Gastric biomarkers: a global review.

BACKGROUND: Gastric cancer is an aggressive disease with a poor 5-year survival and large global burden of disease. The disease is biologically and genetically heterogeneous with a poorly understood carcinogenesis at the molecular level. Despite the many prognostic, predictive, and therapeutic biomarkers investigated to date, gastric cancer continues to be detected at an advanced stage with resultant poor clinical outcomes. MAIN BODY: This is a global review of gastric biomarkers with an emphasis on HER2, E-cadherin, fibroblast growth factor receptor, mammalian target of rapamycin, and hepatocyte growth factor receptor as well as sections on microRNAs, long noncoding RNAs, matrix metalloproteinases, PD-L1, TP53, and microsatellite instability. CONCLUSION: A deeper understanding of the pathogenesis and biological features of gastric cancer, including the identification and characterization of diagnostic, prognostic, predictive, and therapeutic biomarkers, hopefully will provide improved clinical outcomes.

Pattern of Cortical Fracture following Corticotomy for Distraction Osteogenesis.

Corticotomy is an essential procedure for deformity correction and there are many techniques described. However there is no proper classification of the fracture pattern resulting from corticotomies to enable any studies to be conducted. We performed a retrospective study of corticotomy fracture patterns in 44 patients (34 tibias and 10 femurs) performed for various indications. We identified four distinct fracture patterns, Type I through IV classification based on the fracture propagation following percutaneous corticotomy. Type I transverse fracture, Type II transverse fracture with a winglet, Type III presence of butterfly fragment and Type IV fracture propagation to a fixation point. No significant correlation was noted between the fracture pattern and the underlying pathology or region of corticotomy.

Should noncurative resection of the primary tumour be performed in patients with stage iv colorectal cancer? A systematic review and meta-analysis.

PURPOSE: Surgical resection of the primary tumour in patients with advanced colorectal cancer (crc) remains controversial. This review compares survival in patients with advanced crc who underwent surgical resection of the primary tumour with that in patients not undergoing resection, and determines rates of post-operative mortality and nonfatal complications, the primary tumour complication rate, the non-resection surgical procedures rate, and quality of life (qol). METHODS: Reports in the central, medline, and embase databases were searched for relevant studies, which were selected using pre-specified eligibility criteria. The search was also restricted to publication dates from 1980 onward, the English language, and studies involving human subjects. Screening, evaluation of relevant articles, and data abstraction were performed in duplicate, and agreement between the abstractors was assessed. Articles that met the inclusion criteria were assessed for quality using the Newcastle-Ottawa Scale. Data were collected and synthesized per protocol. RESULTS: From among the 3379 reports located, fifteen retrospective observational studies were selected. Of the 12,416 patients in the selected studies, 8620 (69%) underwent surgery. Median survival was 15.2 months (range: 10-30.7 months) in the resection group and 11.4 months (range: 3-22 months) in the non-resection group. Hazard ratio for survival was 0.69 [95% confidence interval (ci): 0.61 to 0.79] favouring surgical resection. Mean rates of postoperative mortality and nonfatal complications were 4.9% (95% ci: 0% to 9.7%) and 25.9% (95%ci: 20.1% to 31.6%) respectively. The mean primary tumour complication rate was 29.7% (95% ci: 18.5% to 41.0%), and the non-resection surgical procedures rate in the non-resection group was 27.6% (95 ci: 15.4% to 39.9%). No study provided qol data. CONCLUSIONS: Although this review supports primary tumour resection in advanced crc, the results have significant biases. Randomized trials are warranted to confirm the findings.

A biomechanical study comparing plate fixation using unicortical and bicortical screws in transverse metacarpal fracture models subjected to cyclic loading.

The use of bicortical screws to fix metacarpal fractures has been suggested to provide no added biomechanical advantage over unicortical screw fixation. However, this was only demonstrated in static loading regimes, which may not be representative of biological conditions. The present study was done to determine whether similar outcomes are obtained when cyclic loading is applied. Transverse midshaft osteotomies were created in 20 metacarpals harvested from three cadavers. Fractures were stabilised using 2.0 mm mini fragment plates fixed with either bicortical or unicortical screw fixation. These fixations were tested to failure with a three-point bending cyclic loading protocol using an electromechanical microtester and a 1 kN load cell. The mean load to failure was 370 N (SD 116) for unicortical fixation and 450 N (SD 135) for bicortical fixation. Significant differences between these two constructs were observed. A biomechanical advantage was found when using bicortical screws in metacarpal fracture plating.

Platelet-rich plasma (PRP) enhances bone healing in non-united critical-sized defects: a preliminary study involving rabbit models.

INTRODUCTION: The use of bone grafts in treating non- or delayed unions as the result of large bone loss is well established. However, despite good outcomes, the time to achieve complete union is still considerably long. To overcome this problem, the use of platelet-rich plasma (PRP) has been advocated albeit with varying success. To determine the true effectiveness of PRP in treating non-/delayed unions, a study was conducted using (n=12) rabbit models. METHODS AND MATERIALS: Critical-sized defects measuring 2cm created in the midshaft of the right rabbit tibias were stabilised using 2.7-mm small fragment plates. A spacer placed in the defects to create a delay in bone union was replaced at 3 weeks with artificial bone grafts (Coragraft®), with or without PRP. The operated limbs were radiographed following the defect creation and at 3, 7 and 11 weeks (at sacrifice). Bone healing and histological changes were later assessed and scored using the appropriate grading systems. Four groups were compared for quality of healing: (group-A) control group, that is, no PRP or Coragraft; (group-B) PRP; (group-C) Coragraft; and (group-D) PRP and Coragraft. RESULTS: Group-D demonstrated the best bone healing based on radiological, histological and gross findings (Kruskall-Wallis: p<0.05). Group-C had significantly higher scores than group-B, whilst group-A had significantly lower scores than all other groups (Mann-Whitney U: p<0.05). CONCLUSION: The use of PRP with bone graft significantly improves the quality of bone healing. However, the use of PRP without bone substitute does not provide adequate repair tissue and, therefore, provides little benefit when used independently.

Uncommon mucosal metastases to the stomach.

BACKGROUND: Metastases to the stomach from an extra-gastric neoplasm are an unusual event, identified in less than 2% of cancer patients at autopsy. The stomach may be involved by hematogenous spread from a distant primary (most commonly breast, melanoma or lung), or by contiguous spread from an adjacent malignancy, such as the pancreas, esophagus and gallbladder. These latter sites may also involve the stomach via lymphatic or haematogenous spread. We present three cases of secondary gastric malignancy. METHODS/RESULTS: The first is a 19-year-old male who received a diagnosis of testicular choriocarcinoma in September 2004. Metastatic malignancy was demonstrated in the stomach after partial gastrectomy was performed to control gastric hemorrhage. The second is a 75-year-old male, generally well, who was diagnosed with adenocarcinoma of the lung in September 2005. Poorly differentiated adenocarcinoma of the lung was demonstrated in a subsequent biopsy of "gastric polyps". The third is an 85-year-old man with no known history of malignancy who presented for evaluation of iron deficiency anemia by endoscopy in February 2006. Biopsies of the colonic and gastric mucosa demonstrated moderately differentiated invasive colonic adenocarcinoma with metastatic deposits in the stomach. CONCLUSION: While the accurate recognition of these lesions at endoscopy is fraught with difficulty, pathological awareness of such uncommon metastases in the gastric mucosa is essential for accurate diagnosis and optimal patient management.

Pseudomyxoma peritonei--a revisit: report of 2 cases and literature review.

BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare, chronic, relapsing, diagnostically challenging and poorly understood disease characterized by disseminated mucinous ascites and peritoneal implants. CASE PRESENTATION: We report two cases of PMP that represent the two biological variants of disseminated peritoneal adenomucinosis (DPAM)--the benign variant and the peritoneal mucinous carcinomatosis (PMCA)--the malignant variant, both of which were characterized by multiple relapses and progression of the disease despite aggressive management. CONCLUSION: Even with a better understanding and recent advances in the management of these cases, PMP remains an enigmatic disease with a protracted clinical course characterized by multiple recurrences despite surgery and/or chemotherapy. Recognition of PMP as a delayed consequence years later should alert all surgeons to be extremely vigilant when treating mucinous neoplasms of the appendix, with special care being directed towards adequate excision and thorough debridement at the initial diagnosis.

Pathological validity of esophageal endoscopy. How real is what we see? Myth or reality?

The purpose of this study was to characterize the spectrum of esophageal pathology at a provincial tertiary care hospital and to evaluate these findings with their respective endoscopic diagnoses. The pathology slides of 183 esophageal biopsies for the year 2000 were reviewed and classified as esophagitis, intestinal metaplasia, low or high grade dysplasia, adenocarcinoma, squamous cell carcinoma or normal. One hundred and fifteen cases (63%) had complete concordant results with respective endoscopic reports. Sixty-eight cases (37%) had discordant results with inaccurate recognition of Barrett's esophagus in 9% and of esophagitis with a false positive in 16% and false negative in 7%. Although esophagoscopy remains a primary investigative tool in gastroesophageal diseases, evaluation of erythema, inflammation and esophagitis can be misleading. Pathologically confirmed esophagitis can occur in a 'normal' esophagus. Accurate endoscopic recognition of short-segment Barrett's remains a diagnostic challenge.

Colonic carcinoid metastatic to the breast.

Metastatic tumors of the breast are uncommon. Breast metastases from nonmammary malignant neoplasms are rare, accounting for approximately 2% of all breast tumors. We report the case of an ileal carcinoid tumor metastatic to the breast 10 years after the initial diagnosis. A 53-year-old woman presented to our clinic with a palpable breast lump. The mammogram was nonspecific. A lumpectomy was performed that, on frozen section, showed a neoplastic lesion. Permanent sections showed that the tumor was composed of sheets of small uniform cells divided into lobules by delicate vascular septa. Immunohistochemical analysis showed that the lesional cells were strongly positive to the neuroendocrine marker panel of antibodies: chromogranin A, neuron-specific enolase, synaptophysin, serotonin, and low-molecular-weight keratin. The lesional cells were negative to cytokeratins 7 and 20, estrogen and progesterone receptors, carcinoembryonic antigen, and c-Erb-B2 antibodies. The presence of pleomorphic neurosecretory-type granules within the cytoplasm of the tumor cells by ultrastructural analysis strongly suggested a metastatic lesion from a midgut carcinoid. A detailed review of the patient's medical records confirmed a right hemicolectomy for an ileal carcinoid with lymph node and omental metastases that had been performed elsewhere 10 years earlier. A detailed pathologic analysis of this lesion by light microscopy, along with histochemical, immunohistochemical, and ultrastructural analyses, aided in confirming the metastatic nature of the current breast lesion.

Male versus female breast cancers. A population-based comparative immunohistochemical analysis.

CONTEXT: The rate of male breast cancer is a small fraction of that observed in females, thus severely limiting our understanding of the pathogenesis of this condition. It remains unclear whether the biological behavior and tumor progression associated with male breast cancer parallel that of the female form. OBJECTIVES: To evaluate the immunohistochemical profile of male breast carcinomas and to compare this profile with that of stage-matched female breast cancers. DESIGN: Seventy-five cases of primary male breast cancer were identified using the records of the Saskatchewan Cancer Foundation over a period of 26 years (1970-1996). Fifty-nine of these cases had formalin-fixed, paraffin-embedded tissue blocks available for the purposes of this study. All cases were reviewed and a standardized modified Bloom-Richardson grading criterion was applied. Estrogen receptor status, progesterone receptor status, c-Erb-B2 expression, p53 expression, and Bcl-2 expression were evaluated by immunohistochemistry. Results from 240 consecutive cases of stage-matched female breast cancers analyzed in the same laboratory were used as a standard set for comparison. RESULTS: Male breast cancers tended to be high grade (85% grade 3) in comparison with the female breast cancers (50% grade 3). In descriptive analysis across all stages of disease, male carcinomas were more frequently estrogen receptor positive (81% vs 69%) than their female counterparts. Despite their high grade, they were less likely to overexpress p53 (9% vs 28%) and Erb-B2 (5% vs 17%) than the female counterparts. There was no significant difference in either progesterone receptor (63% vs 56%) or Bcl-2 (79% vs 76%) overexpression. Stratified analysis by stage-matched controls showed no statistically significant differences among the men and women with stage I disease. However, in stage II-matched samples, statistically significant differences were observed between the 2 groups. The male cancers were more likely to overexpress estrogen receptor (81.6% vs 64.4%, P = .04), progesterone receptor (71.1% vs 47.5%, P = .01), and Bcl-2 (78.9% vs 69.4%, P = .20). They also showed statistically significant lower expression of p53 (7.9% vs 36.3%, P = .001) and Erb-B2 (5.3% vs 23.8% P = .01). CONCLUSION: Male breast cancers display distinct immunophenotypic differences from those occurring in women, implying a different pathogenesis in the evolution and progression of this disease. Such differences may play key roles in therapeutic management, warranting different treatment strategies in comparison to female breast cancers.

Goblet cell carcinoids of the appendix: immunophenotype and ultrastructural study.

BACKGROUND: Goblet cell carcinoids of the appendix are rare neoplasms with uncertain biological behavior. OBJECTIVE: The aims of our study were to evaluate the immunophenotype of this neoplasm with cell cycle/cell proliferation markers and to understand their histogenesis with ultrastructural analysis using conventional carcinoids as a frame of reference. METHODS: Clinical data and archival pathologic material of all goblet cell carcinoids of the appendix recorded by the Saskatchewan Cancer Registry between 1970 and 1998 were reviewed and evaluated by light microscopy, histochemistry, immunohistochemistry, and electron microscopy. RESULTS: Seven cases of goblet cell carcinoids were identified among 110 cases of conventional carcinoids of the appendix. Histopathology revealed widespread infiltration of the periappendiceal fat in all cases, with extensive perineural invasion. The cells stained strongly positive for mucicarmine, periodic acid-Schiff, periodic acid-Schiff diastase, Alcian blue, cytokeratin, and carcinoembryonic antigen. Most cases were positive for synaptophysin. Increased expression of cell proliferation markers and cell cycle markers was observed. Expression of p53 was strong in one case. Electron microscopy demonstrated the presence of mucinous vacuoles of varying sizes and occasional membrane-bound neuroendocrine granules. CONCLUSIONS: Goblet cell carcinoids of the appendix arise from a pluripotent cell with divergent neuroendocrine and mucinous differentiation. These neoplasms are widely invasive; they demonstrate a high cellular proliferation rate and dysregulation of the cell cycle with up-regulation of cyclin D1 and p21, and down-regulation of p16. Complete removal of the tumor is recommended because of the unpredictable biological behavior of this tumor, which includes delayed local recurrences and lung metastases.

Vaginal metastasis of colon cancer.

True vaginal metastases from colonic cancer are exceedingly rare. This often signals an ominous prognosis. More frequently the vagina is synchronously involved by direct contiguous spread from the colonic lesion. We present a case of sigmoid carcinoma with true metastasis to the vagina that was discovered after an interval of 3 weeks when vaginal discharge became evident. To our knowledge, there are only two other papers in the English language previously documenting this phenomenon.

Gallbladder carcinomas: an immunoprognostic evaluation of P53, Bcl-2, CEA and alpha-fetoprotein.

The p53 gene is the most frequently mutated gene in many human cancers, including those of the colon, breast, lung, esophagus, liver and brain. Such genetically mutated tumours are generally associated with progression of the disease and poor clinical outcome. One hundred cases of documented gallbladder carcinomas were reviewed. Twenty-eight cases were randomly selected to evaluate the expression of P53, Bcl-2, carcinoembryonic antigen (CEA) and alpha-fetoprotein, in both the in situ (19 cases) and invasive components (28 cases) of the tumour by the avidin-biotin complex method of immunohistochemistry. These results were correlated with the mean survival intervals in an effort to clarify the progression of the disease and evaluate their role as prognostic markers. Staining to alpha-fetoprotein and Bcl-2 remained consistently negative to weak insignificant staining in both the in situ and invasive components of the tumour in all cases. P53 staining of the invasive part of the tumour was seen in 24 (86%) of the cases and in 17 (89%) of the in situ component. The in situ staining patterns of P53 were not statistically significant in relation to the mean survival. However, in the invasive component, moderate to strong staining tumours, as seen in 15 (54%) cases, were associated with a mean survival of 8.8 months. A similar trend was also observed with staining patterns to CEA. Eighty-nine per cent of the invasive and 84% of the in situ components of the tumour stained positive to CEA. Moderate to strong staining of both the in situ and the invasive components of the tumours was associated with a mean survival of 10.6 months in 76% of cases. This study shows that altered expressions of P53 and CEA are detectable by immunohistochemistry in gallbladder carcinomas. Tumours with increased expression of P53 and CEA of a strong to moderate staining were associated with poor clinical outcomes as evidenced by their mean survival. A stepwise progression of altered CEA and P53 expression may reflect ongoing progression of the disease from the in situ to the invasive phase. However, such trends need to be evaluated in larger numbers and are thus not considered to be true independent prognostic markers.

Skeletal metastases in colorectal carcinomas: a Saskatchewan profile.

PURPOSE: Colorectal cancer is the third leading cause of cancer-related deaths in the world. Death is usually attributed to progress of the disease with recurrence and metastases. Skeletal metastases in primary colorectal cancer is an uncommon event. When such an event occurs, it is usually a late manifestation of the disease. In our study this phenomenon is analyzed in a population-based database. METHODS: This report is a 25-year retrospective review that covers patients with skeletal metastases secondary to colorectal carcinomas registered at The Saskatchewan Cancer Foundation from 1970 to 1995. The latter is the sole registration agency of all cancers in the one million population base of the province of Saskatchewan. RESULTS: A total of 5,352 cases of primary colorectal carcinomas were seen between 1970 and 1995. Of these, 355 had skeletal metastases. The incidence of osseous metastases in our institution is 6.6 percent. Among the latter, 60 cases (16.9 percent) had skeletal metastases only, whereas 295 cases (83.1 percent) had skeletal metastases in combination with lung, liver or brain metastases. This is in keeping with the fact that solitary skeletal metastases from a primary colonic carcinoma is a rare event, with an incidence of 1.1 percent in our institution. The disease-free interval from the time of diagnosis of the cancer to the onset of skeletal metastases ranged from 10 days to 5,309 days. Thirty-eight percent of the cases with skeletal metastases only were alive at the end of five years in comparison with 16 percent of the cases with skeletal and other metastases. However, there was no significant difference in the ten-year survival curves from the onset of osseous metastases in the two groups. The majority were diagnosed by a bone scan or plain radiography or both. Most cases in our institution received a multimodal treatment consisting of radiotherapy in conjunction with palliative surgery or chemotherapy or both. Radiotherapy was, however, the most effective therapy for painful skeletal metastases. CONCLUSION: Skeletal metastasis is a rare event in primary colorectal carcinomas. Among these cases there is an emerging trend of a different clinical-biological behavior pattern between patients who develop solitary skeletal metastases vs. patients with skeletal and other organ metastases.