Edmund K. Bartlett

sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance

Cancer is a disease of ageing. Clinically, aged cancer patients tend to have a poorer prognosis than young. This may be due to accumulated cellular damage, decreases in adaptive immunity, and chronic inflammation. However, the effects of the aged microenvironment on tumour progression have been largely unexplored. Since dermal fibroblasts can have profound impacts on melanoma progression, we examined whether age-related changes in dermal fibroblasts could drive melanoma metastasis and response to targeted therapy. Here we find that aged fibroblasts secrete a Wnt antagonist, sFRP2, which activates a multi-step signalling cascade in melanoma cells that results in a decrease in β-catenin and microphthalmia-associated transcription factor (MITF), and ultimately the loss of a key redox effector, APE1. Loss of APE1 attenuates the response of melanoma cells to DNA damage induced by reactive oxygen species, rendering the cells more resistant to targeted therapy (vemurafenib). Age-related increases in sFRP2 also augment both angiogenesis and metastasis of melanoma cells. These data provide an integrated view of how fibroblasts in the aged microenvironment contribute to tumour progression, offering new possibilities for the design of therapy for the elderly.

The rise in metastasectomy across cancer types over the past decade

Although studies of metastasectomy have been limited primarily to institutional experiences, reports of favorable long‐term outcomes have generated increasing interest. In the current study, the authors attempted to define the national practice patterns in metastasectomy for 4 common malignancies with varying responsiveness to systemic therapy.

Morbidity and mortality after total gastrectomy for gastric malignancy using the American College of Surgeons National Surgical Quality Improvement Program database

BACKGROUND Frequent perioperative morbidity and mortality have been observed in randomized surgical studies for gastric cancer, but specific patient factors associated with morbidity and mortality after total gastrectomy have not been well characterized. METHODS We queried the American College of Surgeons National Surgical Quality Improvement Program database (2005-2011) for all patients with a gastric neoplasm undergoing total gastrectomy. Univariate and multivariate logistic regression analyses were performed to identify factors associated with an increased risk of morbidity or mortality. RESULTS In 1,165 patients undergoing total gastrectomy, 416 patients (36%) experienced a complication, and 55 died (4.7%) within 30 days of operation. In a reduced multivariate model, age >70 years, preoperative weight loss, splenectomy, and pancreatectomy were associated with morbidity, whereas age >70 years, weight loss, albumin <3 g/dL, and pancreatectomy were associated with mortality (P < .05 each). The number of present preoperative risk factors stratified morbidity from 26 to 46%, with an adjacent organ resection (splenectomy, pancreatectomy) associated with 56% morbidity. Similarly, mortality rates ranged from 0.4% in those without risk factors to 5 of 9 patients with all three preoperative factors present. Patients undergoing pancreatectomy had a 13% mortality rate. CONCLUSION Total gastrectomy for malignancy is associated with substantial morbidity and mortality. Identification of high-risk factors may allow more rational patient selection or sequencing of therapy.

Resection of primary leiomyosarcoma of the inferior vena cava (IVC) with reconstruction: A case series and review of the literature

Leiomyosarcoma of the inferior vena cava (IVC) is a rare tumor which presents a unique surgical challenge. We present a series of six cases of leiomyosarcoma resection performed with IVC reconstruction.

Long-term blood pressure control in patients undergoing adrenalectomy for primary hyperaldosteronism.

BACKGROUND Data on long-term blood pressure (BP) control after adrenalectomy for primary hyperaldosteronism are limited. We analyzed long-term outcomes to identify factors predictive of cure. METHODS We performed a retrospective cohort study of patients undergoing adrenalectomy for primary hyperaldosteronism (1997-2013). BP and antihypertensive medications were assessed at long-term follow-up (≥ 12 months). Primary outcome was cure, defined as normotension off antihypertensives. RESULTS Of 85 patients, 15.3% (n = 13) were cured, 54.1% (n = 46) were normotensive while remaining on anti-hypertensives, and 30.6% (n = 26) were hypertensive. Younger age (P = .011), female sex (P < .001), lesser body mass index (P = .018), shorter duration of hypertension (P = .002), lower creatinine (P = .001), and fewer preoperative antihypertensive medications (P < .001) were associated with cure. Female sex, body mass index ≤ 25 kg/m(2), hypertension <5 years, creatinine ≤ 0.8 mg/dL, and <2 antihypertensives were incorporated into a scoring system. For a score of 0-1 (n = 61) the cure rate was 3%; 100% of patients with a score of 4-5 (n = 3) were cured. This scoring system performed comparably to the Aldosterone Resolution Score, which has been used to evaluate short-term postoperative outcomes. CONCLUSION This is the largest study to identify factors associated with long-term BP control after adrenalectomy and incorporate these into a scoring system. These data provide a potential tool to guide preoperative patient counseling.

Outcomes after resection of leiomyosarcomas of the inferior vena cava: a pooled data analysis of 377 cases.

BACKGROUND Primary leiomyosarcomas of the inferior vena cava (IVC) pose unique surgical challenges. Due to the rarity of the disease, little definitive data exists on prognosis and treatment options. METHODS A pooled data analysis was performed on all cases of initial IVC leiomyosarcoma resection identified by literature search (n = 371) and our institutional database (n = 6). Kaplan-Meier and Cox regression analyses were performed to identify factors associated with disease-free survival (DFS) and overall survival (OS). RESULTS Patients were predominantly female (76%, n = 286); the median age of presentation was 55 years. Five-year DFS and OS were 6% and 55%, respectively. Preoperative factors independently associated with decreased OS included older age (HR:1.05, 95% CI:1.00-1.09), larger tumor size (HR:1.14, 95% CI:1.04-1.24), resection of adjacent organ(s) (HR:3.62, 95% CI:1.34-9.77), and R2 resection (HR:7.80, 95% CI:1.94-32.05). Isolated involvement of the suprarenal infrahepatic IVC was associated with longer OS (HR:0.22, 95% CI:0.06-0.78). A scoring system incorporating independent predictors of OS stratified outcomes: score 4-5 (n = 10, median OS 6 months), score 2-3 (n = 88, median OS 23 months) compared to a score of 0-1 (n = 44, median OS 29 months). CONCLUSIONS Following resection of IVC leiomyosarcomas, recurrence is a near certainty; long-term survival, however is possible. The dominant predictors of survival include margin status, tumor size and radical resection. These can be combined into a risk score that has prognostic value.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: a review of factors contributing to morbidity and mortality

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is associated with prolonged survival for appropriately selected patients with peritoneal dissemination of abdominal malignancies. CRS and HIPEC has been criticized for perceived high rates of morbidity and mortality. Morbidity and mortality rates of CRS and HIPEC, however, do not appear dissimilar to those of other large abdominal surgeries, particularly when relevant patient and operative factors are accounted for. The risk of morbidity and mortality following this surgery for a given individual can be predicted in part by a variety of patient and operative factors. While strong data are lacking, the limited data that exists on the matter suggests that the independent contribution of the heated intraperitoneal chemotherapy to CRS and HIPEC morbidity is relatively small. A more thorough understanding of the patient and operative factors associated with CRS and HIPEC morbidity and mortality, as well as the specific complications related to the intraperitoneal chemotherapy, can better inform clinicians in multidisciplinary teams and patients alike in the decision-making for this surgery.

Primary hyperparathyroidism with negative imaging: a significant clinical problem.

Objective:To compare the outcomes for patients undergoing parathyroidectomy for primary hyperparathyroidism by imaging results. Background:Preoperative imaging plays an increasingly important role in the evaluation of primary hyperparathyroidism, and surgical referral may be predicated upon successful imaging. Methods:We performed a retrospective study of patients undergoing initial parathyroidectomy for primary hyperparathyroidism (2002–2014). Patients were classified as nonlocalized when preoperative imaging failed to identify affected gland(s) and localized if successful. Primary outcome was cure, defined as eucalcemia postoperatively. Intraoperative success, defined by intraoperative parathyroid hormone criteria, and complication rates were also analyzed. Localized and nonlocalized patients were matched (1:1) utilizing a propensity score. Logistic regression determined factors associated with localization in the matched cohort. Results:Of 2185 patients, 38.3% (n = 836) were nonlocalized. Nonlocalized patients had smaller parathyroids by size (1.2 vs 1.6 cm, P < 0.001) and mass (250 vs 537 mg, P < 0.001), higher incidence of hyperplasia (12.8% vs 5.4%, P < 0.001) and lower incidence of single adenoma (73.6 vs 86.0%, P < 0.001) compared with localized patients. There was no difference in intraoperative success (93.9 vs 95.6%, P = 0.073) or cure rates (96.2% vs 97.7%, P = 0.291) between nonlocalized and localized groups. In a propensity-matched cohort of 452 patients, there was no significant difference in cure rates (97.8 vs 97.4%, P = 0.760) between nonlocalized patients and matched localized controls. Conclusions:Nonlocalization of abnormal glands preoperatively is not associated with a decreased surgical cure rate for primary hyperparathyroidism. Referral for surgical evaluation should be based on biochemical diagnosis rather than localization by imaging.

Surgery for metastatic neuroendocrine tumors with occult primaries.

INTRODUCTION Neuroendocrine tumors (NETs) frequently metastasize prior to diagnosis. Although metastases are often identifiable on conventional imaging studies, primary tumors, particularly those in the midgut, are frequently difficult to localize preoperatively. MATERIALS AND METHODS Patients with metastatic NETs with intact primaries were identified. Clinical and pathologic data were extracted from medical records. Primary tumors were classified as localized or occult based on preoperative imaging. The sensitivities and specificities of preoperative imaging modalities for identifying the primary tumors were calculated. Patient characteristics, tumor features, and survival in localized and occult cases were compared. RESULTS Sixty-one patients with an intact primary tumor and metastatic disease were identified. In 28 of these patients (46%), the primary tumor could not be localized preoperatively. A median of three different preoperative imaging studies were utilized. Patients with occult primaries were more likely to have a delay (>6 mo) in surgical referral from time of onset of symptoms (57% versus 27%, P = 0.02). Among the 28 patients with occult primary tumors, 18 (64%) were found to have radiographic evidence of mesenteric lymphadenopathy corresponding, in all but one case, to a small bowel primary. In all but three patients (89%), the primary tumor could be identified intraoperatively. CONCLUSION The primary tumor can be identified intraoperatively in a majority of patients with metastatic NETs, irrespective of preoperative localization status. Referral for surgical management should not, therefore, be influenced by the inability to localize the primary tumor.

Preoperative radiation for retroperitoneal sarcoma is not associated with increased early postoperative morbidity

Preoperative radiation (PR) in the management of retroperitoneal sarcoma (RPS) is controversial. Concern for increased perioperative morbidity may influence the decision to recommend PR. Here we compare 30‐day morbidity and mortality (M + M) after resection of RPS with and without PR.