FAM46C/TENT5C functions as a tumor suppressor through inhibition of Plk4 activity.

Polo like kinase 4 (Plk4) is a tightly regulated serine threonine kinase that governs centriole duplication. Increased Plk4 expression, which is a feature of many common human cancers, causes centriole overduplication, mitotic irregularities, and chromosomal instability. Plk4 can also promote cancer invasion and metastasis through regulation of the actin cytoskeleton. Herein we demonstrate physical interaction of Plk4 with FAM46C/TENT5C, a conserved protein of unknown function until recently. FAM46C localizes to centrioles, inhibits Plk4 kinase activity, and suppresses Plk4-induced centriole duplication. Interference with Plk4 function by FAM46C was independent of the latter's nucleotidyl transferase activity. In addition, FAM46C restrained cancer cell invasion and suppressed MDA MB-435 cancer growth in a xenograft model, opposing the effect of Plk4. We demonstrate loss of FAM46C in patient-derived colorectal cancer tumor tissue that becomes more profound with advanced clinical stage. These results implicate FAM46C as a tumor suppressor that acts by inhibiting Plk4 activity.

Long-term outcomes following salvage surgery for locally recurrent rectal cancer: A 15-year follow-up study.

BACKGROUND: Locally recurrent rectal cancer (LRRC) is a complex problem requiring multidisciplinary consultation and specialized surgical care. Given the paucity of published longer-term survival data, skepticism persists regarding the benefit of major extirpative surgery. We investigated ultra-long-term (~15 years) outcomes following radical resection of LRRC and sought relevant clinicopathologic prognostic variables. METHODS: A cohort of 52 consecutive patients who underwent resection of LRRC at our institution between 1997 and 2005 were followed with serial exams and imaging up to the point of death, or 30/06/2019. RESULTS: Median follow-up time was 16.5 years (9.9-18.3) for patients who were alive at last follow-up; only one patient was lost to follow-up, at 9.9 years. For the entire cohort of 52 patients, disease-specific survival (DSS) at 5, 10, and 15 years following salvage surgery was 41%, 33%, and 31%, respectively. All patients who had distant metastatic disease at the time of LRRC resection (n = 6) subsequently died of cancer, at a median of 21 months (4-46). In those without distant metastases at time of salvage surgery (n = 46), DSS at 5, 10, and 15 years was 47%, 38%, and 35%, respectively, median 60 months. Negative resection margin (R0) was independently predictive of superior outcomes. In patients with M0 disease who had R0 resection (n = 37), DSS at 5, 10 and 15 years was 58%, 47%, and 44%, respectively, median 73 months. No patient developed re-recurrence after 5.5 years. CONCLUSIONS: This study demonstrates exceptionally durable long-term cancer-free survival following salvage surgery for LRRC, indicating that cure is possible.

A surgical perspective report on melanoma management.

Management of melanoma includes wide excision with adequate margins and lymph node biopsy depending on the depth of the lesion, with subsequent completion lymphadenectomy for positive sentinel node. Locally advanced disease can be approached in several different ways depending on a variety of patient and disease-specific factors. These include surgical resection, isolated limb perfusion and infusion and intralesional injection therapy such as talimogene laherparepvec, IL-2 and Bacille Calmette-Guerin. Ongoing controversy exists regarding the utility of completion lymphadenectomy, and trials such as MSLT-2 will attempt to shed light on this issue. The future of melanoma management will likely focus on expanding the use of immunotherapy, allowing for narrower surgical margins, particularly in sensitive anatomic areas, and limiting the number of completion lymphadenectomies.

Hypophosphatemia and recovery of post-hepatectomy liver insufficiency.

BACKGROUND: Hypophosphatemia (HP) is frequent following liver resection, and thought to represent use of phosphate during liver regeneration. We sought to evaluate the association of post-hepatectomy HP with liver insufficiency and recovery. METHODS: Liver resections were retrospectively reviewed from 2009 to 2012 at a single institution. We explored the relationship between HP (defined as serum phosphate ≤0.65 mmol/L), occurrence of initial liver insufficiency (ILI) [bilirubin >50 µmol/L, international normalized ratio (INR) >1.7 within 72 hours of surgery] and in-hospital recovery of ILI. Secondary outcomes included 30-day post-operative major morbidity (Clavien grade 3 and 4 complications), mortality, and re-admission. RESULTS: Among 402 patients, 223 (55.5%) experienced HP and 64 (15.9%) met our definition of ILI, of which 53 (82.8%) recovered. Length of stay, 30-day post-operative major morbidity, mortality, and re-admission were similar between patients with and without HP. Among patients with ILI, 44 (68.8%) experienced HP. Following ILI, patients with HP recovered more often than those with NP (90.9% vs. 65.0%; P=0.03). CONCLUSIONS: In patients who experience post-hepatectomy ILI, HP is associated with improved recovery, potentially indicating more efficient liver regeneration. Further studies should explore the usefulness of post-hepatectomy HP as an early prognostic factor of recovery from ILI.

Post-mastectomy Radiation: Should Subtype Factor into the Decision?

BACKGROUND: Traditional indications do not factor molecular subtype into the decision making for post-mastectomy radiation (PMRT). We sought to determine whether constructed subtype was associated with receipt of PMRT in an academic cancer center and to assess differences in locoregional recurrence (LRR) by constructed subtype. METHODS: Patients treated with mastectomy as the primary surgical therapy were identified. Univariate and stepwise multivariate logistic regression analyses examined the association between covariates and PMRT. Kaplan-Meier estimates for the time to either the earlier of LRR or last follow-up were obtained for each subtype, and Cox proportional hazards regression examined the effect of covariates on time to LRR in both univariate analyses and stepwise multivariate analysis. RESULTS: Overall, 884 patients with invasive breast cancer who underwent a primary mastectomy between January 2002 and May 2012 were included in the study. A total of 359 patients (41.6 %) received PMRT. Compared with other subtypes, triple negative (TN; HR-/HER2-) cancers were more likely to be smaller (95 % T1/T2; p = 0.02) and have a lower nodal burden (N0 65 %; p < 0.0001). On multivariate analysis, age < 50 years, lymphovascular invasion (LVI), T stage, N stage, and close or positive margins remained significantly associated with PMRT, while constructed subtype was not associated with PMRT. Compared with all other subtypes, TN had the highest rate of LRR [hazard ratio (HR) 5.70; p < 0.0001]. On multivariable analysis, TN status, LVI, and not receiving chemotherapy were significantly associated with LRR. CONCLUSIONS: Despite significant differences in LRR by constructed subtype, receptor status does not appear to be associated with the receipt of PMRT. In our series, TN cancers had the highest risk of LRR despite their relatively smaller size and limited nodal disease.

Understanding Perioperative Transfusion Practices in Gastrointestinal Surgery-a Practice Survey of General Surgeons.

BACKGROUND: Despite guidelines recommending restrictive red blood cell transfusion (RBCT) strategies, perioperative transfusion practices still vary significantly. To understand the underlying mechanisms that lead to gaps in practice, we sought to assess the attitudes of surgeons regarding the perioperative management of anemia and use of RBCT in patients having gastrointestinal surgery. METHODS: We conducted a self-administered Web-based survey of general surgery staff and residents, in a network of eight academic institutions at the University of Toronto. We developed a questionnaire using a systematic approach of items generation and reduction. We tested face and content validity and test-retest reliability. We administered the survey via emails, with planned reminders. RESULTS: Total response rate was 48.1 % (62/125). Half (51.0 %) of respondents stated that they were unlikely to conduct a preoperative anemia work-up. About 54.0 % reported ordering preoperative oral iron supplementation for anemia. Most respondents indicated using a 70 g/L hemoglobin trigger (92.0 %) for transfusion. Factors increasing thresholds above 70 g/L included cardiac comorbidity (58.0 %), acute cardiac disease (94.0 %), symptomatic anemia (68.0 %), and suspected bleeding (58.0 %). With those factors, the transfusion threshold often increased above 90 g/L. Respondents perceived RBCTs to increase the postoperative morbidity (62 %), but not to impact the mortality (48 %) and cancer recurrence (52 %). Institutional protocols (68.0 %), blood conservation clinics (44.0 %), and clinical practice guidelines (84.0 %) were believed to encourage restrictive use of RBCTs. CONCLUSION: Self-reported perioperative transfusion practices for GI surgery are heterogeneous. Few respondents investigated preoperative anemia. Stated use of RBCT indications varied from recommendations in published guidelines for patients with symptomatic anemia. Establishing team consensus and implementing local blood management guidelines appear necessary to improve uptake of evidence-based recommendations.

The impact of pancreaticojejunostomy versus pancreaticogastrostomy reconstruction on pancreatic fistula after pancreaticoduodenectomy: meta-analysis of randomized controlled trials.

BACKGROUND: Pancreatic fistula (PF) remains a common source of morbidity following pancreaticoduodenectomy (PD). Despite numerous studies, the optimal method of pancreatic remnant reconstruction is controversial. This study examines the hypothesis that pancreaticogastrostomy (PG) is associated with a lower risk for PF after PD compared with pancreaticojejunostomy (PJ). METHODS: Five electronic databases and the grey literature were searched for randomized controlled trials (RCTs) comparing PJ and PG after PD. Two reviewers independently selected studies, extracted data and assessed methodology. The primary outcome was the occurrence of PF of International Study Group on Pancreatic Fistula (ISGPF) Grade B or C. RESULTS: Four RCTs including 676 patients were included. Pancreaticogastrostomy reduced the risk for PF [relative risk (RR) 0.41, 95% confidence interval (CI) 0.21-0.62] without any difference between high- and low-risk patients. Absolute risk reduction for PF was 4% (95% CI 2.4-5.6) in low-risk patients compared with 10% (95% CI 6.5-14.8) in high-risk patients undergoing PG rather than PJ. The strength of evidence for PF outcome was moderate according to the GRADE classification. CONCLUSIONS: Reconstruction by PG decreases the rate of PF in comparison with PJ. Surgeons should consider reconstructing the pancreatic remnant following PD with PG, particularly in patients at high risk for PF.

Mucinous tumor of the appendix with limited peritoneal spread: is there a role for expectant observation?

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is now the standard management for mucinous tumors of appendiceal origin at many centers. We examined the role of expectant observation (EO) in patients who had undergone an initial resection at the time of referral to our center and who had limited residual disease. METHODS: We performed a retrospective review of patients referred to Mount Sinai/Princess Margaret Hospitals, Toronto, for consideration of surgical management of peritoneal malignancy between January 1998 and December 2009. One hundred and three patients with primary mucinous appendiceal malignancy were identified. EO, consisting of regularly scheduled imaging and clinical review, was selected for asymptomatic patients with low-grade tumor and no/limited disease on imaging. Overall survival (OS) and progression-free survival (PFS) were determined. RESULTS: Management consisted of supportive care in 7 patients, systemic chemotherapy in 7, referral for CRS with HIPEC in 8, CRS without HIPEC at our center in 51, and EO in 30. In the CRS group, 5-year OS was 74 % and PFS was 56 %; both OS and PFS were predicted by extent of residual disease after cytoreduction (p = 0.014 and p = 0.011, respectively). In the EO group, 5-year OS and PFS were 95 and 82 %, respectively. Two patients in the EO group subsequently underwent CRS for progression on imaging. CONCLUSIONS: In well-selected patients who have undergone initial resection for low-grade mucinous tumor of the appendix with limited peritoneal spread, a formal program of observation can result in excellent 5-year OS and PFS. Longer-term follow-up will help define the benefits and risks of this approach.

Suppression of cancer progression by MGAT1 shRNA knockdown.

Oncogenic signaling promotes tumor invasion and metastasis, in part, by increasing the expression of tri- and tetra- branched N-glycans. The branched N-glycans bind to galectins forming a multivalent lattice that enhances cell surface residency of growth factor receptors, and focal adhesion turnover. N-acetylglucosaminyltransferase I (MGAT1), the first branching enzyme in the pathway, is required for the addition of all subsequent branches. Here we have introduced MGAT1 shRNA into human HeLa cervical and PC-3-Yellow prostate tumor cells lines, generating cell lines with reduced transcript, enzyme activity and branched N-glycans at the cell surface. MGAT1 knockdown inhibited HeLa cell migration and invasion, but did not alter cell proliferation rates. Swainsonine, an inhibitor of α-mannosidase II immediately downstream of MGAT1, also inhibited cell invasion and was not additive with MGAT1 shRNA, consistent with a common mechanism of action. Focal adhesion and microfilament organization in MGAT1 knockdown cells also indicate a less motile phenotype. In vivo, MGAT1 knockdown in the PC-3-Yellow orthotopic prostate cancer xenograft model significantly decreased primary tumor growth and the incidence of lung metastases. Our results demonstrate that blocking MGAT1 is a potential target for anti-cancer therapy.

Is there benefit in referring patients with fibromyalgia to a specialist clinic?

OBJECTIVE: To examine the benefit of specialist rheumatology consultation and followup for the first 238 patients referred to a tertiary care fibromyalgia (FM) clinic with emphasis on final diagnosis and outcome. METHODS: A retrospective chart review was performed for the first 238 patients attending a rheumatology subspecialty FM clinic. The main variables of interest were management received at the clinic, final diagnosis, and outcome. RESULTS: The final diagnosis was FM in 68%, and some other condition in the remaining 32%. Specialist contact was identified as useful in 73% of the total patient group, 96 with FM and 74 with non-FM. In the patients with FM who received followup in the clinic, outcome was judged favorable in 54%, whereas 46% showed no change or decline in health status. CONCLUSION: An important value of specialist rheumatology contact for patients with a symptom suggestive of diffuse musculoskeletal pain is to ensure that some other potentially treatable condition is not overlooked, rather than the provision of ongoing care for those with FM. Continued followup in a specialist clinic for patients with a primary diagnosis of FM is of questionable benefit.