Philip J. Crowe

Meta-analysis of sentinel node imprint cytology in breast cancer

Intraoperative diagnosis of breast cancer metastases in axillary sentinel nodes is desirable to avoid a second operation for lymphadenectomy. Imprint or touch‐preparation cytology is a popular technique that has high specificity and a wide range of sensitivity.

STAT3 inhibition, a novel approach to enhancing targeted therapy in human cancers (Review)

Signal transducer and activator of transcription 3 (STAT3) regulates many critical functions in human normal and malignant tissues, such as differentiation, proliferation, survival, angiogenesis and immune function. Constitutive activation of STAT3 is implicated in a wide range of human cancers. As such, STAT3 has been studied as a tumour therapeutic target. This review aimed principally to summarise the updated research on STAT3 inhibition studies and their therapeutic potential in solid tumours. Recent literature associated with STAT3 inhibition was reviewed through PubMed and Medline database, followed by critical comparison and analysis. Constitutive activation of STAT3 has been identified as abnormal and oncogenic. The pathway of STAT3 activation and signal transduction identifies 3 approaches for inhibition: modulating upstream positive or negative regulators, regulating RNA (DN-STAT3, anti-sense RNA, siRNA and microRNA) or targeting STAT3 protein at different domains. The last approach using small molecule STAT3 inhibitors has been the most examined so far with both preclinical and clinical studies. Targeting STAT3 using a specific inhibitor may be a useful cancer treatment approach, with the potential for a broad clinical impact.

Urokinase-type plasminogen activator and its receptor in colorectal cancer: Independent prognostic factors of metastasis and cancer-specific survival and potential therapeutic targets

Urokinase‐type plasminogen activator (uPA) and its receptor (uPAR), plasminogen (Plg), and plasminogen activator inhibitors‐1 and ‐2 (PAI‐1 and PAI‐2) have been observed in many cancers and may contribute to progression and metastasis. In our study, we examined the expression of the 5 proteins by immunohistochemistry in 59 consecutive primary colorectal cancers (CRC) and correlated the protein expression with patient outcome. In addition, we determined the effect of down‐regulation of uPAR on the invasive/metastatic capability of CRC cells, by measuring antisense‐uPAR transfected HCT116 and control cell lines, in terms of uPAR expression, uPA‐binding activity, invasiveness through Matrigel in vitro and metastasis after cecal orthotopic implantation in nude mice in vivo. We found that higher expression of uPA or uPAR in primary tumor tissues was positively correlated with distant metastasis of CRC (Mann‐Whitney, p < 0.02) and negatively correlated with both patient overall survival (OS) and cancer‐specific survival (CSS; Cox model, p < 0.04). The prognostic value of uPA and uPAR for both OS and CSS was independent of other variables (multivariate Cox model, p < 0.007). Antisense‐uPAR transfected HCT116 cells, which expressed significantly lower levels of total cellular and cell surface uPAR proteins and uPA‐binding activity compared with either wild‐type or cells transfected with vector alone (Bonferroni, p < 0.05/3), consistently showed decreased invasiveness through Matrigel (Bonferroni, p < 0.05/3) and decreased metastasis formation in nude mice (Fisher, p < 0.05). Our data suggest that uPAR and uPA are independent prognostic factors in CRC; anti‐uPAR treatment, which affects both uPAR and uPA levels, may have potential for new treatment of the disease. Int. J. Cancer 89:431–439, 2000.

Hypomagnesemia and Hypocalcemia after Thyroidectomy: Prospective Study

Abstract. Hypomagnesemia after total thyroidectomy has not been studied extensively. Our anecdotal experience suggests that it may be important in some patients after thyroid excision. The hypomagnesemic hypocalcemic syndrome has been described in other disease states in which a state of functional hypoparathyroidism exists. This study was designed to determine the incidence of hypomagnesemia after total thyroidectomy and relate it to hypocalcemia and symptoms during the postoperative period. A prospective study of all patients undergoing total thyroidectomy between September 1994 and July 1996 was performed. Patient data, thyroid function, retrosternal extension, initial versus reoperative surgery, operative details, parathyroid resection, and pathology were recorded. Calcium, magnesium, electrolytes, blood count, liver function tests, and albumin were measured prior to surgery and twice daily during the postoperative period. Fifty patients underwent total thyroidectomy: 68% were hypocalcemic, 72% were hypomagnesemic, and 36% were symptomatic during the postoperative period. Hypomagnesemia and gender were associated with hypocalcemia. Volume of fluid and neck dissection were associated with low magnesium levels. Hypomagnesemia and parathyroid resection were risk factors for symptoms after thyroidectomy. No patients developed permanent hypoparathyroidism. Transient hypocalcemia and hypomagnesemia occur frequently after total thyroidectomy. The etiology of this phenomenon is probably multifactorial. Patients are more likely to be symptomatic when both cations are low, and attempting to correct only hypocalcemia may prolong symptoms. It is important to monitor both calcium and magnesium levels after total thyroidectomy and to correct deficiencies to facilitate prompt resolution of symptoms.

Comprehensive mapping of p53 pathway alterations reveals an apparent role for both SNP309 and MDM2 amplification in sarcomagenesis

Purpose: Reactivation of p53 tumor suppressor activity in diseases such as soft-tissue sarcoma is considered an attractive means of targeted therapy. By systematically assessing alterations affecting the p53 pathway, we aimed to (a) classify sarcoma subtypes, (b) define a potential role in malignancy, and (c) identify potential patient biomarkers in this heterogeneous disease. Experimental Design: We have mapped mutational events in a panel of 192 benign or malignant bone and soft-tissue sarcomas. Analyses included TP53 and CDKN2A mutational and SNP status, MDM2 and MDM4 amplification and MDM2 SNP309 status. Results: We found an inverse relationship between MDM2 amplification and TP53 mutations, with a predominantly wild-type CDKN2A background. A high rate of point mutations in TP53 was observed uniquely in leiomyosarcoma, osteosarcoma, and MFH. Both MDM2 and MDM4 were also amplified in a subtype-specific manner, which was frequently seen as a coamplification event. We have also analyzed the risk allele frequencies for MDM2 SNP309, and show that the G allele was strongly associated with both liposarcomas and MDM2 amplification. Conclusions: Our data emphasize the critical role of p53 inactivation in sarcomagenesis, whereby different pathway alterations may be related to the heterogeneity of the disease. Moreover, we observed a strong association of malignancy with TP53 mutation, or MDM2 amplification and the presence of a G allele in SNP309, especially in lipoma versus liposarcoma. We propose, therefore, that MDM2 markers along with TP53 sequencing should be considered as patient biomarkers in clinical trials of sarcomas using MDM2 antagonists. Clin Cancer Res; 17(3); 416–26. ©2010 AACR.

Pelvic exenteration for advanced pelvic malignancy.

Pelvic exenteration is a demanding, yet potentially curative operation, for patients with advanced pelvic cancer. The majority will present with recurrence after prior surgery and radiotherapy. After exenteration, 5-year survival is 40% to 60% in patients with gynecologic cancer as compared to 25% to 40% for patients with colorectal cancer. Physiologic age and absence of co-morbidities appear to be more important when selecting patients for exenteration than chronological age. Careful pre-operative staging, including either computed tomography (CT) scan or magnetic resonance imaging (MRI), usually will identify patients with distant metastases, extrapelvic nodal disease, or disease involving the pelvic sidewall (which generally precludes surgery). The recent application of intra-operative radiotherapy or postoperative high-dose brachytherapy for patients with more advanced pelvic disease, which may include sidewall involvement, may expand the standard indications for exenteration. However, the intent of this procedure, with or without radiotherapy, should be resection of all tumor with the aim of cure since the place of palliative exenteration is controversial at best. The operative details of exenteration are presented, as are two surgical approaches to composite resection of pelvic structures in continuity with sacrectomy. Filling the pelvis with large tissue flaps, usually a rectus abdominus flap, has decreased morbidity rates, particularly with small bowel complications. Peri-operative mortality is usually 5% to 10%, and significant morbidity occurs in over 50% of patients. Restorative techniques for both urinary and gastrointestinal tracts can diminish the need for stomas and, along with vaginal reconstruction, can significantly improve quality of life for many patients after exenteration. These advances in surgery and radiotherapy help make the procedure a viable option for patients with otherwise incurable pelvic malignancy.

Acute-care surgical service: a change in culture

The provision of acute surgical care in the public sector is becoming increasingly difficult because of limitation of resources and the unpredictability of access to theatres during the working day. An acute‐care surgical service was developed at the Prince of Wales Hospital to provide acute surgery in a more timely and efficient manner. A roster of eight general surgeons provided on‐site service from 08.00 to 18.00 hours Monday to Friday and on‐call service in after‐hours for a 79‐week period. An acute‐care ward of four beds and an operating theatre were placed under the control of the rostered acute‐care surgeon (ACS). At the end of each ACS roster period all patients whose treatment was undefined or incomplete were handed over to the next rostered ACS. Patient data and theatre utilization data were prospectively collected and compared to the preceding 52‐week period. Emergency theatre utilization during the day increased from 57 to 69%. There was a 11% reduction in acute‐care operating after hours and 26% fewer emergency cases were handled between midnight and 08.00 hours. There was more efficient use of the entire theatre block, suggesting a significant cultural change. Staff satisfaction was high. On‐site consultant‐driven surgical leadership has provided significant positive change to the provision of acute surgical care in our institution. The paradigm shift in acute surgical care has improved patient and theatre management and stimulated a cultural change of efficiency.

Current clinical regulation of PI3K/PTEN/Akt/mTOR signalling in treatment of human cancer

AbstractPurpose PTEN is an essential tumour suppressor gene which encodes a phosphatase protein that antagonises the PI3K/Akt/mTOR antiapoptotic pathway. Impairment of this tumour suppressor pathway potentially becomes a causal factor for development of malignancies. This review aims to assess current understanding of mechanisms of dysfunction involving the PI3K/PTEN/Akt/mTOR pathway linked to tumorigenesis and evaluate the evidence for targeted therapy directed at this signalling axis.MethodsRelevant articles in scientific databases were identified using a combination of search terms, including “malignancies”, “targeted therapy”, “PTEN”, and “combination therapy”. These databases included Medline, Embase, Cochrane Review, Pubmed, and Scopus.ResultsPI3K/PTEN expression is frequently deregulated in a majority of malignancies through genetic, epigenetic, and post-transcriptional modifications. This contributes to the upregulation of the PI3K/Akt/mTOR pathway which has been the focus of intense clinical studies. Targeted agents aimed at this pathway offer a novel treatment approach in a variety of haematologic malignancies and solid tumours. Compared to single-agent use, greater response rates were obtained in combination regimens, supporting further investigation of suitable drug combinations in a broad spectrum of malignancies.ConclusionActivation of the PI3K/PTEN/Akt/mTOR pathway is implicated both in the pathogenesis of malignancies and development of resistance to anticancer therapies. Therefore, PI3K/Akt/mTOR inhibitors are a promising therapeutic option, in association with systemic cytotoxic and biological therapies, to enable sustained clinical outcomes in cancer treatment. Therapeutic strategies could be tailored according to appropriate biomarkers and patient-specific mutation profiles to maximise benefit of combination therapies.

Pattern of equestrian injuries presenting to a Sydney teaching hospital

Background:  Equestrian activities are associated with a high rate of injury. Attempts to reduce the incidence and severity of injury require accurate characterization of risk factors and pattern of injury. The present study was performed to analyse the injuries seen at an Australian centre where a large number of equestrian injuries present.

Higher expression of oncoproteins c-myc, c-erb B-2/neu, PCNA, and p53 in metastasizing colorectal cancer than in nonmetastasizing tumors.

AbstractBackground: Expression of individual oncogenes may predict outcome in patients with metastatic colorectal cancer (CRC). We studied the oncogene profile in the tumors of patients with CRC and assessed their value as predictors of liver metastases. Methods: The oncoproteins c-myc, c-erbB-2/neu (c-neu), PCNA and p53, were measured by immunohistochemistry in sections of metastasizing human CRC (n=34) and their liver secondaries as well as in sections of nonmetastasizing CRC (n=25). Results: The metastasizing primary CRC expressed proliferating-cell nuclear antigen (PCNA), c-neu, and c-myc at significantly higher levels than the nonmetastasizing primary cancer. p53 was also overexpressed in the metastatic group compared with the nonmetastasizing CRC, but this difference was not significant. The frequency of expression of all these markers was similar in the metastasizing primary CRC and the liver secondaries from the same patients. There was no correlation between the expression of the individual markers and histological grade, DNA ploidy, and subsequent local recurrence and lung metastasis and survival. However, when both groups were assessed together, positive expression of c-myc was more likely to occur in poorly differentiated tumors, whereas PCNA expression increased with more advanced Dukes stages. Conclusion: These results suggest that the overexpression of c-myc, c-neu, PCNA, and p53 may occur in CRC that are likely to metastasise to the liver.