Preparation and characterization of stationary phase gradients on C8 liquid chromatography columns.

Continuous C8 stationary phase gradients are created on commercial Waters Symmetry Shield RP8 columns by strategically cleaving the C8 moieties in a time-dependent fashion. The method relies on the controlled infusion of a trifluoroacetic acid/water/acetonitrile solution through the column to cleave the organic functionality (e.g., C8) from the siloxane framework. The bond cleavage solution is reactive enough to cleave the functional groups, even with polar groups embedded within the stationary phase to protect the silica. Both the longitudinal and radial heterogeneity were evaluated by extruding the silica powder into polyethylene tubing and evaluating the percent carbon content in the different sections using thermogravimetric analysis (TGA). TGA analysis shows the presence of a stationary phase gradient in the longitudinal direction but not in the radial direction. Two different gradient profiles were formed with good reproducibility by modifying the infusion method: one exhibited an 'S'-shaped gradient while the other exhibited a steep exponential-like gradient. The gradients were characterized chromatographically using test mixtures, and the results showed varied retention characteristics and an enhanced ability to resolve nicotine analytes.

Advancing the use of molecularly imprinted polymers in bioanalysis: the selective extraction of cotinine in human urine.

Aim: To characterize a molecularly imprinted polymer via precipitation polymerization for the extraction of cotinine in urine. Methods: The polymer was created via precipitation polymerization. Physical characteristics of the polymer were assessed via scanning electron microscopy, Fourier transform infrared spectroscopy and thermogravimetric analysis. The polymer adsorption capacity was assessed and an solid-phase extraction method from urine by LC-MS/MS was developed. Results: The polymer had small, spherical morphology and little thermal decomposition. The extraction method yielded cotinine recoveries of 77-103% in urine. The molecularly imprinted polymer adsorption capacity for cotinine was 448.2 ± 2.1 µg/mg. Common interferants did not affect cotinine's extraction. Conclusion: The resulting polymer was determined to be specific for cotinine and can be used for the detection of cotinine in urine for clinical samples.

Development and Validation of Nomograms to Predict Survival in Patients Undergoing Complete Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy for Pseudomyxoma Peritonei of Appendiceal Origin.

Importance: Pseudomyxoma peritoni, a rare condition characterized by mucinous ascites and peritoneal deposits, mainly originates from a ruptured mucinous appendix tumor and is considered an indolent disease but can progress and become fatal. Optimal treatment to improve cure and survival rates involves complete cytoreductive surgery (CCRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Accurate predictive models are useful in supporting and informing treatment strategies and stratifying patient follow-up. Objective: To evaluate the prognostic significance of clinically important variables and generate validated nomograms to predict overall (OS) and disease-free survival (DFS) following CCRS and hyperthermic intraperitoneal HIPEC for pseudomyxoma peritonei (PMP) of appendiceal origin. Design, Setting, and Participants: This retrospective study used prospectively collected data on patients who had cytoreductive surgery (CRS) and HIPEC in a single institution between 1994 and 2018. The cohort was randomly allocated into development (70%) and validation (30%) sets. Univariate and multivariate analyses were performed with Cox proportional hazards regression. Main Outcomes and Measures: A prediction model was developed with significant prognostic factors identified by multivariate analysis. The model's prognostic performance was evaluated with the concordance index (C index). The nomogram was calibrated by comparing the predicted and observed probabilities. Results: Of 2637 CRS and HIPEC operations, 1102 patients (female, 64.4%; median age [IQR], 57.0 [48.0-66.0] years) (41.8%) had CCRS for PMP of appendiceal origin. Elevated tumor markers, peritoneal carcinomatosis index, gastrectomy, and tumor grade were independent predictive factors for DFS. Gender, age, elevated tumor makers, peritoneal carcinomatosis index, and tumor grade influenced OS. The nomograms were generated with respective prognostic factors. The nomograms showed good performance in predicting survival. Median OS of the cohort was 16.5 years (95% CI, 13.7-19.2) with a 5-year probability of survival of 80.2%. The median DFS was 10.3 years (95% CI, 7.2- 13.3) and the 5-year probability of recurrence-free survival was 60.5%. Conclusions and Relevance: Clinically important independent predictors for survival and recurrence were selected to develop the nomograms for OS and DFS. These 2 nomograms are user friendly and useful tools for patient management with clinical trial design applications.

Coherent Coupling of Two Remote Magnonic Resonators Mediated by Superconducting Circuits.

We demonstrate microwave-mediated distant magnon-magnon coupling on a superconducting circuit platform, incorporating chip-mounted single-crystal Y_{3}Fe_{5}O_{12} (YIG) spheres. Coherent level repulsion and dissipative level attraction between the magnon modes of the two YIG spheres are demonstrated. The former is mediated by cavity photons of a superconducting resonator, and the latter is mediated by propagating photons of a coplanar waveguide. Our results open new avenues toward exploring integrated hybrid magnonic networks for coherent information processing on a quantum-compatible superconducting platform.

Indications and long-term outcomes of preoperative inferior vena caval filters in 111 patients at high risk of pulmonary embolism undergoing major abdominal surgery.

AIMS: Patients with abdominal cancer requiring major surgical intervention are at high risk of venous thromboembolic events (VTE), particularly pulmonary emboli (PE). A proportion of patients with cancer can present with, or have had, major VTEs prior to definitive surgical treatment. Preoperative percutaneous inferior venal caval filters (IVCF) may reduce the risk of PE. The aim of this study was to assess the indications, complications, retrieval rates, and long-term outcome of IVCFs in patients undergoing major abdominal surgery. METHODS: This was a retrospective analysis of a prospective IVCF database between 2007 and 2018 of all patients with IVCF insertion prior to major abdominal surgery. The indications for an IVCF, procedural complications and surgical interventions were recorded. RESULTS: Overall, 111 patients had IVCF insertion. IVCF placement failed in one patient with gross abdominal disease. Indications for an IVCF were: prior PE in 65/111 (59%) and major vein thrombus in 42 (38%). Overall, 26/111 (23%) had the IVCF removed at a median of 91 days. In two patients IVCF removal failed. At follow-up of the 85 patients who had the IVCF left in situ, six developed filter-related thrombus and 13 a deep vein thrombosis (DVT). Four patients had a PE with an indwelling IVCF. CONCLUSION: Preoperative IVCF may reduce perioperative PE in patients at high risk of thrombosis undergoing major abdominal surgery where early anticoagulation is contraindicated. Long-term follow-up of retained IVCF suggests that major problems are infrequent, though further thrombosis may occur and long-term anticoagulation may be needed.

Managing Recurrent Pseudomyxoma Peritonei in 430 Patients After Complete Cytoreduction and HIPEC: A Dilemma for Patients and Surgeons.

BACKGROUND: Epithelial appendiceal neoplasms are uncommon peritoneal malignancies causing a spectrum of disease including pseudomyxoma peritonei (PMP). The optimal management is cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). Despite complete CRS (CCRS), recurrence develops in almost 45% of patients. No consensus exists for the optimal treatment of recurrent disease, with treatment strategies including repeat CRS, watch-and-wait, and palliative chemotherapy. This report aims to describe evolving management strategies for a large cohort with recurrence after CCRS. METHODS: This retrospective study analyzed a prospective database of patients with recurrence after CCRS for appendiceal neoplasms from 1994 to 2017 who had long-term follow-up evaluation with tumor markers and computed tomography (CT). RESULTS: Overall, 430 (37.6%) of 1145 PMP patients experienced recurrence at a median of 19 months. Of these 430 patients 145 (33.7%) underwent repeat CRS, 119 (27.7%) had a watch-and-wait approach, and 119 (27.7%) had palliative chemotherapy. The patients with recurrence had a median overall survival (OS) of 39 months, a 3-year survival of 74.6%, a 5-year survival of 57.4%, and a 10-year survival of 36.5%. In the multivariate analysis, the patients who had recurrence within 1 year after primary CRS (hazard ratio [HR], 3.55), symptoms at recurrence (HR, 3.08), a high grade of disease or adenocarcinoma pathology (HR, 2.94), signet ring cells (HR, 1.91), extraperitoneal metastatic disease (HR, 1.71), or male gender (HR, 1.61) had worse OS. The OS was longer for the patients who had repeat CRS (HR, 0.41). The patients who underwent repeat CCRS had a 3-year OS of 87.5%, a 5-year OS of 78.1%, and a 10-year OS of 67.9%. CONCLUSIONS: Dilemmas persist around the optimal management of patients with recurrence after CRS and HIPEC for appendiceal tumors. Selected patients benefit from repeat CRS, particularly those with favorable tumor biology and focal disease.

Single centre guidelines for radiological follow-up based on 775 patients treated by cytoreductive surgery and HIPEC for appendiceal pseudomyxoma peritonei.

AIM: Pseudomyxoma peritonei (PMP) is an uncommon malignancy, generally originating from a ruptured epithelial tumour of the appendix. Despite successful cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), some patients recur. Currently there are no guidelines on the methods, frequency and intensity of follow-up. METHODS: Between 1994 and 2016, 1070 patients underwent surgery for a perforated epithelial tumour of the appendix, predominantly with PMP. Overall (OS) and Disease Free Survival (DFS) were documented by annual CT scanning and evaluated according to the Kaplan-Meier method. The influence of histological differentiation was investigated. RESULTS: Overall, 775/1070 (72%) had complete cytoreductive surgery (CCRS) and HIPEC. Histological classification was low grade PMP in 615 (79.4%), high grade PMP in 134 (17.3%) and adenocarcinoma in 26 (3.4%). DFS and OS were significantly worse for high grade disease, with the steepest decline for both in the first three years. DFS curves, for low as well as high grade PMP, levelled off at year 6 at approximately 60% and 20% respectively. Thereafter there were few recurrences in either group. CONCLUSION: Annual CT of the abdomen and pelvis in the first six years appears to be adequate follow-up for low grade PMP. In high grade PMP, additional imaging of the chest and more frequent surveillance, during the first three years postoperatively, may detect recurrent disease earlier. From year 6 on, reduced frequency of follow-up is proposed, independent of the histology. This long-term follow-up in a large number of patients gives insight into tumour behavior after CCRS and HIPEC for PMP and guides intensity of surveillance.

Goblet cell carcinomas of the appendix: rare but aggressive neoplasms with challenging management.

Goblet cell carcinomas (GCC) are a rare, aggressive sub-type of appendiceal tumours with neuroendocrine features, and controversy exists with regards to therapeutic strategy. We undertook a retrospective review of GCC patients surgically treated at two tertiary referral centres. Clinical and histopathological data were extracted from a prospectively maintained database. Survival analyses utilised Kaplan-Meier methodology. Twenty-one patients were identified (9 females). Median age at diagnosis was 55 years (range 32-77). There were 3, 6 and 9 grade 1, 2 and 3 tumours, respectively. One, 10, 5 and 5 patients had stage I, II, III and IV disease at diagnosis, respectively. There were 8, 10 and 3 Tang class A, B and C tumours, respectively. Index operation was appendectomy (n = 12), right hemicolectomy (n = 6) or resections including appendix/right colon, omentum and the gynaecological system (n = 3). Eight patients underwent completion right hemicolectomy. Surgery for recurrence included small bowel resection (n = 2), debulking with peritonectomy and heated intraperitoneal chemotherapy, and hysterectomy and bilateral salpingo-oophorectomy (all n = 1). Median follow-up was 30 months (range 2.5-123). One-, 3- and 5-year OS was 79.4, 60 and 60%, respectively. Mean OS (1-, 3-, and 5-year OS) for Tang class A, B and C tumours were 73.1 months (85.7, 85.7, 51.4%), 83.7 months (all 66.7%) and 28.5 months (66.7, 66.7%, not reached), respectively. Chromogranin A/B and 68Ga-DOTATATE PET/CT were not useful in follow-up, but CEA, CA 19-9, CA 125 and 18F-FDG PET/CT identified tumour recurrence. GCC must be clearly discriminated from relatively indolent appendiceal neuroendocrine neoplasms. 18F-FDG PET/CT and CEA/CA19-9/CA 125 are useful in detecting recurrence of GCC.

The pre-operative neutrophil-lymphocyte ratio predicts overall and disease-free survival following cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with pseudomxyoma peritonei of appendiceal origin.

AIM: The neutrophil-lymphocyte ratio (NLR) and other inflammation-based scores have been used as a prognostic tool to predict survival in solid tumours including pseudomyxoma peritonei (PMP). The aim was to evaluate the prognostic value of this marker and risk stratify PMP patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: Retrospective analysis was conducted of a prospectively collected database of patients with PMP who underwent CRS and HIPEC between 1994 and 2015. The NLR was calculated by dividing the pre-operative neutrophil count by lymphocyte count. Predicted overall survival (OS) and disease-free interval (DFI) were calculated using a Kaplan-Meier survival model. RESULTS: The study included 699 patients, stratified into four groups as defined by their NLR. Group A: 200 (28.6%) patients (NLR = 0.10-2.00), Group B: 160 (22.8%) patients (NLR = 2.10-2.78), Group C: 184 (26.3%) patients (NLR = 2.79-4.31) and Group D: 155 (22.2%) patients (NLR ≥ 4.32). The median follow-up for this cohort was 36 months. The predicted DFI was 132.2, 113.1, 84.4 and 47.9 months and the OS was 141.1, 117.6, 88.7 and 51.2 months for Groups A, B, C and D, respectively. As the NLR increases, there is a reduction in long-term survival. CONCLUSION: The pre-operative NLR is cost effective and has equivalent prognostic value to pre-operative tumour markers for patients with PMP treated with CRS and HIPEC. The NLR is a reliable tool that may have a role in predicting outcomes following CRS and HIPEC for patients with PMP of appendiceal origin.

A Consensus for Classification and Pathologic Reporting of Pseudomyxoma Peritonei and Associated Appendiceal Neoplasia: The Results of the Peritoneal Surface Oncology Group International (PSOGI) Modified Delphi Process.

Pseudomyxoma peritonei (PMP) is a complex disease with unique biological behavior that usually arises from appendiceal mucinous neoplasia. The classification of PMP and its primary appendiceal neoplasia is contentious, and an international modified Delphi consensus process was instigated to address terminology and definitions. A classification of mucinous appendiceal neoplasia was developed, and it was agreed that "mucinous adenocarcinoma" should be reserved for lesions with infiltrative invasion. The term "low-grade appendiceal mucinous neoplasm" was supported and it was agreed that "cystadenoma" should no longer be recommended. A new term of "high-grade appendiceal mucinous neoplasm" was proposed for lesions without infiltrative invasion but with high-grade cytologic atypia. Serrated polyp with or without dysplasia was preferred for tumors with serrated features confined to the mucosa with an intact muscularis mucosae. Consensus was achieved on the pathologic classification of PMP, defined as the intraperitoneal accumulation of mucus due to mucinous neoplasia characterized by the redistribution phenomenon. Three categories of PMP were agreed-low grade, high grade, and high grade with signet ring cells. Acellular mucin should be classified separately. It was agreed that low-grade and high-grade mucinous carcinoma peritonei should be considered synonymous with disseminated peritoneal adenomucinosis and peritoneal mucinous carcinomatosis, respectively. A checklist for the pathologic reporting of PMP and appendiceal mucinous neoplasms was also developed. By adopting the classifications and definitions that were agreed, different centers will be able to use uniform terminology that will allow meaningful comparison of their results.

Complete cytoreduction for pseudomyxoma peritonei is optimal but maximal tumor debulking may be beneficial in patients in whom complete tumor removal cannot be achieved.

BACKGROUND: Pseudomyxoma peritonei is a diffuse peritoneal malignancy that generally originates form a perforated appendiceal tumor. Optimal treatment requires extensive surgical resection to achieve complete cytoreduction combined with hyperthermic intraperitoneal chemotherapy. In a proportion of patients this is impossible, in particular, owing to extensive irresectable small-bowel involvement. There is ongoing debate as to the role of maximal tumor debulking in such cases. OBJECTIVE: : The aim of this study was to assess the outcomes of patients who underwent major tumor debulking for pseudomyxoma peritonei of appendiceal origin and to compare outcomes with patients who had complete cytoreduction during the same period. DESIGN: This is a retrospective study. SETTINGS: This investigation was conducted at a tertiary referral center for peritoneal surface malignancy. PATIENTS: A prospective database of 953 consecutive patients with peritoneal malignancy undergoing surgery at a UK national referral center between 1994 and 2012 was analyzed. Of these patients, 748 (78%) had surgery for pseudomyxoma peritonei of appendiceal origin. MAIN OUTCOME MEASURES: Survival, morbidity, and mortality in both groups were compared. Univariate and multivariate analyses were performed to identify negative prognostic factors in the group that underwent major tumor debulking. RESULTS: Complete cytoreductive surgery was achieved in 543/748 (73%) patients, and 205 (27%) had maximal tumor debulking. Median age was 56 years (172 (31.7%) men) in the complete cytoreductive surgery group and 59 years (108 (52.7%) men) in the maximal tumor debulking group. Overall survival at 3, 5, and 10 years was 90%, 82%, and 64% in the complete cytoreductive group and 47%, 30%, and 22% in the maximal tumor debulking group. The median survival in the maximal tumor debulking group was 32.8 months (95% CI, 24.1-41.5). LIMITATIONS: The retrospective analysis of prospective data was a limitation of this study. CONCLUSIONS: Maximal tumor debulking may help patients with pseudomyxoma peritonei in whom complete cytoreduction cannot be achieved with almost half alive at 3 years with long-term survival in some.

Total mesorectal excision results in low local recurrence rates in lymph node-positive rectal cancer.

PURPOSE: Most series report lymph node involvement as the main predictor for local recurrence. The principal lymphatic drainage of the rectum is to nodes in the mesorectum and then nodes along the superior rectal and inferior mesenteric arteries. If total mesorectal excision provides adequate block dissection of the lymphatics of the rectum, good local control with low rates of local recurrence should be achieved even in node-positive disease. METHODS: Prospective data on all rectal cancers have been collected since 1978; 170 patients with Dukes C rectal cancer have undergone anterior resection and total mesorectal excision. We did not perform any internal iliac node dissections. Follow-up data were analyzed for local recurrence and distant recurrence. RESULTS: The local recurrence rate was 2 percent for Dukes A cases, 4 percent for Dukes B, and 7.5 percent for Dukes C ( P = 0.0127). The systemic recurrence rate was 8 percent for Dukes A, 18 percent for Dukes B, and 37 percent for Dukes C ( P = 0.0001). CONCLUSIONS: If surgical priority is given to the difficult task of excision of the whole mesorectum, anterior resection with total mesorectal excision in node-positive rectal cancer, local recurrence rates of < 10 percent can be achieved.

The etiology, clinical presentation, and management of pseudomyxoma peritonei.

PMP is a rare condition, which, although of "borderline malignancy," is invariably fatal. Difficulties exist with the definition of PMP. It has been broadly applied to include a heterogenous group of pathologic lesions that present clinically with "jelly belly" due to mucinous ascites. The relatively few reports in the literature commonly use different pathologic definitions, and there is no consensus on the point of separation between PMP and carcinomatosis secondary to a mucinous adenocarcinoma. Sugarbaker has suggested "the term pseudomyxoma peritonei syndrome be strictly applied to a pathologically and prognostically homogenous group of cases characterized by histologically benign peritoneal tumors that are frequently associated with an appendiceal mucinous adenoma." This definition excludes all cases with mucinous adenocarcinoma. The optimal treatment is undoubtedly complete tumor excision, by complex surgical peritonectomy procedures, taking on average 10 hours. Surgery is usually combined with intraperitoneal, and now intraoperative heated chemotherapy. These techniques have a high morbidity and mortality. The rarity of the condition, together with the risks associated with definitive treatment, suggests that such treatment ought to be centralized in a few centers, covering a large population. The search continues for safer, less aggressive treatments, but is hampered by a lack of hard evidence and the absence of experimental animal or human models to evaluate emerging strategies.