSECs. Also, polyIC dramatically induced the expressions of CXCL10 in LSECs both in vivo and in vitro. And in vitro, after treated by polyIC, the CXCL10 expression in the medium and cells were all elevated. What’s more, CXCL10/CXCR3 signaling blockade by CXCR3 Ab attenuated the combinational effects of polyIC and ICBs. Meanwhile, after CXCL10/CXCR3 signaling blockade, the accumulation, proliferation and activation of CTLs were all inhibited. Conclusions: PolyIC specifically targets LSECs to induce CXCL10 expression and secretion, which contributes to the CTLs transformation and enhanced efficiency of ICBs in the treatment of HCC.
Comparison of different images in gross target volume delineating on VX2 nasopharyngeal transplantation tumor models.
Authors: Wen QingLian , Xiang ZhangQiang
Published: October 2019

127

Background: To determine the optimum conditions for diagnosis of nasopharyngeal carcinoma, we established VX2 rabbit model to delineate gross target volume (GTV) in different imaging methods. Methods:The orthotopic nasopharyngeal carcinoma (NPC) was established in sixteen New Zealand rabbits. After 7-days inoculation, the rabbits were examined by CT scanning and then sacrificed for pathological examination. To achieve the best delineation, different GTVs of CT, MRI, 18F-FDG PET/CT, and 18F-FLT PET/CT images were correlated with pathological GTV (GTVp). Results: We found 45% and 60% of the maximum standardized uptake value (SUVmax) as the optimal SUV threshold for the target volume of NPC in 18F-FDG PET/CT and 18F-FLT PET/CT images, respectively (GTVFDG45% and GTVFLT60%). Moreover, the GTVMRI and GTVCT were significantly higher than the GTVp ( P ≤ 0.05), while the GTVFDG45% and especially GTVFLT60% were similar to the GTVp ( R = 0.892 and R = 0.902, respectively; P ≤ 0.001). Conclusions: Notably, the results suggested that 18F-FLT PET/CT could reflect the tumor boundaries more accurately than 18F-FDG PET/CT, MRI and CT, which makes 18F-FLT PET-CT more advantageous for the clinical delineation of the target volume in NPC. Keywords: Nasopharyngeal carcinoma; Gross tumor volume; Magnetic resonance imaging, Computed tomography; 18F-FLT PET/CT; 18F-FDG PET/CT
Ned-170: A combination anti-cancer therapy targeting late stage, heavily pre-treated solid tumor malignancies.
Authors: Garmey Edward Graeme , Meetze Kristan , Martell Bridget
Published: October 2019

141

Background: NED-170 is a 7-component regimen of both marketed drugs and nutraceuticals with established safety and tolerability profiles and antineoplastic activity. These components, including metronomically-dosed cyclophosphamide (CTX), metformin, naltrexone, alpha lipoic acid, genistein, curcumin, and melatonin, target four key pathways driving tumor growth and metastasis. Methods: NED-170 was evaluated pre-clinically for tolerability and efficacy using a murine CT-26 syngeneic xenograft model. After tumor volume reached 80-120 mm³, mice were randomized into three groups of 10. Experimental arms included: NED-170 allometrically scaled to provide comparable exposure to human clinical trial doses, vehicle, CTX alone, or an anti-PD-1 antibody. In parallel to these studies, a compassionate expanded access program (EAP) was established in 2013 as a precursor to formal clinical trials. To date, 21 pts. with stage IIIc/IV advanced solid tumor malignancies (5 ovarian, 6 sarcoma, 4 Br. Ca, 2 NSCLC, & 4 other cancers) who either sought alternatives to standard-of-care (SOC) chemotherapy or whose tumors progressed through available SOC options have been enrolled. Results: In pre-clinical studies, NED-170 demonstrated 78% tumor growth inhibition (TBI) which exceeded vehicle in a statistically significant fashion (p < 0.001). In contrast, anti-PD-1 treatment failed to achieve anti-tumor activity and CTX alone achieved 50% TBI. In parallel, 21 EAP pts. have been treated with a combined 1,217 months (mos.) of NED-170 therapy (median = 11.8 mos; range = 1.0-60.2). For all pts., the regimen has been safe and well-tolerated with no drug-related grade-3-4 adverse events or dose reductions/discontinuations reported. Observational data reported by pts. or physicians demonstrated that 81% of pts. derived benefit and improved quality of life in this late stage setting. Conclusions: Based on these encouraging data, NED-170 may provide late stage cancer pts. with a safe, effective, and lower cost alternative to standard chemotherapy. A multinational phase 1-2b clinical trial commencing in late 2019 is planned.
Innovations at scale only, capable of offering access to care solution: Example of district cancer care model (Pendharkar model).
Authors: Pendharkar Dinesh , Verma Vijayendra Kumar , Kumar Vinod , Nagar Hemraj , Khatri Sanjay
Published: October 2019

19

Background: Sustainable development goals and voluntary global NCD targets 2025 plan to achieve 80% coverage by essential NCD medicines and technologies and drug therapy and counselling coverage to the tune of 50%. This can only be achieved by making coverage wider, going to periphery and urgently creating workforce capable of doing such an activity at scale. District cancer care model (Pendharkar model) tried to involve these principles and shown a scalable acceptance by the health system. Methods: To expand the access administratively, most peripheral but medically most suitable, district hospitals, were used to create nodal cancer units. To achieve the scale, all districts of a state were targeted. For creating an alternate workforce existing medical officers and nurses were utilised. Results: Over a period of 5 years seven states of India, having a population of more than 250 million, have agreed to join the programme.176 districts have created nodal cancer units with physician and two nurses in-charge of the programme. They delivery variety of care including counselling, chemotherapy, supportive, palliative, follow up care. They serve as nodal units for public education driving government programmes including public education. At least 300-500 patients avail the services on a daily basis, including more than 200 chemotherapy procedures in a day. On world cancer day educational activities happened in all these districts simultaneously creating massive impact. Conclusions: This unique innovative model has proven that health system changes can be brought at very large scale using existing government possibilities. Available infrastructure, human resource, minimal financial changes with administrative reforms can lead to impactful change in access to cancer care at scale.
Mutational analysis of >14,000 NGS tests from community oncology practices: The Sarah Cannon molecular landscape.
Authors: Burris III Howard A. , Schlauch Daniel , Sharma Yasha , Picard Shaita , Higgins Connor , Misch Amanda , Lachs Rebecca , O'Connor Niall , Correll Mick , Spigel David R. , Jones Suzanne Fields , Dilks Holli Hutcheson , McKenzie Andrew
Published: October 2019

26

Background: Utilization of NGS-based testing for patients in community oncology settings continues to grow. A comprehensive analysis of the molecular landscape of > 14,000 patients with commercial tissue-based and plasma-based NGS (tbNGS and pbNGS) testing from Sarah Cannon’s (SC) network of community oncologists between 2012 and 2018 was performed. These data aid clinical trial design/feasibility and identify rare and actionable mutations in the community oncology setting. Methods: Medical Oncologists in the SC network ordered NGS-based molecular profiling for their patients as standard of care. Data from multiple commercial vendors starting in 2012 were harmonized and analyzed. Results: On average, tbNGS (n = 8938) and pbNGS (n = 5419) tests revealed 14 and 4 mutations/sample, respectively. The top 10 mutated genes from both tbNGS and pbNGS - tests are in the table. The most predominant mutation-types detected were SNVs in both tbNGS and pbNGS tests, and gene amplifications were detected in ~40% of tbNGS and ~22% of pbNGS tests. MET amplifications (range: 2 - 40 copies (pbNGS) and 6 - 82 copies (tbNGS)) and ERBB2 amplifications (range: 2.1 - 90.2 copies (pbNGS) and 4 - 293 copies (tbNGS)) were detected in 1.6% (MET-tbNGS) and 4.6% (MET-pbNGS) and 4.2% (ERBB2-tbNGS) and 2.69% (ERBB2-pbNGS) of patients, respectively, and informed clinical trial enrollment. Of the fusions detected, 28 NTRK rearrangements were detected (NTRK1 – 16, NTRK2 – 5, NTRK3 – 7) by tissue-based testing and 3 (NTRK1) fusions were detected by plasma-based tests. Conclusions: These data describe the mutational landscape of NGS tests ordered within community oncology practices. SC’s data infrastructure links NGS-based testing data and clinical data to support real world evidence research, and highlights the need for healthcare IT systems to marry clinical and genomic data for clinical decision support and clinical research. [Table: see text]
Carcinoembryonic antigen (CEA) as a candidate prognostic marker of nonmucinous pneumonic adenocarcinoma (P-ADC) of the lung.
Authors: Nakamura Satoru , Fukuda Minoru
Published: October 2019

28

Background: Serum level of CEA as a prognostic marker in NSCLC is well known. In patients with non-mucinous P-ADC, there were some paradoxical cases with high CEA, in spite of improved symptom and chest X-ray after chemotherapy including first-generation EGFR-TKI. Methods: We retrospectively comfirmed serum level of CEA of five patients, including four patients with non-mucinous P-ADC and one patient with mucinous P-ADC, between 2001-2007, all Japanese female without smoking history, 66-78 years old (mean 73.6 y.o.). All of them revealed abnormal pneumonic shadow on chest X-ray, and were diagnosed by TBLB or cytology. These cases were all stage IIIB or IV, and were applied to chemotherapy including first-generation EGFR-TKI. We had measured serum CEA as possible from initial diagnosis and pre or post chemotherapy including first-generation EGFR-TKI to death. OS were between 25~66 months with four patients of non-mucinous P-ADC, and 9 month with one patient of mucinous P-ADC. Other tumor marker such as CYFRA and Pro GRP were all almost normal range. Results: CEA of three patients with non-mucinous P-ADC was elevated according to worsened symptom and X-ray, and were all highly maintained or increased in spite of improved symptom and X-ray after chemotherapy including first-generation EGFR-TKI. CEA of one patient with non-mucinous P-ADC was normal range in initial diagnosis, and no more measured. She has got symptom free and improved chest X-ray after chemotherapy. In one patient with mucinous P-ADC, serum CEA was normal range, so no longer measured. This patient was no effective for chemotherapy, and was dead 9 month after the initial diagnosis. Number of cases was quite few, so further examination is favorable. Furthermore, All cases were exaggerated finally, they might be resistant to first-generation EGFR-TKI. Conclusions: In three patients with non-mucinous P-ADC of the lung, serum CEA was paradoxically highly maintained or elevated in spite of improved symptom and chest X-ray after chemotherapy including first-generation EGFR-TKI. Therefore, serum CEA is a candidate for useful prognostic marker of non-mucimous P-ADC of the lung.
Validation and utilization of NGS-based HEMEaccuTest panel and analysis software for hematological malignancies.
Authors: Choi Hyun-Jeung , Lee In-Seon , Lee Min Kyoung , Jung Kyongyong , Lee Keunsook Kathy , Moon YoungJoon , Kim Kwang Joong
Published: October 2019

29

Background: Hematological malignancies are forms of cancer that originates in blood-forming tissue, such as bone marrow, or in the cells of the immune system. Detection of genetic alteration in hematological malignancies are increasingly important because of diverse variants associated with classification and diagnosis of subtypes, and prognostic and therapeutic-response prediction. Next-generation sequencing (NGS) is a powerful technology to simultaneously analyze multiple genes to identify clinically well-described variants, as well as rare variants related to hematological malignancies for clinical diagnostics. Methods: We developed the targeted NGS panel (HEMEaccuTest) and automatic analysis software (NGeneAnalySys) for estimating pathogenicity of genetic variants related to hematological malignancies. HEMEaccuTest covers entire coding region of 108 genes that have putatively known for associations with the diseases according to the WHO, NCCN and ELN guidelines. The diagnostic utility of HEMEaccuTest and NGeneAnalySys were validated using reference materials and clinical specimens. Results: The results showed that pathogenic variants were effectively detected with an average coverage depth of 600X and a minimum coverage depth of 100X. It demonstrated an excellent limit of detection, with 100% sensitivity for SNVs at 2% VAF and for indel at 4% VAF. In addition, the analytical sensitivity, specificity and precision of the panel were higher compared to conventional methods such as Sanger sequencing, FISH, and real-time PCR. Noticeably, the approximately 300-bp-size insertions of FLT3-ITD was efficiently detected by a simulating algorithm. Conclusions: This analytical validation study demonstrated that HEMEaccuTest and NGeneAnalySys can be an excellent and useful tool for disease definition and therapeutic strategy in hematological malignancies. NGeneAnalySys provides the evidence-based categorization and clinical interpretation supported by Tier classification (Therapeutic, Prognostic, Diagnostic) of professional guidelines (ACMG/AMP, AMP/ASCO/CAP. etc).
Predicting survival in advanced cancers by applying machine learning to clinical narratives.
Authors: Lin Frank Po-Yen , Jameson Michael B. , Epstein Richard J.
Published: October 2019

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Background: We previously showed that a text mining approach can identify clinical prognostic factors from electronic medical records (EMR) in patients with advanced cancers (1). Here we further examine whether clinical narratives can be exploited to build prognostic tools by applying a machine-learning (ML) approach. Methods: A retrospective study of all patients with stage IV tumors was conducted at a single tertiary cancer centre. The text corpus was formed by extracting narratives from initial consultation letters authored by oncologists, and a feature learning pipeline (2) was then used to extract text features correlating to survival. Five classes of ML algorithms was then applied for survival prediction. Classification performance was assessed by stratified cross-validation and compared with Eastern Cooperative Oncology Group (ECOG) performance scores. Results: EMR were available for analysis in 4791 of 7043 patients from 2001-2017, and in 2211 of these cases ECOG performance scores were available. By applying ML on features extracted from EMR text, survival of patients at 2, 6, 12, 26, 52, and 80 weeks was predicted, with areas under the receiver operating characteristic (ROC) curve of 0.82, 0.80, 0.77, 0.72, 0.72, and 0.76 respectively. ML outperformed ECOG score in predicting patient prognosis between 12-16 weeks ( p < 0.05) and after 52 weeks ( p < 0.05), and was non-inferior at all other time points. Random forest was the best algorithm for the prognostic classification task. Feature filtering threshold was important to classification accuracy ( p < 0.001). Conclusions: In patients with advanced cancers, ML analysis of clinical narratives can be used to automate prognostication with greater accuracy than is currently obtainable from ECOG status. References: 1. Int Med J 2018; 48: S5: 8, 2. Sci Rep 2017; 7: 6918.
AI oncology algorithm and dynamic real-world learning health care system for precision oncology.
Authors: Petak Istvan , Hegedus Csilla , Tihanyi Dora , Doczi Robert , Filotas Peter , Mate Attila , Bacskai Miklos , Schwab Richard , Valyi-Nagy Istvan T.
Published: October 2019

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Background: Most tumours harbor multiple driver genetic alterations and many driver alterations are linked to multiple targeted therapies with various level of evidence. In addition, a specific treatment can be linked to multiple genetic alterations in the same tumor. Several public and private databases and software solutions are available to link driver alterations to treatments options, but in clinical practice of precision oncology we need a solution to select the right treatment for our patients based on the highest level of evidence also in case of complex molecular profiles. Methods: We have developed an AI oncology algorithm and rule-engine to prioritise treatment options for every cancer patient based on the individual molecular of their tumor. This IT solution can now prioritise 1200 compounds in clinical use or clinical development based on the computing of 24,000 evidence-based associations (“rules”) between drivers, targets and compounds. The software calculates a numeric score, the “aggregated evidence level” for each driver alterations and compounds. We have linked this decision support software to a dynamic patient case management system, which records responds to therapy to create learning system to provide dynamic decision support through several lines of therapies of each patient and to use real-life evidence to further improve the algorithm. Results: Our first results indicate that system allows individualised decision of diagnostic option between single gene tests to comprehensive 600 gene NGS panels and identification of actionable alterations in 83% of cancer cases. Conclusions: This system can be a first working solution to standardise clinical decisions precision oncology, which also helps the real-life evaluation of novel multigene molecular diagnostic tests and therapies to find their best indications and accelerate their reimbursement by insurance companies and national health funds.
Pattern of expression of CDX2 in colorectal cancer and its role in prognosis.
Authors: Singh Jagdeep
Published: October 2019

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Background: CDX2 (Caudal Homeobox2), a nuclear protein, is essential for the proliferation and development of intestinal epithelial cells and is frequently down-regulated during tumorigenesis. We have evaluated the pattern of expression of CDX2 in all stages of CRC (Colorectal Cancer) and its association with prognosis. Methods: We performed CDX2 staining by immunohistochemistry (IHC) on the available biopsy block of patients of CRC registered with Medical Oncology, JIPMER, from January 2014-January 2018. CDX2 scoring was done in semi-quantitative method. Results: 286 patients were registered during this period, of which only 110 biopsy blocks were available for staining. Of 110 patients, 77 (70%) constituted colon cancer and 33(30%) were rectal cancer. The median age was 54.2 years, 62 (56.4%) being male and 48 (43.6%) female with male to female ratio 1.3:1. In the study cohort, 33(30%) patients had stage II, 30 (27.3%) stage III and 47(42.7%) were stage IV. 73 (66.4%) were positive for CDX2 and 37 (33.4%) were negative. Lack of CDX2 was significantly associated with advanced stage, rectal site, poor grade of differentiation and presence of lympho-vascular invasion (LVSI). With median follow-up of 16 months, PFS (progression free survival) at 2 years was 30% for CDX2 negative compared to 67% for CDX2 positive (P = 0.009), while OS (overall survival) ) at 2 years was 46% for CDX2 negative versus 77% for positive (P = 0.01). Conclusions: Lack of CDX2 is associated with significantly worse PFS and OS, serves as poor prognostic factor in CRC. Lack of CDX2 expression is associated with advanced stage, higher tumor grade and presence of LVSI.
Genetic mutations associated with lung cancer metastasis to the brain.
Authors: Su ChunXia , Zhou Juan , Chu Xiangling , Zhao Jing
Published: October 2019

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Background: Lung cancer is the most common cause of mortality in both men and women, accounting for one-quarter of all cancer deaths. Most lung cancer-associated deaths result from metastasis, especially brain metastasis. Metastasis associated mutations are important biomarkers for metastasis prediction and outcome improvement. The current study aimed to reveal the molecular mechanisms and the genetic alterations involved in metastasis from lung tumors to the brain. Methods: We carried out whole exome sequencing (WES) of the primary tumors and the corresponding brain metastases from 15 patients with metastatic non-small-cell lung carcinoma. Results: We identified novel lung cancer metastases associated genes (CHEK2P2, BAGE2, AHNAK2) and epigenetic factors (miR-4436A, miR-6077). Lung-brain metastasis samples have more similar Ti/Tv(transition/transversion) profile with brain cancer. Focal adhesion, PI3K-Akt signaling pathway, MAPK signaling pathway are some of the most important tumor onset and metastasis pathways. Alternative splicing, Methylation and EGF-like domain are important metabolic abnormal for the lung-metastasis cancers. Conclusions: We conducted a pairwise lung-brain metastasis based WES and identified some novel metastasis related mutations which provided potential biomarkers for prognosis and targeted therapeutics.
Expression of CD47 and CALR in myeloproliferative neoplasms: Potential new therapeutic targets.
Authors: Rinaldi Ciro Roberto , Boasman Kristian , Simmonds Matthew
Published: October 2019

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Background: In solid tumours, calreticulin (CALR) overexpression produces a pro-phagocytic signal and is counteracted by concomitant expression of anti- phagocytic CD47, reflecting an apoptosis vs survival mechanism. Increases of both CALR and CD47 on the cell membrane have been observed in response to chemotherapy, however their role in myeloid malignancies is poorly understood. We investigated the expression of CALR and CD47 in patients with essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF). Methods: Mononuclear cells were collected from peripheral blood of 27 MPN patients (8 PV, 16 ET, 3 MF), and from 4 controls. In total 14 patients received cyto-reductive therapies (Hydroxyurea, Anagrelide and Ruxolitinib). Cells were fractionised into 4 compartments: membrane, cytoplasm, cytosol and nucleus. Proteins were extracted using TRIzol, with CALR and CD47 protein expression analysed by western blotting. Results: Total CALR and CD47 protein expression increased in MPN samples comparing with controls (CALR- 7.9 vs 5.1; CD47- 2.7 vs 2.2 fold). CD47 showed higher expression on MPN cells membranes when compared with CALR (22% vs 13.9%). We observed a significant reduction of CALR when patients are treated with cyto-reductive agents (ET- untreated 43.3% vs treated 2%, PV- 3.6% vs 2.2%, ET- 21% vs 11%). Interestingly we have observed a significant increase in CD47 after treatment in MF and PV (CD47 in MF- untreated 11.8% vs treated 34.3%, PV-11.4% vs 35.9%), suggesting an anti-phagocytic effect induced by cytotoxic drugs. In ET however, CD47 expression is reduced after treatment (22% vs 16.6%), suggesting instead a pro-phagocytic effect. Conclusions: CD47, is overexpressed on the membrane of patients with MPN suggesting a role for CD47 as a strong anti-phagocytic signal responsible for immune survival in MPN. MPN patients decreased CALR expression during therapy, but we observed a significant difference in CD47 expression in different MPN types. Anti-CD47 antibodies could represent a new strategy to enhance the pro-phagocytic signal via increasing the CALR expression, and in combination with standard cyto-reduction therapy, might represent a new therapeutical strategy in MPN.