Glove and instrument changing to prevent tumour seeding in cancer surgery: a survey of surgeons' beliefs and practices.

Background: Some surgeons change gloves and instruments after the extirpative phase of cancer surgery with the intent of reducing the risk of local and wound recurrence. Although this practice is conceptually appealing, the evidence that gloves or instruments act as vectors of cancer-cell seeding in the clinical setting is weak. To determine the potential effect of further investigation of this question, we surveyed the practices and beliefs of a broad spectrum of surgeons who operate on cancer patients. Methods: Using a modified Dillman approach, a survey was mailed to all 945 general surgeons listed in the College of Physicians and Surgeons of Ontario public registry. The survey consisted of multiple-choice and free-text response questions. Responses were tabulated and grouped into themes, including specific intraoperative events and surgeon training. Predictive variables were analyzed by chi-square test. Results: Of 459 surveys returned (adjusted response rate: 46%), 351 met the inclusion criteria for retention. Of those respondents, 52% reported that they change gloves during cancer resections with the intent of decreasing the risk of tumour seeding, and 40%, that they change instruments for that purpose. The proportion of respondents indicating that they take measures to protect the wound was 73% for laparoscopic cancer resections and 31% for open resections. Training and years in practice predicted some of the foregoing behaviours. The most commonly cited basis for adopting specific strategies to prevent tumour seeding was "gut feeling," followed by clinical training. Most respondents believe that it is possible or probable that surgical gloves or instruments harbour malignant cells, but that a cancer recurrence proceeding from that situation is unlikely. Conclusions: There is no consensus on how gloves and instruments should be handled in cancer operations. Further investigation is warranted.

Clinical features and outcomes of 20 patients with abdominopelvic desmoplastic small round cell tumor.

INTRODUCTION: Desmoplastic small round cell tumor (DSRCT) is a rare mesenchymal malignancy. We describe our experience with treating DSRCT at a large sarcoma referral center. METHODS: A retrospective chart review was performed on DSRCT patients referred to our institution (1998-2014). Pathology specimens were reviewed to confirm the diagnosis. Clinical and imaging were extracted and summarized with descriptive statistics. Univariate analysis was performed to evaluate the association between patient, tumor, and treatment variables and overall survival (OS). RESULTS: In this study cohort of 20 patients, median age at presentation was 29 y (range 18-43) and 90% were male. Fifty-five percent presented with metastasis. Patients underwent chemotherapy (n = 20), radiation therapy (n = 3), and cytoreductive surgery (CRS) (n = 5). Median OS was 22 m (interquartile range: 12-28 m). Five-year OS rate was 20%. Extra-abdominal metastasis was associated with a higher hazard ratio (HR) of mortality (HR: 3.1, 95% C.I. 1.0-9.4, p = 0.04), while CRS improved OS (HR: 0.1, 95% C.I. 0.03-0.7, p = 0.02). CONCLUSIONS: Despite aggressive treatment, less than half of the patients were dead of DSRCT within 2 years of presentation. Although a select group of patients who underwent CRS had improved OS, novel treatments are urgently needed.

Negative predictive value of preoperative computed tomography in determining pathologic local invasion, nodal disease, and abdominal metastases in gastric cancer.

BACKGROUND: Before undergoing curative-intent resection of gastric adenocarcinoma (ga), most patients undergo abdominal computed tomography (ct) imaging to determine contraindications to resection (local invasion, distant metastases). However, the ability to detect contraindications is variable, and the literature is limited to single-institution studies. We sought to assess, on a population level, the clinical relevance of preoperative ct in evaluating the resectability of ga tumours in patients undergoing surgery. METHODS: In a provincial cancer registry, 2414 patients with ga diagnosed during 2005-2008 at 116 institutions were identified, and a primary chart review of radiology, operative, and pathology reports was performed for all patients. Preoperative abdominal ct reports were compared with intraoperative findings and final pathology reports (reference standard) to determine the negative predictive value (npv) of ct in assessing local invasion, nodal involvement, and intra-abdominal metastases. RESULTS: Among patients undergoing gastrectomy, the npv of ct imaging in detecting local invasion was 86.9% (n = 536). For nodal metastasis, the npv of ct was 43.3% (n = 450). Among patients undergoing surgical exploration, the npv of ct for intra-abdominal metastases was 52.3% (n = 407). CONCLUSIONS: Preoperative abdominal ct imaging reported as negative is most accurate in determining local invasion and least accurate in nodal assessment. The poor npv of ct should be taken into account when selecting patients for staging laparoscopy.

A novel role for Plk4 in regulating cell spreading and motility.

Polo family kinase 4 (Plk4) is required for mitotic progression, and is haploinsufficient for tumor suppression and timely hepatocyte polarization in regenerating liver. At the same time, recent evidence suggests that Plk4 expression may have a role in clinical cancer progression, although the mechanisms are not clear. Here we identify a gene expression pattern predictive of reduced motility in Plk4(+/-) murine embryonic fibroblasts (MEFs) and validate this prediction with functional assays of cell spreading, migration and invasion. Increased Plk4 expression enhances cell spreading in Plk4(+/-) MEFs and migration in human embryonic kidney 293T cells, and increases invasion by DLD-1 colon cancer cells. Plk4 depletion impairs invasion of wild-type MEFs and suppresses invasion by MDA-MB231 breast cancer cells. Cytoskeletal reorganization and development of polarity are impaired in Plk4-deficient cells that have been stimulated to migrate. Endogenous Plk4 phosphorylated at the autophosphorylation site S305 localizes to the protrusions of motile cells, coincident with the RhoA GEF Ect2, GTP-bound RhoA and the RhoA effector mDia. Taken together, our findings reveal an unexpected activity of Plk4 that promotes cell migration and may underlie an association between increased Plk4 expression, cancer progression and death from metastasis in solid tumor patients.

Long-term outcomes following resection of retroperitoneal recurrence of colorectal cancer.

BACKGROUND: The role of curative-intent surgery for retroperitoneal recurrence (RPR) of colorectal cancer (CRC) remains controversial. We previously showed 0% mortality and acceptable morbidity in patients who underwent resection of RPR.(1) Here we examine long-term overall and disease-free survival (OS, DFS). METHODS: We identified patients who underwent resection for RPR of CRC between 01/1999 and 02/2010 from two prospective CRC databases. RESULTS: The study cohort was composed of 48 patients (26 women) whose median age was 60 (36-80) years. Eleven patients had previously undergone resection of a different focus of disease recurrence, and 8 patients had additional site(s) of distant metastatic disease at the time of RPR resection. Following surgery for RPR, 5 patients were left with gross residual disease, and 6 had microscopically positive margins. Median follow-up was 32 (3-127) months. At last follow-up, 13 patients had died of cancer and 1 of other causes. For the entire cohort of 48 patients, 5-year OS was 70% (median 80 mo). In univariate analysis, OS was reduced in younger patients (p = 0.003) and in those with gross residual disease (p = 0.033). In patients who had grossly complete resection, 5-year DFS was 49% (median 38 mo). Predictors of reduced DFS on multivariable analysis were young age and R1 resection. CONCLUSION: OS and DFS after resection of RPR in well-selected patients were favorable. Patients with RPR of CRC should be considered for curative-intent surgery with careful discussion at multidisciplinary cancer conference.

Qualitative assessment of patient experiences following sacrectomy.

BACKGROUND AND OBJECTIVES: The primary objective was to investigate patient experiences following sacral resection as a component of curative surgery for advanced rectal cancers, soft tissue and bone sarcomas. METHODS: Qualitative methods were used to examine the experiences, decision-making, quality of life, and supportive care needs of patients undergoing sacrectomy. Patients were identified from two prospective databases between 1999 and 2007. A semi-structured interview guide was generated and piloted. Patient interviews were transcribed verbatim and analyzed using standard qualitative research methodology. Grounded theory guided the generation of the interview guide and analysis. RESULTS: Twelve patients were interviewed (6 female, 32-82 years of age). The mean interview time was 34 min. Five themes were identified, including: (1) the life-changing impact of surgery on both patients' and their family's lives, (2) patient satisfaction with immediate care in hospital, (3) significant chronic pain related to sacrectomy, (4) patients' need for additional information regarding long-term recovery, and (5) patients' gratitude to be alive. CONCLUSIONS: Sacrectomy is a life-changing event for patients and their families. Patients undergoing sacrectomy need further information regarding the long-term consequences of this procedure. This need should be addressed in both preoperative multi-disciplinary consultations and at follow-up visits.

Comparative expression of the mitotic regulators SAK and PLK in colorectal cancer.

BACKGROUND: Disruption of normal mechanisms for cell cycle regulation is important in carcinogenesis. SAK and PLK are members of the polo family of serine threonine kinases, which in lower organisms have been shown to be required for the precise regulation of mitosis. Studies of human polo family members have focused on PLK, which has been found to be overexpressed in several tumor types, with the degree of overexpression correlating with adverse clinical outcome. However, PLK expression had not previously been analyzed in colorectal cancer. SAK, a polo family member with unique properties, had not been systematically studied in any tumor type. METHODS: In this study, SAK expression was evaluated in a series of sporadic human colorectal cancer specimens (n = 74) and compared with that of PLK. Expression was assessed by reverse transcription-polymerase chain reaction. RESULTS: In the majority of cases, both SAK and PLK were more highly expressed in tumor tissue than in adjacent normal intestinal mucosa. Levels of SAK and PLK expression in tumor relative to paired normal mucosa correlated directly with patient age and with each other but did not correlate with tumor stage. These results suggest a mechanism for augmented disruption of mitotic regulation in older patients. CONCLUSIONS: The polo family mitotic regulators SAK and PLK are both aberrantly expressed in colorectal cancer. The potential prognostic significance of SAK and PLK expression in colorectal cancer will be evaluated in the future.

Palliative general surgical procedures.

Two types of procedure may be indicated in incurable patients. The first is palliative, in which the goal of intervention is relief of symptoms. The second type is supportive, where the procedure is a technical intervention done as part of a multidisciplinary treatment plan. The most minimally invasive but effective procedure is chosen. Procedures are categorized by the type of symptom the procedure is intended to relieve. This article emphasizes the principles involved in patient selection and outcome assessment in order to identify areas where more research is needed.

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.

Malignant gastrointestinal stromal tumors of the small intestine: a review of 50 cases from a prospective database.

BACKGROUND: Malignant gastrointestinal stromal tumors (M-GIST) are rare mesenchymal tumors originating in the wall of the gastrointestinal (GI) tract. Previous studies have included limited numbers of patients, and most included malignant and benign cases from throughout the GI tract. We reviewed the experience of a single tertiary cancer care center with M-GIST of the small intestine only. METHODS: A prospective database identified all patients seen from 1989 to 1998. Clinical and pathological data, treatment, and outcome were analyzed. Overall median follow-up time was 24 months (range, 1-176 months). RESULTS: Fifty patients (31 male, 19 female) were identified. Mean age at diagnosis was 55 years. Disease was localized in 11 patients, locally advanced (invasion into adjacent organs/peritoneum) in 24 patients, perforated in 4 patients, multiple primary lesions in 2 patients, and distant metastases in 9 patients. All patients underwent resection, which was complete in 70%. Locoregional recurrence (LR) developed in 43% (median, 25 months), and distant metastases in 59% (median, 21 months) of patients at risk. At last follow-up, 14 patients were alive (6 disease-free), 2 had died disease-free, and 34 died with recurrent disease. Overall survival (OS) was similar for localized and locally advanced disease; OS also was similar for patients with multiple primaries and distant metastases at diagnosis. Patients were grouped into three stages: (I) patients with localized and locally advanced disease; (II) patients with perforated; and (III) patients with multiple primaries and distant metastases. Actuarial OS at 5 years was 41% (n = 50)--42% for those with complete resection and 8% for incomplete resection. Univariable analysis showed that earlier stage at diagnosis (P = .001) and completeness of resection (P = .004) predicted for longer OS. CONCLUSIONS: Most patients with M-GIST of the small intestine relapse following resection, but survival may be prolonged. In univariable analysis, stage at presentation and complete resection were significant prognostic variables for OS; grade was not significant. Localized and locally advanced M-GIST of the small intestine have a mean OS > 5 years. Complete resection should be the goal of initial surgical treatment.

Recent progress in the management of retroperitoneal sarcoma.

Retroperitoneal sarcomas (RPS) are rare tumours that typically present late and carry a poor prognosis even following grossly complete resection. In an attempt to improve the outlook for patients with RPS, sarcoma specialists have employed various adjuvant therapies, including extermal beam radiation, intraoperative radiation, brachyradiation and systemic chemotherapy. This article reviews the presentation and prognosis of RPS, and focuses on the results of new treatment strategies compared with conventional management.A Medline search of the English literature was performed to identify all retrospective and prospective reports relating to the management of adult RPS published since 1980. Series that did not analyse RPS separately from other intra-abdominal or extra-abdominal sarcomas or other malignancies were excluded, and information on investigation, presentation, prognostic factors, treatment and outcome was extracted from the remaining reports. Survival and local control data were collected from reports that contained at least 30 cases of RPS (n = 31).While surgical resection remains the cornerstone of treatment for RPS, the majority of patients will relapse and die from sarcoma within 5 years of resection. Adjuvant radiation may improve these results, but further trials are required to definitively demonstrate its benefit. Possible reasons for the failure of conventional treatment are discussed, and alternative strategies designed to overcome these obstacles are presented.

Regulation of human monocyte proMMP-9 production by fetuin, an endogenous TGF-beta antagonist.

Members of the matrix metalloproteinase family of enzymes degrade specific components of the extracellular matrix. MMP-9 is a type IV/V collagenase necessary for normal osteogenesis and is increased in inflammatory and neoplastic conditions. In such destructive diseases as emphysema and arthritis, and in epithelial cancers, MMP-9 is produced by cells of the monocyte lineage. Fetuin, a prominent serum glycoprotein, binds to and inactivates TGF-beta family members and through this mechanism regulates osteogenesis (Binkert et al., 1999, J Biol Chem 274:28514-28520.). We studied the effects of TGF-beta1 and fetuin on proMMP-9 release by the human monocyte line THP-1. Exogenous TGF-beta1 stimulated proMMP-9 release by THP-1 cells, with half-maximal stimulation at approximately 0.01 ng/ml TGF-beta1. Human fetuin (0.5-2 microM) partially inhibited this stimulation. Human fetuin alone stimulated THP-1 monocyte proMMP-9 release, with half maximal stimulation at approximately 0.25 microM fetuin. Neutralizing antibody specific for TGF-beta1 also stimulated proMMP-9 release, suggesting that endogenously-derived TGF-beta1 has an inhibitory effect. In freshly isolated human peripheral blood monocytes, fetuin stimulated proMMP-9 release with a dose-response curve similar to that observed in THP-1 cells. Human fetuin also activated proMMP-9 present in THP-1 conditioned medium. Taken together, these data suggest that under physiological conditions, fetuin facilitates matrix degradation by monocyte-derived MMP-9, both by opposing the autocrine inhibitory effect of endogenous TGF-beta1 on proMMP-9 release, and by activating proMMP-9 in the pericellular milieu. Conversely, fetuin may limit the stimulation of monocyte proMMP-9 release by high levels of exogenous TGF-beta1. Such modulation could prove important under pathological conditions where TGF-beta1 derived from paracrine sources is abundant, such as in epithelial malignancies.

The local management of soft tissue sarcoma.

Soft tissue sarcomas (STS) are rare tumors arising from the connective tissues. STS can arise at any anatomic site, can demonstrate varied behavior and prognosis, and therefore present a formidable challenge in management. The local treatment of STS demands technical complexity in the application of diagnostic tools, including pathology and imaging, as well as treatment approaches, including surgical ablation and reconstruction, radiotherapy, and, in defined cases, chemotherapy. The understanding of the management of these lesions is profoundly dependent on the multidisciplinary setting, where experience has been gained and skills are available to increase the likelihood of a successful result. Several proven options are available for optimal local management, and the choice of approach depends on the prevailing practice and resource profile of the treating center. With modern approaches, the local control rate can be expected to be at least 90% for extremity lesions, which constitute the most common STS. The experience in other anatomic sites is less favorable as a result of a combination of late diagnosis, technically difficult access sites, and possibly less familiarity with these less common presentations. The disappointing results make it all the more important for patients to be referred to a multidisciplinary setting with experience in sarcoma management to maximize the chance of successful local outcome.

Approaches to local salvage of soft tissue sarcoma after primary site failure.

Improvements in pretreatment evaluation and the wider application of specialized multidisciplinary care have substantially reduced the risk of local recurrence for patients with soft tissue sarcomas arising at any site, and the recurrences that are still seen are often those that are most difficult to manage effectively. The management strategy for an isolated local recurrence of soft tissue sarcoma is usually similar to that used for primary disease. With appropriate pretreatment evaluation and salvage therapy that includes a multidisciplinary approach, most patients with local recurrence can expect local disease control and a good functional outcome. The development of effective management of a local recurrence is often a complex problem. The necessary decisions are influenced by the tumor location, disease extent, and previous local therapy. The need for specialized care is stressed. Patient evaluation, management strategies, and expected outcome for various clinical scenarios are discussed.

Metastatic colorectal cancer cells induce matrix metalloproteinase release by human monocytes.

Matrix metalloproteinases-2 (MMP-2) and -9 (MMP-9) facilitate tumor invasion and metastasis via basement membrane degradation. In colorectal cancer (CRC) specimens, MMP production is largely stromal in origin, implicating monocytes (M phi s) and fibroblasts. We hypothesize that CRC cells induce stromal cell MMP production. This study examines the differential effect of metastatic and non-metastatic CRC cells on M phi MMP production. The human M phi line THP-1 was co-cultured with either a non-metastatic human CRC cell line (SW620-P) or a metastatic clone (SW620-S5) established by serial cecal transplantation of SW620-P in nude mice. Conditioned medium MMP activity and cellular MMP mRNA expression were assessed by gelatinase zymography and Northern blot analysis, respectively. Neither CRC line released MMP-2 or MMP-9. Isolated THP-1 M phi s produced basal levels of both MMP-2 and MMP-9. The level of MMP-9 activity was increased moderately by co-culture of M phi s with the metastatic SW620-S5 clone, but decreased by the non-metastatic SW620-P cells. MMP-2 activity was greatly augmented by co-culturing M phi s with SW620-S5 cells, but was not affected by SW620-P cells. The stimulatory effect of SW620-S5 cells on MMP-2 secretion was confirmed by Western blot analysis. Both isolated and co-cultured M phi s expressed MMP-2 mRNA while SW620-S5 cells under similar conditions did not, implicating M phi s as the source of increased MMP-2 activity. Since the induction of MMP-2 activity was not associated with a parallel increase in M phi MMP-2 mRNA, the modulation of M phi MMP-2 release appears to be post-transcriptionally regulated. Metastatic CRC cells are distinct from non-metastatic cells in their ability to induce M phi MMP release. This observation emphasizes the role of M phi-derived MMPs in facilitating CRC invasion and metastasis and suggests modulation of stromal cell MMP production by CRC cells in a paracrine fashion.

Relative roles of Na+/H+ exchange and vacuolar-type H+ ATPases in regulating cytoplasmic pH and function in murine peritoneal macrophages.

Two distinct mechanisms have been shown to mediate cytoplasmic pH (pHi) recovery in acid-loaded peritoneal macrophages (M phi s): Na+/H+ exchange and H+ extrusion by vacuolar-type (V-type) H+ ATPases. The present studies examined the relative roles of these two systems in maintaining pHi and cell function. Measurements of M phi pHi and superoxide (O2-) production in response to stimulation with 12-O-tetradecanoyl phorbol 13-acetate (TPA) were made at physiological or acidic extracellular pH (pHo) levels. The V-type H+ ATPase inhibitor, bafilomycin A1, and the potent Na+/H+ exchange inhibitor, N-ethyl-N-propylamino amiloride (EPA), were used to examine the contributions of these ion transporters to pHi regulation and cell function. At pHo 7.35, the complementary activities of the Na+/H+ antiport and the V-type H+ ATPase mediate pHi homeostasis. At pHo 6.7, maintenance of pHi depends primarily on H+ ATPase activity: bafilomycin A1 reduced pHi from 6.8 +/- 0.02 in control cells to 6.59 +/- 0.01 (P < 0.01) while EPA was without effect. The functional importance of V-type H+ ATPase-activity in preserving pHi homeostasis at acidic extracellular pH levels was reflected by the impairment of O2- production at pHo 6.70 when H+ ATPase activity was inhibited: bafilomycin A1 reduced O2- production from 13.9 +/- 1.0 to 9.3 +/- 0.6 nmoles/10(6) cells/40 min, in control and bafilomycin A1-treated cells, respectively (P < 0.05), while EPA had no effect. In subsequent studies, pHi was independently manipulated using the ionophore nigericin. Lowering pHi from 6.80 to 6.60 reduced O2- production from 15.3 +/- 1.8 to 9.8 +/- 1.6 nmoles/10(6) cells/40 min (P < 0.05), indicating that the cytoplasmic acidification resulting from inhibition of H+ ATPases at low pHo could account for the associated impairment of O2- production. In a more profoundly acidic environment (pHo 6.35), H+ ATPases remained active in regulating pHi, but could not preserve a sufficiently physiological pHi to support respiratory burst activity. V-type H+ ATPases constitute the dominant mechanism by which the pHi of peritoneal M phi s is maintained in an acidic extracellular environment.

Lipopolysaccharide impairs macrophage cytoplasmic pH regulation under conditions simulating the inflammatory microenvironment.

Within the acidic inflammatory milieu, macrophages (m phi s) must maintain their cytoplasmic pH (pHi) within a range conducive to optimal function. It was previously shown that metabolism of L-arginine at concentrations present in vitro in RPMI medium (1.14 mM) impairs the ability of m phi s to regulate pHi. However, concentrations of L-arginine in vivo reportedly range from approximately 100 microM in serum to less than or equal to 50 microM in wounds. To investigate the potential in vivo relevance of this inhibition, m phi pHi regulation was examined following incubation with low concentrations of L-arginine that mimic the inflammatory microenvironment, in the presence or absence of lipopolysaccharide (LPS). pHi regulation was evaluated as the ability of thioglycolate-elicited murine peritoneal m phi s to recover from an imposed cytoplasmic acid load. The m phi pHi was measured using a pH-sensitive fluorescent probe. Following incubation for 2 h in the absence of LPS, the pHi recovery rate was equivalent in cells incubated with and without L-arginine. Coincubation with LPS, however, resulted in marked inhibition of pHi recovery at L-arginine concentrations as low as 12.5 microM. The inhibition was not due to LPS alone, since LPS without L-arginine was not inhibitory. Inhibition of pHi recovery was observed at LPS concentrations ranging from 10 ng/ml to 10 micrograms/ml. The L-arginine-dependent inhibition was apparent within 60 min of exposure to LPS, in both freshly harvested cells and cells preincubated for 2 h in the absence of L-arginine and then exposed to both L-arginine and LPS. Under conditions mimicking the in vivo setting, LPS-stimulated L-arginine metabolism impairs m phi pHi regulation. Modulation of pHi by this mechanism may compromise m phi function within the acidic microenvironment of inflammation.