A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics.

BACKGROUND: Although several experimental therapeutics for Ebola virus disease (EVD) have been developed, the safety and efficacy of the most promising therapies need to be assessed in the context of a randomized, controlled trial. METHODS: We conducted a trial of four investigational therapies for EVD in the Democratic Republic of Congo, where an outbreak began in August 2018. Patients of any age who had a positive result for Ebola virus RNA on reverse-transcriptase-polymerase-chain-reaction assay were enrolled. All patients received standard care and were randomly assigned in a 1:1:1:1 ratio to intravenous administration of the triple monoclonal antibody ZMapp (the control group), the antiviral agent remdesivir, the single monoclonal antibody MAb114, or the triple monoclonal antibody REGN-EB3. The REGN-EB3 group was added in a later version of the protocol, so data from these patients were compared with those of patients in the ZMapp group who were enrolled at or after the time the REGN-EB3 group was added (the ZMapp subgroup). The primary end point was death at 28 days. RESULTS: A total of 681 patients were enrolled from November 20, 2018, to August 9, 2019, at which time the data and safety monitoring board recommended that patients be assigned only to the MAb114 and REGN-EB3 groups for the remainder of the trial; the recommendation was based on the results of an interim analysis that showed superiority of these groups to ZMapp and remdesivir with respect to mortality. At 28 days, death had occurred in 61 of 174 patients (35.1%) in the MAb114 group, as compared with 84 of 169 (49.7%) in the ZMapp group (P = 0.007), and in 52 of 155 (33.5%) in the REGN-EB3 group, as compared with 79 of 154 (51.3%) in the ZMapp subgroup (P = 0.002). A shorter duration of symptoms before admission and lower baseline values for viral load and for serum creatinine and aminotransferase levels each correlated with improved survival. Four serious adverse events were judged to be potentially related to the trial drugs. CONCLUSIONS: Both MAb114 and REGN-EB3 were superior to ZMapp in reducing mortality from EVD. Scientifically and ethically sound clinical research can be conducted during disease outbreaks and can help inform the outbreak response. (Funded by the National Institute of Allergy and Infectious Diseases and others; PALM ClinicalTrials.gov number, NCT03719586.).

Interactions between cardiology and oncology drugs in precision cardio-oncology.

Recent advances in treatment have transformed the management of cancer. Despite these advances, cardiovascular disease remains a leading cause of death in cancer survivors. Cardio-oncology has recently evolved as a subspecialty to prevent, diagnose, and manage cardiovascular side effects of antineoplastic therapy. An emphasis on optimal management of comorbidities and close attention to drug interactions are important in cardio-oncologic care. With interdisciplinary collaboration among oncologists, cardiologists, and pharmacists, there is potential to prevent and reduce drug-related toxicities of treatments. The cytochrome P450 (CYP450) family of enzymes and the P-glycoprotein (P-g) transporter play a crucial role in drug metabolism and drug resistance. Here we discuss the role of CYP450 and P-g in drug interactions in the field of cardio-oncology, provide an overview of the cardiotoxicity of a spectrum of cancer agents, highlight the role of precision medicine, and encourage a multidisciplinary treatment approach for patients with cancer.

Indoleamine 2,3-Dioxygenase-1 Expression in Adrenocortical Carcinoma.

BACKGROUND: Indoleamine 2,3-dioxygenase 1 (IDO-1) is overexpressed in many human carcinomas and a successful target for therapy in mouse models. Prognosis of patients with advanced adrenocortical carcinoma (ACC) is poor due to the lack of effective treatments, and new therapies are therefore needed. Herein, we investigate whether IDO-1 is expressed in human ACC tissues. METHODS: 53 tissue samples from patients with ACC, adrenal adenoma (AA), adrenocortical tumors (ACTs), and normal adrenal were identified. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded slides for IDO-1. Samples were scored for cytoplasmic staining as per intensity and the percent of positive cells and for stromal staining by percent of positive cells. Tumor characteristics, PD-L1, PDL-2, and CD-8+ T-lymphocyte expression were also determined. RESULTS: Samples from 32 ACC, 3 ACT, 15 AA, and 3 normal adrenal were analyzed. IDO-1 was expressed in tumor tissue in 22 of 32 ACC samples, compared with 8 of 15 AA sample (P = 0.344). IDO-1 expression was significantly increased in stromal tissue of ACC samples (16 of 33), compared with AA samples (0 of 15) (P = 0.001). IDO-1 expression in ACC and AA samples was associated with PD-L2 expression (P = 0.034). IDO-1 expression in ACC stromal tissue was associated with CD8+ T-lymphocyte infiltration (P = 0.028). CONCLUSIONS: IDO-1 is expressed in a majority of ACC samples. Its expression in tumor tissue is associated with PD-L2 expression, and expression in stroma is associated with CD8+ cell infiltration. IDO-1 inhibition, alone or in combination with PD-1 inhibition, could therefore be an interesting target in treatment of ACC.

Should 68Ga-DOTATATE PET/CT be Performed Routinely in Patients with Neuroendocrine Tumors Before Surgical Resection?

BACKGROUND: The only potential cure for neuroendocrine tumors (NETs) is operative resection, which may also offer a survival benefit for advanced disease. We aimed to assess the role of 68Ga-DOTATATE PET/CT in preoperative planning and compared its performance to CT with IV contrast and MRI with Eovist®, for abdominal NETs. METHODS: Records of patients who underwent 68Ga-DOTATATE PET/CT in addition to MRI with Eovist® and/or CT with IV contrast were retrospectively evaluated. The effect of imaging findings on surgical management and characteristics of detected lesions were analyzed. Descriptive statistics were used. RESULTS: Of 21 patients who underwent 68Ga-DOTATATE PET/CT prior to surgical resection, five (24%) had a change in surgical management due to findings. In three patients, 68Ga-DOTATATE PET/CT identified the primary tumor. In two patients, 68Ga-DOTATATE PET/CT helped clarify equivocal hepatic lesions seen on MRI with Eovist®. MRI with Eovist® had the highest number of lesions found (median 13, versus 9 on CT and 9.5 on 68Ga-DOTATATE PET/CT). DOTATATE-avid lesions were on average larger than lesions seen only on MRI with Eovist® (1.6 cm versus 0.6 cm, p = 0.0002). The optimal cutoff point for detection by 68Ga-DOTATATE PET/CT was a size of 0.95 cm, with a sensitivity of 56% and specificity of 98%. CONCLUSIONS: Preoperative 68Ga-DOTATATE PET/CT is useful only in a subset of patients undergoing surgical resection for NETs. MRI with Eovist® is superior at identifying liver metastases when compared to 68Ga-DOTATATE PET/CT and should therefore be used routinely before hepatic cytoreduction of NETs.

A Randomized, Controlled Trial of ZMapp for Ebola Virus Infection.

BACKGROUND: Data from studies in nonhuman primates suggest that the triple monoclonal antibody cocktail ZMapp is a promising immune-based treatment for Ebola virus disease (EVD). METHODS: Beginning in March 2015, we conducted a randomized, controlled trial of ZMapp plus the current standard of care as compared with the current standard of care alone in patients with EVD that was diagnosed in West Africa by polymerase-chain-reaction (PCR) assay. Eligible patients of any age were randomly assigned in a 1:1 ratio to receive either the current standard of care or the current standard of care plus three intravenous infusions of ZMapp (50 mg per kilogram of body weight, administered every third day). Patients were stratified according to baseline PCR cycle-threshold value for the virus (≤22 vs. >22) and country of enrollment. Oral favipiravir was part of the current standard of care in Guinea. The primary end point was mortality at 28 days. RESULTS: A total of 72 patients were enrolled at sites in Liberia, Sierra Leone, Guinea, and the United States. Of the 71 patients who could be evaluated, 21 died, representing an overall case fatality rate of 30%. Death occurred in 13 of 35 patients (37%) who received the current standard of care alone and in 8 of 36 patients (22%) who received the current standard of care plus ZMapp. The observed posterior probability that ZMapp plus the current standard of care was superior to the current standard of care alone was 91.2%, falling short of the prespecified threshold of 97.5%. Frequentist analyses yielded similar results (absolute difference in mortality with ZMapp, -15 percentage points; 95% confidence interval, -36 to 7). Baseline viral load was strongly predictive of both mortality and duration of hospitalization in all age groups. CONCLUSIONS: In this randomized, controlled trial of a putative therapeutic agent for EVD, although the estimated effect of ZMapp appeared to be beneficial, the result did not meet the prespecified statistical threshold for efficacy. (Funded by the National Institute of Allergy and Infectious Diseases and others; PREVAIL II ClinicalTrials.gov number, NCT02363322 .).

Medical planning for very large events: Special Olympics World Games Los Angeles 2015.

Mass gathering events that involve special populations have challenges that require unique medical planning. The key to a successful mass event is in the preparation, planning, and communication. Concerns in communication such as language barriers, age of participants, and intellectual disability should be addressed early in the planning. In the event of a mass casualty disaster, there should be a clear chain of command and escalation policy. The primary concern of the sports medicine team is to ensure safety for the participation of an athlete. The risk of injury to an athlete varies depending on the event and venue. The sporting venue may require special consideration for access to athletes, crowd control, and ingress/egress of medical personnel and transports. In order to ensure safety and efficient care, it is paramount to have the necessary medical planning and preparedness to manage a large-scale sporting event.

2,3-Diphenyl-1,3-thia-zolidin-4-one.

The title compound, C15H13NOS, is a chiral mol-ecule crystallized as a racemate, with two molecules in the asymmetric unit. In each of the mol-ecules, the five-membered thia-zine ring has an envelope conformation, with the S atom forming the flap. In one mol-ecule, the angle between the two phenyl-ring planes is 82.77 (7)°, while in the other it is 89.12 (6)°. In the crystal, mol-ecules are linked into chains along the b-axis direction by C-H⋯O hydrogen bonds.

2-(3-Nitro-phen-yl)-3-phenyl-2,3-di-hydro-4H-1,3-benzo-thia-zin-4-one.

The title compound, C20H14N2O3S, has three aromatic rings, viz. (i) a phenyl ring, (ii) a 3-nitro-phenyl and (iii) a 1,3-benzo-thia-zine fused-ring system. The dihedral angle between (i) and (ii) is 85.31 (15)°, between (ii) and (iii) is 81.33 (15)° and between (i) and (iii) is 75.73 (15)°. The six-membered 1,3-thia-zine ring has an envelope conformation with the C atom in the 2-position forming the flap. In the crystal, mol-ecules are linked by weak C-H⋯O inter-actions, forming a three-dimensional network.

Understanding Opioid Prescribing Practices of Resident Physicians.

BACKGROUND: To compare opioid prescribing practices of resident physicians across a variety of surgical and nonsurgical specialties; to identify factors which influence prescribing practices; and to examine resident utilization of best practice supplemental resources. METHODS: An anonymous survey which assessed prescribing practices was completed by residents from one of several different subspecialties, including internal medicine, obstetrics and gynecology, general surgery, neurosurgery, orthopedic surgery, and urology. Fisher's exact test assessed differences in prescribing practices between specialties. RESULTS: Only 35% of residents reported receiving formal training in safe opioid prescribing. Overall, the most frequently reported influences on prescribing practices were the use of standardized order sets for specific procedures, attending preference, and patient's history of prescribed opioids. Resident physicians significantly underutilize best practice supplemental resources, such as counseling patients on pain expectations prior to prescribing opioid medication; contacting established pain specialists; screening patients for opioid abuse; referring to the Prescription Monitoring Program; and counseling patients on safe disposal of unused pills (P < .001). DISCUSSION: The incorporation of comprehensive prescribing education into resident training and the utilization of standardized order sets can promote safe opioid prescribing.

Effectiveness and Clinical Usefulness of Electronic Agenda-setting in Psychiatric Practices: A South Texas Psychiatric PBRN Study.

There is a general consensus that the doctor-patient interview should be as productive and efficient as possible. This is becoming increasingly difficult in a health care insurance system that demands shorter appointment times. Clinicians must therefore find ways to condense the clinical encounter without sacrificing quality. The purposes of this study were: (1) to facilitate shared decision-making between psychiatrist and patient via pre-visit patient agenda-setting, (2) to evaluate the effectiveness and ease of use of the agenda-setting tool, and (3) to determine patient and clinician satisfaction with the clinical encounter. Patients completed questionnaires to assist in agenda-setting via an electronic tablet while in the waiting area before seeing the psychiatrist. Both patients and psychiatrists then completed post-visit questionnaires to assess their satisfaction with the encounter. We measured patient satisfaction and the extent to which the psychiatrist addressed concerns before and after the visit, as well as ease of use for the patient, psychiatrist satisfaction, and clinical helpfulness to the treating psychiatrist. Additional analyses also indicated that there was a significant increase in patient satisfaction scores, compared with an average of all previous visits, and a significant increase in the number of concerns addressed during the current visit when compared with the average number of previous concerns addressed. Patients reported little difficulty using the tablet. Similarly, psychiatrists reported that the device was helpful in the clinical setting and they expressed high levels of satisfaction with the visit. We hope our work will encourage others to use this agenda-setting tool in their practices to facilitate better patient care.

Lessons from an international trial evaluating vaccination strategies for recovered inpatients with COVID-19 (VATICO).

The protection provided by natural versus hybrid immunity from COVID-19 is unclear. We reflect on the challenges from trying to conduct a randomized post-SARS-CoV-2 infection vaccination trial study with rapidly evolving scientific data, vaccination guidelines, varying international policies, difficulties with vaccine availability, vaccine hesitancy, and a constantly evolving virus.

Genetically Encoded Split-Luciferase Biosensors to Measure Endosome Disruption Rapidly in Live Cells.

Endosomal escape is a critical step in the intracellular delivery of biomacromolecular drugs, but a quantitative, high-throughput study of endosomal-vesicle disruption remains elusive. We designed two genetically encoded split-luciferase turn-on reporter assays that can be measured rapidly in well plates on live cells using a luminometer. Both systems use nonluminescent N-terminal and C-terminal luciferase fragments that can reconstitute a functional luminescent enzyme when they are colocalized by their fusion partners. The first system uses luciferase-fragment fusion to Galectin 8 (Gal8) and CALCOCO2. Gal8 and CALCOCO2 interact following endosomal-vesicle disruption to facilitate luciferase complementation into the active enzyme, enabling a luminescence readout (G8C2 system). The second system expresses the N-terminal carbohydrate recognition domain (N-CRD) of Gal8 fused to each luciferase fragment (G8G8 system). Following endosome disruption, G8-NCRD binds to exposed glycans inside endosomes, concentrating both fragments in close proximity and reconstituting active luciferase. The G8G8 system emerged as the lead reporter candidate and was further characterized by comparing it to previously reported Gal8-YFP tracking using microscopy. We also characterized the G8G8 system response to several commercial and research drug-delivery reagents: DOTAP lipid, JetPEI, Lipofectamine 2000, and a library of polymers with known endosomal-escape activity, revealing dose-dependent increases in luminescence due to endosomal disruption. These new reporters provide a first-in-class luminescent assay to rapidly detect endosome disruption in a high-throughput format while excluding toxic formulations. Endosome-disruption screening with these turn-on assays has the potential to accelerate and to improve the rigor of programs focused on the discovery and development of intracellular biologic drug-delivery formulations.

Operative resection in early stage pancreatic neuroendocrine tumors in the United States: Are we over- or undertreating patients?

BACKGROUND: Many current guidelines recommend nonoperative management for pancreatic neuroendocrine tumors <2 cm. The objective of this study was to evaluate the utilization and outcomes of resection for these pancreatic neuroendocrine tumors in the United States. METHODS: Using the National Cancer Database (2004-2014), 3,243 cases of T1 (≤2.0 cm) pancreatic neuroendocrine tumors were identified. Additional patient and tumor characteristics were examined. Multivariate models were used to identify factors that predicted resection and to assess patient survival after resection. RESULTS: 75% of pancreatic neuroendocrine tumors measuring 0 to 1.0 cm and 80% of pancreatic neuroendocrine tumors measuring >1.0 and ≤2.0 cm were resected. Eighty-four pancreatic neuroendocrine tumors were functional, of which 82% were resected. Variables influencing resection included positive lymph nodes, tumor in body or tail of pancreas, well or moderately differentiated tumors, and resection at academic medical centers (odds ratio 1.5-4.9). When controlling for other variables, patients with pancreatic neuroendocrine tumors 1 to 2 cm who underwent resection had a prolonged 5-year survival rate (hazard ratio 0.51, confidence interval 0.34-0.75) when compared with those who did not undergo resection. This survival benefit of resection was not found for pancreatic neuroendocrine tumors 0 to 1 cm (hazard ratio = 0.63, confidence interval 0.36-1.11). CONCLUSIONS: Contrary to many current recommendations, most patients with pancreatic neuroendocrine tumors ≤2.0 cm undergo surgical resection in the United States. A survival benefit was found for resection of pancreatic neuroendocrine tumors 1 to 2 cm, suggesting that current recommendations should perhaps be revised.

Risk factors associated with positive resection margins in patients with adrenocortical carcinoma.

BACKGROUND: Positive resection margins are associated with worse survival after surgery for adrenocortical carcinoma (ACC). We aimed to identify risk factors for positive margins post-resection. METHODS: The NCDB was queried for ACC patients from 2006 to 2015. Patients with positive versus negative resection margins post-surgery were compared using Chi-square tests. Survival based on adjuvant treatment was assessed using Kaplan-Meier curves. RESULTS: 1,973 patients with ACC were identified, 217 (11.0%) with positive margins. Multivariable analysis identified extra-adrenal extension (HR 4.92, p < 0.001), lymph node metastases (HR 2.64, p = 0.001), and distant metastases (HR 1.53, p = 0.03) as risk factors for positive margins. No significant difference in margin status existed between patients who had an open versus minimally invasive procedure (p = 0.6). Positive margin patients receiving adjuvant radiation (p = 0.007) or combined chemo-radiation (p = 0.001) had the longest survival. CONCLUSION: No modifiable risk factors were identified, but patients with positive margins receiving adjuvant radiation or chemo-radiation had the longest survival.

Crystal structure of a 1:1 adduct of tri-phenyl-tin chloride with 3-cyclo-hexhyl-2-phenyl-1,3-thia-zolidin-4-one.

In the centrosymmetric (racemic) title compound, chlorido-(3-cyclo-hexhyl-2-phenyl-1,3-thia-zolidin-4-one-κO)tri-phenyl-tin(IV), [Sn(C6H5)3Cl(C15H19NOS)], the tin(IV) atom exhibits a trigonal-bipyramidal coordination geometry with the three phenyl groups in equatorial positions and the chloride anion and ligand oxygen atom present at axial sites [O-Sn-Cl = 175.07 (14)°]. The thia-zolidinone ring of the ligand adopts an envelope conformation with the S atom as the flap. The dihedral angles between the heterocycle ring plane (all atoms) are 44.3 (9)° with respect to the pendant C-phenyl plane and 34.3 (11)° to the N-cyclo-hexyl ring (all atoms). The C-phenyl and N-cyclo-hexyl ring are close to orthogonal to each other, with a dihedral angle of 81.1 (4)° between them. In the crystal, mol-ecules are linked by weak C-H⋯Cl hydrogen bonds to generate [001] chains.

National Treatment Practice for Adrenocortical Carcinoma: Have They Changed and Have We Made Any Progress?

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare malignancy with a dismal prognosis. Two landmark trials published in 2007 and 2012 showed efficacy for adjuvant mitotane in resectable ACC and etoposide/doxorubicin/cisplatin plus mitotane for unresectable ACC, respectively. In this study, we used the National Cancer Database to examine whether treatment patterns and outcomes changed after these trials. METHODS: The National Cancer Database was used to examine treatment patterns and survival in patients diagnosed with ACC from 2006 to 2015. Treatment modalities were compared within that group and with a historical cohort (1985 to 2005). χ2 tests were performed, and Cox proportional hazards models were created. RESULTS: From 2006 to 2015, 2752 patients were included; 38% of patients (1042) underwent surgery alone, and 31% (859) underwent surgery with adjuvant therapy. Overall 5-year survival rates for all stages after resection were 43% (median, 41 months) in the contemporary cohort and 39% (median, 32 months) in the historical cohort. After 2007, patients who underwent surgery were more likely to receive adjuvant chemotherapy (P = 0.005), and 5-year survival with adjuvant chemotherapy improved (41% vs 25%; P = 0.02). However, survival did not improve in patients with unresectable tumors after 2011 compared with 2006 to 2011 (P = 0.79). Older age, tumor size ≥10 cm, distant metastases, and positive margins were associated with lower survival after resection (hazard ratio range: 1.39 to 3.09; P < 0.03). CONCLUSIONS: Since 2007, adjuvant therapy has been used more frequently in patients with resected ACC, and survival for these patients has improved but remains low. More effective systemic therapies for patients with ACC, especially those in advanced stages, are desperately needed.

Primary Tumor Site Affects Survival in Patients with Gastroenteropancreatic and Neuroendocrine Liver Metastases.

BACKGROUND: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are commonly present with metastatic disease, and the liver is the most frequent metastatic site. Herein, we studied whether primary tumor site affects survival in patients with GEP-NETs and liver metastases (NELM). As a secondary endpoint, we studied whether extrahepatic disease and surgical resection impact survival in this patient population. METHODS: Patients with NELM diagnosed from 2006 to 2014 were identified from the National Cancer Database. Kaplan-Meier curves and nested Cox proportional hazards were used to assess variables associated with survival. RESULTS: 2947 patients with well- or moderately differentiated GEP-NETs and NELM met the inclusion criteria for this study. Patients with small bowel NETs survived the longest of all GEP-NETs with NELM (median not reached). Rectal and gastric NETs with NELM had the shortest survival (median 31 months). Patients with extrahepatic metastases who underwent any operation survived longer than those managed nonoperatively (median survival 38.7 months vs. 18.6 months, p = 0.01). On multivariable analysis, operations on the primary tumor and distant metastatic site (HR 0.23-0.43 vs. no surgery), treatment at an academic/research hospital, Charlson comorbidity index of 0, no extrahepatic metastases, and younger age were associated with prolonged survival (p < 0.01). CONCLUSIONS: Primary tumor site affects survival in patients with GEP-NETs and NELM. Surgical resection seems beneficial for all GEP-NETs with NELM, even in the presence of extrahepatic metastases.

68Gallium-DOTATATE positron emission tomography-computed tomography (PET CT) changes management in a majority of patients with neuroendocrine tumors.

BACKGROUND: 68Gallium-DOTATATE positron emission tomography-computed tomography (PET CT) has shown superior accuracy in detecting grade 1 and 2 neuroendocrine tumors over previous imaging modalities and was recently included in National Comprehensive Cancer Network guidelines. It remains unclear which patients benefit most from this imaging modality. We therefore reviewed our initial experience with 68Gallium-DOTATATE PET CT to evaluate its usefulness in diagnosing, staging, and surveilling neuroendocrine tumors. METHODS: Records of patients who underwent 68Gallium-DOTATATE PET CT from March to December 2017 were prospectively evaluated. The primary endpoint was whether 68Gallium-DOTATATE PET CT changes treatment in patients with neuroendocrine tumors. Descriptive statistics, Fisher exact tests, and nested logistic regressions were conducted. RESULTS: A total of 50 consecutive patients were included. Of these, 41 patients (82%) had a biopsy-proven neuroendocrine tumor at the time of imaging. The remaining 9 patients (18%) had symptoms or biochemistry suggestive of a neuroendocrine tumor with negative cross-sectional imaging. 68Gallium-DOTATATE PET CT changed management in 33 patients (66%). There were 24 patients with intermodality changes in management and 9 patients with intramodality changes in management. Patients with scans performed for staging had a higher likelihood of a change in management (P = .006). CONCLUSION: Performing 68Gallium-DOTATATE PET CT should be considered for staging and surveillance of neuroendocrine tumors because it is frequently associated with changes in management.

Resection of primary tumor may prolong survival in metastatic gastroenteropancreatic neuroendocrine tumors.

BACKGROUND: Patients with gastroenteropancreatic neuroendocrine tumors often present with stage IV disease. Primary tumor resection in these patients remains controversial. Herein, we studied the impact of primary tumor removal, identified variables associated with prolonged survival for each neuroendocrine tumor subtype, and determined factors that influence surgeons to perform primary tumor resection. METHODS: Patients with metastatic gastroenteropancreatic neuroendocrine tumors diagnosed from 2004 to 2014 were identified from the National Cancer Database. Nested Cox proportional hazards and logistic regression models were used to assess variables associated with survival and primary resection. RESULTS: A total of 14,510 patients met inclusion criteria. On multivariable analysis, resection of the primary tumor and grade 1 or 2 tumors was associated with prolonged survival in all subtypes (P < .001). Organ-specific variables associated with prolonged survival in patients undergoing primary tumor resection included the following: low grade for all organs; young age for pancreatic, small intestinal, colonic, and rectal neuroendocrine tumor; tumor size for colonic and rectal neuroendocrine tumor; and tumor location for colonic neuroendocrine tumor. Low tumor grade was found to be significantly associated with removal of the primary tumor across all organs. CONCLUSION: This study is the first suggesting that primary tumor resection is associated with prolonged survival for all gastro-entero-pancreatic NETs. Additional variables related to survival for each NET subtype were identified and might help select patients who benefit from primary tumor removal.

Development of osteopromotive poly (octamethylene citrate glycerophosphate) for enhanced bone regeneration.

The design and development of bioactive materials that are inherently conducive for osteointegration and bone regeneration with tunable mechanical properties and degradation remains a challenge. Herein, we report the development of a new class of citrate-based materials with glycerophosphate salts, ß-glycerophosphate disodium (ß-GP-Na) and glycerophosphate calcium (GP-Ca), incorporated through a simple and convenient one-pot condensation reaction, which might address the above challenge in the search of suitable orthopedic biomaterials. Tensile strength of the resultant poly (octamethylene citrate glycerophosphate), POC-ßGP-Na and POC-GP-Ca, was as high as 28.2 ±â€¯2.44  MPa and 22.76 ±â€¯1.06  MPa, respectively. The initial modulus ranged from 5.28 ±â€¯0.56  MPa to 256.44 ±â€¯22.88  MPa. The mechanical properties and degradation rate of POC-GP could be controlled by varying the type of salts, and the feeding ratio of salts introduced. Particularly, POC-GP-Ca demonstrated better cytocompatibility and the corresponding composite POC-GP-Ca/hydroxyapatite (HA) also elicited improved osteogenic differentiation of human mesenchymal stem cells (hMSCs) in vitro, as compared to POC-ßGP-Na/HA and POC/HA. The superior in-vivo performance of POC-GP-Ca/HA microparticle scaffolds in promoting bone regeneration over POC-ßGP-Na/HA and POC/HA was further confirmed in a rabbit femoral condyle defect model. Taken together, the tunability of mechanical properties and degradation rates, together with the osteopromotive nature of POC-GP polymers make these materials, especially POC-GP-Ca well suited for bone tissue engineering applications. STATEMENT OF SIGNIFICANCE: The design and development of bioactive materials that are inherently conducive for osteointegration and bone regeneration with tunable mechanical properties and degradation remains a challenge. Herein, we report the development of a new class of citrate-based materials with glycerophosphate salts, ß-glycerophosphate disodium (ß-GPNa) and glycerophosphate calcium (GPCa), incorporated through a simple and convenient one-pot condensation reaction. The resultant POC-GP polymers showed significantly improved mechanical property and tunable degradation rate. Within the formulation investigated, POC-GPCa/HA composite further demonstrated better bioactivity in favoring osteogenic differentiation of hMSCs in vitro and promoted bone regeneration in rabbit femoral condyle defects. The development of POC-GP expands the repertoire of the well-recognized citrate-based biomaterials to meet the ever-increasing needs for functional biomaterials in tissue engineering and other biomedical applications.