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SLC3A2 (4F2hc, CD98) is an adaptor to the SLC7A exchangers and has undergone extensive repositioning of N-glycosylation sites with vertebrate evolution, presumably in synchrony with the species-specific demands of metabolism. The SLC3A2*SLC7A5 heterodimer imports essential amino acids (AA) and thereby stimulates mTOR signaling, while SLC3A2*SLC7A11 imports cystine required for glutathione synthesis and mitigation of oxidative stress. Analysis of SLC3A2 N-glycans revealed stable site-specific profiles of Golgi remodeling, apart from the conserved N365 site where branching and poly-N-acetylglucosamine content were sensitive to the insertion of lost ancestral sites and to metabolism. N-glycans at N381 and N365 stabilized SLC3A2 in the galectin lattice and opposed endocytosis, while N365 which is nearest the membrane, also promoted down-regulation by galectin-driven clathrin-independent endocytosis (glycolipid-lectin GL-Lect). This is the first report of both positive and negative regulation by galectin binding to N-glycans that are strategically positioned in the same membrane glycoproteins. Proteomics analysis in SLC3A2 mutant HeLa cells with induced re-expression of SLC3A2 as bait revealed the canonical non-N-glycosylated interactors, SLC7A5 and SLC7A11 exchangers, but also AA transporters that were dependent on SLC3A2 N-glycosylation, and are themselves, N-glycosylated AA/Na+symporters (SLC7A1, SLC38A1, SLC38A2, SLC1A4, SLC1A5). The results suggest that the N-glycans on SLC3A2 regulate clustering of SLC7A exchangers with AA/Na+symporters, thereby promoting Gln/Glu export-driven import of essential AA and cystine, with the potential to adversely impact redox balance. The evolution of modern birds (Neoaves) led to improved control of bioenergetics with the loss of genes including SLC3A2, SLC7A-5, -7, -8, -10, BCAT2, KEAP1, as well as duplications of SLC7A9, SLC7A11 and the Golgi branching enzymes MGAT4B and MGAT4C known to enhance affinities for galectins. Analyzing the fate of these and other genes in the down-sized genomes of birds, spanning ∼10,000 species and >100 Myr of evolution, may reveal the mystery of their longevity with prolonged vitality.Key PointsGolgi N-glycan remodeling at each site on SLC3A2 differs with the microenvironment.The galectin lattice and GL-Lect mediated endocytosis act as opposing forces on trafficking, controlled by N-glycans at the distal N381 and membrane proximal N365 sites, respectively.Mutation at N381 or N365 decreased SLC3A2 association with SLC7A5, SLC7A11 and N-glycosylated AA/Na+symporters as well as the capacity to mitigate stress.Clustering of SLC3A2*SLC7A exchangers, with AA/Na+symporter and ATPase Na+/K+exchanger promotes growth but continuously consumes ATP in non-proliferating cells.Bird evolution has improved bioenergetics with the deletion of SLC3A2 and associated transporters; - replaced by transporters of keto acids and a re-enforced galectin lattice.Abstract Figure

Introduction. Currently, factors such as size, mitotic rate, and degree of necrosis have been shown to influence survival in patients with solitary fibrous tumors (SFTs); however, there remains no consensus regarding the associations between tumor characteristics and the malignant nature of these tumors. The aim of this article was to identify factors that would help in prognosticating SFTs and to validate the MD Anderson Cancer Center (MDACC) SFT nomogram in the largest known series of SFTs treated in an Asian population. Methods. A retrospective review of all patients with a diagnosis of SFT treated surgically in our institution between 2005 and 2015 was carried out. Basic demographics, clinicopathological, and surgical factors were analyzed for association with clinical outcomes. Factors that predicted for distant recurrence (DR) and poor survival were identified as high-risk features. The MDACC nomogram was validated by assessing the extent of discrimination, quantified using Harrell’s concordance index (C-index). Results. Fifty-nine patients were included in analysis. Significant univariate associations for DR were found for mitotic rate ( P = .05) and presence of necrosis ( P = .04). Significant univariate associations for overall survival were found for presence of recurrence ( P = .035), presence of necrosis ( P = .072), and mitotic rate ( P = .033). The C-index associated with the nomogram was 0.75. Conclusion. There is a negative association for DR and overall survival, with the mitotic rate and presence of necrosis. We propose that SFTs with these features should be regarded as high risk. The MDACC nomogram generally predicts well for patients in an Asian population.

Aim To review our experience in the management of retroperitoneal sarcomas (RPSs) in a single institution, with a predominantly Asian population, and identify associated prognostic factors for overall survival (OS), disease-free survival (DFS) and local recurrence. Materials and methods All RPSs diagnosed and managed at our center between January 2000 and March 2014 were included. Exclusion criteria included patients whose medical records were untraceable and patients who underwent biopsy but did not undergo resection. The variables studied were age, gender, histological subtype, tumor size, tumor grade, surgical margins, type of presentation of tumor (primary or recurrent) and presence of contiguous organ resection. The primary outcome measured was OS. Results Eighty-five patients underwent resection of RPS with curative intent. Eight patients underwent adjuvant chemotherapy and 15 patients underwent radiotherapy. The median DFS was 21 months (range: 0–146) and median OS was 45 months (range: 1–233). On univariate analysis, resection margin (P = 0.04), tumor grade (P = 0.011) and type of presentation of tumor (P = 0.007) were found to significantly affect OS. Patients with tumor adherent to contiguous organs had a greater OS as compared to patients with tumor invasive into the contiguous organs (P = 0.02). Conclusion An aggressive surgical approach in primary and recurrent RPS is associated with good OS. Complete resection, with contiguous organ resection if necessary should be performed to achieve microscopically negative surgical margins to allow for long-term survival. However, tumor biology remains the main determinant for OS.

Aim A nomogram for prediction of 12-year sarcoma-specific survival has been developed based on patients with soft tissue sarcomas treated in Memorial Sloan Kettering Cancer Centre (MSKCC). We aim to evaluate the predictive accuracy of the MSKCC sarcoma nomogram in a cohort of patients treated at an Asian institution. This has not been validated in an Asian population and thus its universal applicability remains unproven. Materials and methods Between 1990 and 2013, 840 adult patients underwent treatment for primary soft tissue sarcoma (STS) at the National Cancer Centre Singapore. Patients who presented with locally recurrent or metastatic disease were excluded from the analysis. The variables included in the MSKCC nomogram included age at diagnosis, tumor size, histologic grade, histologic subtype, depth and site. A total of 399 patients were left for analysis. The nomogram was validated by assessing its extent of discrimination and level of calibration. Results All patients had deep tumors. Disease occurred most commonly in the lower extremity (n = 149 [37.3%]), the most common histologic subtype was “Others” (angiosarcoma, ewing's sarcoma, endometrial stromal sarcoma, sarcoma NOS [not otherwise specified] and rhabdomyosarcoma). Sixty-four percent of all patients had high-grade tumors while 36% had low-grade tumors. The median patient age at diagnosis was 54 years (range: 17–88 years). The median follow up time for all patients and surviving patients were 29 (range: 1–174) and 33 (range: 1–157) months, respectively. The observed 5- and 10-year sarcoma-specific survival were 55% and 33%, respectively. The concordance index was 0.71. For level of calibration, the observed correspondence between predicted and actual outcomes suggest that the MSKCC nomogram generally predicts well for patients with higher survival probability, but consistently overpredicts survival for the other groups, in our cohort of patients. Conclusion The MSKCC sarcoma nomogram was found to be accurate in terms of extent of discrimination. In terms of level of calibration, it generally predicts well for patients with higher survival probability, but consistently overpredicts survival for the other groups in our population.

Metastasectomy is accepted as standard of care for selected patients with colorectal pulmonary metastases (CLM); however, the role of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal peritoneal metastases (CPM) is not universally accepted. We aim to compare oncological outcomes of patients with CLM and CPM after pulmonary resection and CRS-HIPEC, respectively, by comparing overall survival (OS) and disease-free survival (DFS). A retrospective review of 49 CLM patients who underwent pulmonary resection, and 52 CPM patients who underwent CRS-HIPEC in a single institution from January 2003 to March 2015, was performed. The 5-year OS for CLM patients and CPM patients were 59.6 and 40.5%, respectively (p = 0.100), while the 5-year DFS were 24.0 and 14.2%, respectively (p = 0.173). CPM patients had longer median operative time (8.38 vs. 1.75 h, p

AIM This study aims to review patient and disease factors that predict survival after palliative surgery for intestinal perforation from metastases in advanced malignancies, with a goal to help decision-making in this clinical scenario. Secondary aims include validation of the UC Davis Cancer Centre nomogram to predict risk of 30-day morbidity and mortality for patients with disseminated malignancy undergoing surgical intervention. METHODS The following factors were examined: age, preoperative albumin, total white blood cell count, creatinine, site of metastases, presence of ascites, presence of sepsis, steroid use, presence of dyspnea, presence of significant weight loss, preoperative chemotherapy, preoperative radiotherapy, type of operative procedure performed, Eastern Cooperative Oncology Group (ECOG) status, length of surgery, duration of inhospitalization and mortality. For univariate analysis, independent t-test and Fisher's exact test were used to analyze the association of continuous and categorical variables, respectively. For multivariate analysis, logistic regression using likelihood ratios was used. The nomogram was validated by assessing its extent of discrimination (c-index). RESULTS Twenty palliative operations for intestinal perforation were performed during this period. On univariate analysis, presence of dyspnea, decreased preoperative levels of albumin and high ECOG status were significant predictors of increased mortality. On multivariate analysis, high ECOG status and decreased preoperative albumin were statistically significant. The concordance index in our data set was 0.64. CONCLUSION Preoperative levels of albumin (>20 g/L) and low ECOG status (≤1) were independently associated with favorable postoperative outcomes. In patients with favorable prognostic factors such as absence of dyspnea, high preoperative levels of albumin and low ECOG status, surgical management should be considered. Conversely, in patients with unfavorable prognostic factors, medical management should be considered to avoid unnecessary surgery.

The evaluation of lymph nodes and the role of groin dissection for groin sarcomas has been controversial where there have not been previous studies or guidelines published. In this study, we aim to first formulate a clinical approach in the evaluation of regional lymph nodal metastases. Second, we aim to also evaluate the role of regional lymphadenectomy in the setting of pathologically involved regional lymph nodes for groin sarcomas.In total, 43 consecutive patients with groin sarcomas underwent treatment at the National Cancer Centre Singapore between 2002 and 2015. Univariate comparisons were performed using the log-rank test. A Cox multivariate analysis was performed for disease-specific survival to identify independent prognostic factors.The median disease-free survival was 18 months (range, 1 to 180 mo). The median overall survival (OS) was 28 months (range, 3 to 180 mo). In total, 28 patients underwent a groin dissection. Of the 28 patients who underwent groin dissections, 15 had negative lymph node involvement, 7 had positive lymph node involvement and 6 had lymphovascular invasion.On univariate analysis, grade (P=0.047) and clinical and/or radiological involvement (P=0.039) were significant for regional lymph nodal metastases.The 5-year OS for patients with positive lymph nodes was 31%.Our study suggests that the evaluation of lymph nodes via groin dissections in groin sarcomas in the Asian population should be based primarily on clinical and radiologic evidence. Regional lymph node dissection seems to confer OS benefit in patients with these high-risk tumors and can improve local control of disease.

A review of a single-centre experience of pelvic exenteration as a treatment modality for patients with locally advanced primary and recurrent rectal cancer. The perioperative outcomes, morbidity and long term oncological outcomes are reviewed.Patients undergoing pelvic exenterations for recurrent and locally advanced rectal cancer between 1 January 2006 and 1 August 2012 were identified from a prospective database. All patients underwent pre-operative staging investigations with computed tomography (CT) scan of chest, abdomen and pelvis and pelvic magnetic resonance imaging (MRI). Patients with locally advanced primary rectal cancer were counselled for pre-operative chemoradiation. Structures such as the urinary bladder and female reproductive organs were resected en bloc where indicated with the lesion. Urological or plastic reconstructions were employed where indicated. The primary outcome measured was overall survival and secondary outcomes measured were time to local recurrence (LR) and systemic recurrence. Disease-free survival was examined by the Kaplan-Meier Method (Fig. 1).Pelvic exenterations were performed in 13 patients with a median age of 59 (range 26-81). The rate of major post-operative complications was 8% (n = 1), where the patient had anastomotic leakage. There were no mortalities in the perioperative period. All patients were operated with curative intent and negative circumferential margins were shown in 9 out of 13 patients (70%). The DFS was 19.4 and the OS was 22.5 months.An aggressive approach with en bloc resection of organs involved provides survival benefit to patients with locally advanced primary and recurrent rectal cancer with an acceptable morbidity profile.

This study aims to review patient and disease factors that predict survival after palliative surgery for intestinal perforation from metastases in advanced malignancies, with a goal to help decision-making in this clinical scenario. Secondary aims include validation of the UC Davis Cancer Centre nomogram to predict risk of 30-day morbidity and mortality for patients with disseminated malignancy undergoing surgical intervention.The following factors were examined: age, preoperative albumin, total white blood cell count, creatinine, site of metastases, presence of ascites, presence of sepsis, steroid use, presence of dyspnea, presence of significant weight loss, preoperative chemotherapy, preoperative radiotherapy, type of operative procedure performed, Eastern Cooperative Oncology Group (ECOG) status, length of surgery, duration of inhospitalization and mortality. For univariate analysis, independent t-test and Fisher's exact test were used to analyze the association of continuous and categorical variables, respectively. For multivariate analysis, logistic regression using likelihood ratios was used. The nomogram was validated by assessing its extent of discrimination (c-index).Twenty palliative operations for intestinal perforation were performed during this period. On univariate analysis, presence of dyspnea, decreased preoperative levels of albumin and high ECOG status were significant predictors of increased mortality. On multivariate analysis, high ECOG status and decreased preoperative albumin were statistically significant. The concordance index in our data set was 0.64.Preoperative levels of albumin (20 g/L) and low ECOG status (≤1) were independently associated with favorable postoperative outcomes. In patients with favorable prognostic factors such as absence of dyspnea, high preoperative levels of albumin and low ECOG status, surgical management should be considered. Conversely, in patients with unfavorable prognostic factors, medical management should be considered to avoid unnecessary surgery.

Portomesenteric gas together with pneumatosis intestinalis is a rare radiological finding and is usually associated with bowel ischaemia, extensive bowel necrosis and a high mortality rate. We report a case of portomesenteric venous gas found with extensive secondary pneumatosis intestinalis in the small bowel, stomach and distal oesophagus on radiographic images with an insidious presentation. Here we review the case and discuss the pathophysiology, diagnosis and management of portomesenteric gas associated with bowel ischaemia.

The liver and peritoneum are common sites of colorectal metastases. Hepatectomy for colorectal liver metastases (CLM) is considered gold standard treatment. We attempt to compare the survival outcomes for CLM patients after hepatectomy to that of patients with colorectal peritoneal metastases (CPM) who underwent cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). A retrospective review of patients with CPM and CLM who underwent surgery between January 2003 and May 2011 was performed. The overall (OS) and disease-free survivals (DFS) were compared. There were 22 patients with CPM who underwent CRS and HIPEC and 186 patients who underwent hepatectomy for CLM. Patients with CPM had a 3-year OS of 39 % and DFS of 27.7 %. CLM patients showed a 3-year OS of 58.5 % and a DFS of 28.8 %. Most recurrences for CPM occurred within 2 years, while CLM patients continue to develop systemic recurrences over 3 years, showing a gradual decline in DFS and OS during this period of time. Our results show that CRS and HIPEC for CPM confer good OS and DFS rates and that the DFS after CRS and HIPEC is comparable to that after hepatectomy for CLM.

Background Patients with congenital choledochal cyst are at risk of the development of hepatobiliary malignancy, with recommended treatment of choledochal cyst being surgical excision. The development of cholangiocarcinoma more than 10 years after excision of choledochal cysts is rare, with less than 21 cases reported in the literature from 1972 to 2014. This is the first reported case of metachronous recurrence after a previously excised adenocarcinoma within a choledochal cyst. Case presentation Herein, we review the case of a patient with cholangiocarcinoma arising 13 years post excision of a Todani type 1 choledochal cyst and discuss the theories of carcinogenesis and long-term management of patients with choledochal cysts. The long-term development of a malignancy must be considered in these patients. Conclusions Reviewing all published cases to date, regular follow-up post resection did not improve on the resectability and long-term survival of these patients. Patients presenting with symptoms did not prejudice against resectability. Despite curative resection, median survival was dismal. Optimal long-term follow-up strategies for these patients remain to be elucidated.