Carol J. Swallow

Late mitotic failure in mice lacking Sak, a polo-like kinase

Polo-like kinases in yeast, flies, and mammals regulate key events in mitosis. Such events include spindle formation at G2/M, the anaphase-promoting complex (APC) at the exit from mitosis, the cleavage structure at cytokinesis, and DNA damage checkpoints in G2/M. Polo-like kinases are distinguished by two C-terminal polo box (pb) motifs, which localize the enzymes to mitotic structures. We previously identified Sak, a novel polo-like kinase found in Drosophila and mammals. Here, we demonstrate that the Sak kinase has a functional pb domain that localizes the enzyme to the nucleolus during G2, to the centrosomes in G2/M, and to the cleavage furrow during cytokinesis. To study the role of Sak in embryo development, we generated a Sak null allele, the first polo-like kinase to be mutated in mice. Sak(-/-) embryos arrested after gastrulation at E7.5, with a marked increase in mitotic and apoptotic cells. Sak(-/-) embryos displayed cells in late anaphase or telophase that continued to express cyclin B1 and phosphorylated histone H3. Our results suggest that Sak is required for the APC-dependent destruction of cyclin B1 and for exit from mitosis in the postgastrulation embryo.

Nucleolar release of Hand1 acts as a molecular switch to determine cell fate

The bHLH transcription factor Hand1 is essential for placentation and cardiac morphogenesis in the developing embryo. Here we implicate Hand1 as a molecular switch that determines whether a trophoblast stem cell continues to proliferate or commits to differentiation. We identify a novel interaction of Hand1 with a protein that contains an I-mfa (inhibitor of myogenic factor) domain that anchors Hand1 in the nucleolus where it negatively regulates Hand1 activity. In the trophoblast stem-cell line Rcho-1, nucleolar sequestration of Hand1 accompanies sustained cell proliferation and renewal, whereas release of Hand1 into the nucleus leads to its activation, thus committing cells to a differentiated giant-cell fate. Site-specific phosphorylation is required for nucleolar release of Hand1, for its dimerization and biological function, and this is mediated by the non-canonical polo-like kinase Plk4 (Sak). Sak is co-expressed in Rcho-1 cells, localizes to the nucleolus during G2 and phosphorylates Hand1 as a requirement for trophoblast stem-cell commitment to a giant-cell fate. This study defines a novel cellular mechanism for regulating Hand1 that is a crucial step in the stem-cell differentiation pathway.

TOPGEAR: a randomised phase III trial of perioperative ECF chemotherapy versus preoperative chemoradiation plus perioperative ECF chemotherapy for resectable gastric cancer (an international, intergroup trial of the AGITG/TROG/EORTC/NCIC CTG)

BackgroundThe optimal management of patients with resectable gastric cancer continues to evolve in Western countries. Following publication of the US Intergroup 0116 and UK Medical Research Council MAGIC trials, there are now two standards of care for adjuvant therapy in resectable gastric cancer, at least in the Western world: postoperative chemoradiotherapy and perioperative epirubicin/cisplatin/fluorouracil (ECF) chemotherapy.We hypothesize that adding chemoradiation to standard perioperative ECF chemotherapy will achieve further survival gains. We also believe there are advantages to administering chemoradiation in the preoperative rather than postoperative setting. In this article, we describe the TOPGEAR trial, which is a randomised phase III trial comparing control arm therapy of perioperative ECF chemotherapy with experimental arm therapy of preoperative chemoradiation plus perioperative ECF chemotherapy.Methods/DesignEligible patients with resectable adenocarcinoma of the stomach or gastroesophageal junction will be randomized to receive either perioperative chemotherapy alone (3 preoperative and 3 postoperative cycles of ECF) or perioperative chemotherapy plus preoperative chemoradiation. In the chemoradiation arm, patients receive 2xa0cycles of ECF plus chemoradiation prior to surgery, and then following surgery 3 further cycles of ECF are given.The trial is being conducted in two Parts; Part 1 (phase II component) has recruited 120 patients with the aim of assessing feasibility, safety and preliminary efficacy of preoperative chemoradiation. Part 2 (phase III component) will recruit a further 632 patients to provide a total sample size of 752 patients. The primary endpoint of the phase III trial is overall survival. The trial includes quality of life and biological substudies, as well as a health economic evaluation. In addition, the trial incorporates a rigorous quality assurance program that includes real time central review of radiotherapy plans and central review of surgical technique.DiscussionTOPGEAR is an international, intergroup collaboration led by the Australasian Gastro-Intestinal Trials Group (AGITG), in collaboration with the Trans-Tasman Radiation Oncology Group (TROG), European Organisation for Research and Treatment of Cancer (EORTC) and the NCIC Clinical Trials Group. It addresses a globally significant question that will help inform future international standards for clinical practice in resectable gastric cancer.Trial registrationAustralian New Zealand Clinical Trials Registry: ACTRN12609000035224. Registered 30 May 2009

TOPGEAR: A Randomized, Phase III Trial of Perioperative ECF Chemotherapy with or Without Preoperative Chemoradiation for Resectable Gastric Cancer: Interim Results from an International, Intergroup Trial of the AGITG, TROG, EORTC and CCTG

BackgroundPostoperative chemoradiation and perioperative chemotherapy using epirubicin/cisplatin/5-fluorouracil (ECF) represent two standards of care for resectable gastric cancer. In the TOPGEAR (Trial Of Preoperative therapy for Gastric and Esophagogastric junction AdenocaRcinoma) trial, we hypothesized that adding preoperative chemoradiation to perioperative ECF will improve survival; however, the safety and feasibility of preoperative chemoradiation have yet to be determined.MethodsTOPGEAR is an international phase III trial in which patients with adenocarcinoma of the stomach were randomized to perioperative ECF alone or with preoperative chemoradiation. The ECF-alone group received three preoperative cycles of ECF, while the chemoradiation group received two cycles of preoperative ECF followed by chemoradiation. Both groups received three postoperative cycles of ECF. A planned interim analysis of the first 120 patients was conducted, and was reviewed by the Independent Data Safety Monitoring Committee to assess treatment compliance, toxicity/safety, and response rates.ResultsThe proportion of patients who received all cycles of preoperative chemotherapy was 93% (ECF group) and 98% (chemoradiation group), while 65 and 53%, respectively, received all cycles of postoperative chemotherapy. Overall, 92% of patients allocated to preoperative chemoradiation received this treatment. The proportion of patients proceeding to surgery was 90% (ECF group) and 85% (chemoradiation group). Grade 3 or higher surgical complications occurred in 22% of patients in both groups. Furthermore, grade 3 or higher gastrointestinal toxicity occurred in 32% (ECF group) and 30% (chemoradiation group) of patients, while hematologic toxicity occurred in 50 and 52% of patients.ConclusionsThese results demonstrate that preoperative chemoradiation can be safely delivered to the vast majority of patients without a significant increase in treatment toxicity or surgical morbidity.

Function and quality of life after transanal excision of rectal polyps and cancers.

PurposeThe purpose of this study was to determine the functional outcomes and health-related quality of life of patients after transanal excision of rectal cancers or polyps and to assess the relationship between functional outcomes and health-related quality of life.MethodsAll patients having a transanal excision at the Mount Sinai Hospital from 1989 to 2002 were included if the indication for surgery was a benign or malignant neoplasm. Physician charts were reviewed, and patients and their physicians were contacted to obtain follow-up information. Continence was assessed by using the Continence Score described by Jorge and Wexner and the Fecal Incontinence Quality of Life instrument by Rockwood and Lowry.ResultsEighty-two patients fit the inclusion criteria (42 males; mean age, 71u2009±u200913.7xa0years). Of these, 29 had villous adenomas, 2 had carcinoids, and 1 had a hyperplastic polyp. Fifty had cancers, including 34 with T1, 14 with T2, and 2 with T3 cancers. Seven patients had a low anterior resection or abdominoperineal resection within two months of transanal excision because of advanced features of cancer. Five patients had salvage abdominoperineal resections or low anterior resections for local recurrences. Five patients died of rectal cancer (including 3 who had salvage surgery) and an additional seven patients died of other causes. Functional results were assessed in 58 of 61 eligible patients. The mean Continence Score postoperatively was 3.5u2009±u20093.9 compared with 2.4u2009±u20093.7 preoperatively (Pu2009=u20090.03). The mean Fecal Incontinence Quality of Life scores after surgery in all patients were 3.9u2009±u20090.3, 3.6u2009±u20090.6, 3.7u2009±u20090.3, 3.7u2009±u20090.6 in the domains of lifestyle, coping, depression, and embarrassment, respectively, after surgery, indicating high quality of life. Using Spearman’s correlation, we found that the continence scores after surgery correlated well with the Fecal Incontinence Quality of Life scores. In the domains of lifestyle (Spearman’s correlationu2009=u2009−0.69), coping and behavior (Spearman’s correlationu2009=u2009−0.7), and embarrassment (Spearman’s correlationu2009=u2009−0.61) but did not correlate well with the domain of depression (Spearman’s correlationu2009=u2009−0.17).ConclusionsAlthough functional results are worsened in a minority of patients after transanal excision, quality of life is high in the majority of patients.

Mucinous Tumor of the Appendix with Limited Peritoneal Spread: Is There a Role for Expectant Observation?

AbstractBackgroundnCytoreductive 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.MethodsWe 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 hundredxa0and 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.ResultsManagement 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 74xa0% and PFS was 56xa0%; both OS and PFS were predicted by extent of residual disease after cytoreduction (pxa0=xa00.014 and pxa0=xa00.011, respectively). In the EO group, 5-year OS and PFS were 95 and 82xa0%, respectively. Two patients in the EO group subsequently underwent CRS for progression on imaging.ConclusionsIn 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.