The role of infiltrating lymphocytes in the neo-adjuvant treatment of women with HER2-positive breast cancer.

BACKGROUND: Pre-treatment tumour-associated lymphocytes (TILs) and stromal lymphocytes (SLs) are independent predictive markers of future pathological complete response (pCR) in HER2-positive breast cancer. Whilst studies have correlated baseline lymphocyte levels with subsequent pCR, few have studied the impact of neoadjuvant therapy on the immune environment. METHODS: We performed TIL analysis and T-cell analysis by IHC on the pretreatment and 'On-treatment' samples from patients recruited on the Phase-II TCHL (NCT01485926) clinical trial. Data were analysed using the Wilcoxon signed-rank test and the Spearman rank correlation. RESULTS: In our sample cohort (n = 66), patients who achieved a pCR at surgery, post-chemotherapy, had significantly higher counts of TILs (p = 0.05) but not SLs (p = 0.08) in their pre-treatment tumour samples. Patients who achieved a subsequent pCR after completing neo-adjuvant chemotherapy had significantly higher SLs (p = 9.09 × 10-3) but not TILs (p = 0.1) in their 'On-treatment' tumour biopsies. In a small cohort of samples (n = 16), infiltrating lymphocyte counts increased after 1 cycle of neo-adjuvant chemotherapy only in those tumours of patients who did not achieve a subsequent pCR. Finally, reduced CD3 + (p = 0.04, rho = 0.60) and CD4 + (p = 0.01, rho = 0.72) T-cell counts in 'On-treatment' biopsies were associated with decreased residual tumour content post-1 cycle of treatment; the latter being significantly associated with increased likelihood of subsequent pCR (p < 0.01). CONCLUSIONS: The immune system may be 'primed' prior to neoadjuvant treatment in those patients who subsequently achieve a pCR. In those patients who achieve a pCR, their immune response may return to baseline after only 1 cycle of treatment. However, in those who did not achieve a pCR, neo-adjuvant treatment may stimulate lymphocyte influx into the tumour.

The prognostic value of tumour regression grade following neoadjuvant chemoradiation therapy for rectal cancer.

AIM: To date, there is no uniform consensus on whether tumour regression grade (TRG) is predictive of outcome in rectal cancer. Furthermore, the lack of standardization of TRG grading is a major source of variability in published studies. The aim of this study was to evaluate the prognostic impact of TRG in a cohort of patients with locally advanced rectal cancer treated with neoadjuvant chemoradiation therapy (CRT). In addition to the Mandard TRG, we utilized four TRG systems modified from the Mandard TRG system and applied them to the cohort to assess which TRG system is most informative. METHOD: One-hundred and fifty-three patients with a T3/T4 and/or a node-positive rectal cancer underwent neoadjuvant 5-fluorouracil-based CRT followed by surgical resection. RESULTS: Thirty-six (23.5%) patients achieving complete pathological response (ypCR) had a 5-year disease-free survival (DFS) rate of 100% compared with a DFS rate of 74% for 117 (76.5%) patients without ypCR (P = 0.003). The Royal College of Pathologists (RCPath) TRG best condenses the Mandard five-point TRG by stratifying patients into three groups with distinct 5-year DFS rates of 100%, 86% and 67%, respectively (P = 0.001). In multivariate analysis, pathological nodal status and circumferential resection margin (CRM) status, but not TRG, remained significant predictors of DFS (P = 0.002, P = 0.035 and P = 0.310, respectively). CONCLUSION: Our findings support the notion that ypCR status, nodal status after neoadjuvant CRT and CRM status, but not TRG, are predictors of long-term survival in patients with locally advanced rectal cancer.

Inflammatory pseudotumours of the liver--role of dynamic MRI scan and surgical exploration.

Inflammatory pseudotumours of the liver are extremely rare benign lesions. They were first described by Pack and Baker in 1953. They usually present with raised inflammatory markers and nonspecific abdominal symptoms. Most of these lesions are picked up incidentally on ultrasound scans. Diagnosis of these lesions poses a dilemma and a challenge due to their radiological similarities to other liver lesions such as hepatocellular carcinoma HCC. In this article we describe our experience in its diagnosis and management.

Signal pathway profiling of epithelial and stromal compartments of colonic carcinoma reveals epithelial-mesenchymal transition.

Molecular crosstalk, including reciprocal stimulation, is theorized to take place between epithelial cancer cells and surrounding non-neoplastic stromal cells. This is the rationale for stromal therapy, which could eliminate support of a cancer by its genetically stable stroma. Epithelial-stromal crosstalk is so far poorly documented in vivo, and cell cultures and animal experiments may not provide accurate models. The current study details stromal-epithelial signalling pathways in 35 human colon cancers, and compares them with matched normal tissues using quantitative proteomic microarrays. Lysates prepared from separately microdissected epithelium and stroma were analysed using antibodies against 61 cell signalling proteins, most of which recognize activated phospho-isoforms. Analyses using unsupervised and supervised statistical methods suggest that cell signalling pathway profiles in stroma and epithelium appear more similar to each other in tumours than in normal colon. This supports the concept that coordinated crosstalk occurs between epithelium and stroma in cancer and suggests epithelial-mesenchymal transition. Furthermore, the data herein suggest that it is driven by cell proliferation pathways and that, specifically, several key molecules within the mitogen-activated protein kinase pathway may play an important role. Given recent findings of epithelial-mesenchymal transition in therapy-resistant tumour epithelium, these findings could have therapeutic implications for colon cancer.

Laparoscopic colorectal resection: initial experience in a specialist unit.

The adoption of the laparoscopic approach to colorectal resection has been slow amongst colorectal surgeons principally due to concerns regarding oncological safety. Recent randomized controlled trials have confirmed both the safe and some advantage of this procedure have been performing laparoscopic assisted colorectal resection since 2002 and have now performed over 100 cases on non consecutive and selected patients. We have reviewed our experience with the introduction of this technique. 61 patients were operated on for cancer and 39 for benign disease mainly Crohn's and diverticular disease. Operative time was a median of 128 minutes over the course of study. Conversion rate was 5%. Pathological analysis of the resected specimens in the cancer cases revealed adequate lymph node harvest and margins. No patient had a positive margin and no port site metastasis have been seen. Duration of ileus and length of stay were a median of 0 and 6 days. Post operative morbidity and mortality were comparable to open colorectal surgery with the exception of port site herniation which occurred in 4% of patients. This study suggests that a laparoscopic approach to colorectal resection can be successfully introduced in an Irish hospital setting. The challenge facing Irish surgery is to disseminate this technique in a controlled and safe manner for Irish patients.

Array-based proteomics: mapping of protein circuitries for diagnostics, prognostics, and therapy guidance in cancer.

The human proteome, due to the enormity of post-translational permutations that result in large numbers of isoforms, is much more complex than the genome and alterations in cancer can occur in ways that are not predictable by translational analysis alone. Proteomic analysis therefore represents a more direct way of investigating disease at the individual patient level. Furthermore, since most novel therapeutic targets are proteins, proteomic analysis potentially has a central role in patient care. At the same time, it is becoming clear that mapping entire networks rather than individual markers may be necessary for robust diagnostics as well as tailoring of therapy. Consequently, there is a need for high-throughput multiplexed proteomic techniques, with the capability of scanning multiple cases and analysing large numbers of endpoints. New types of protein arrays combined with advanced bioinformatics are currently being used to identify molecular signatures of individual tumours based on protein pathways and signalling cascades. It is envisaged that analysing the cellular 'circuitry' of ongoing molecular networks will become a powerful clinical tool in patient management.

Pediatric window falls: not just a problem for children in high rises.

BACKGROUND: Window falls are a frequent cause of injury (15/100,000) among Chicago preschool children. In Boston and New York, public health efforts have successfully decreased window fall injuries. Local data are needed to develop appropriate interventions for Chicago. OBJECTIVE: To describe the housing characteristics and types of injuries among children who fell from windows treated in a Chicago pediatric trauma center. METHODS: Children treated in a pediatric trauma center for injuries related to window falls between 1995 and 2002 were identified retrospectively. We reviewed family demographics, the circumstances of the fall, and types of injuries. Site visits were performed to determine the height and type of building and type of window where the fall took place. RESULTS: The authors reviewed 90 cases; 55 were male. The median age was 2 years. Ninety eight percent of falls were reported to be from the third floor or lower. Site visits (n=77) showed that 96% of the buildings were four storeys or lower. The median length of hospital stay was two days (range 0--24 days). The most common injuries were head trauma and extremity fractures. Three patients died, and an additional three patients were discharged to rehabilitation centers. CONCLUSIONS: Some window falls result in serious injury. In Chicago, most falls were from modest heights (2nd/3rd floor windows) in buildings of four or fewer storeys, rather than from "high rises". Strategies to prevent window falls should be directed to the owners and occupants of this type of housing.

How reliable are SIDS rates?

There is increasing concern with using SIDS as a diagnosis, especially where the postmortem examination reveals additional findings that may be contributory to the death exclusion. This report shows how varying the criteria for a diagnosis of SIDS significantly alters the SIDS rate in Ireland.

Association between cyclooxygenase-2-expressing macrophages, ulceration and microvessel density in colorectal cancer.

AIM: In colorectal carcinomas, cyclooxygenase-2 (COX-2) is expressed predominantly by epithelial cells and is implicated in tumour progression. Tumour-associated macrophages may influence tumour growth, proliferative rate and angiogenesis and also express COX-2 when activated. Thus they may play an important stromal-epithelial role in carcinogenesis. Tauhe aim of this study was to define the relationship between microvessel density (MVD), tumour COX-2 and macrophage COX-2 expression. METHODS AND RESULTS: Sixty-five cases of formalin-fixed paraffin-embedded colorectal cancer were included in the study. Tissues were immunostained for COX-2, CD68 (macrophage marker) and CD34 (endothelial marker to assess MVD). Thirty-six cases were grossly ulcerated cancers and 29 cases showed focal/microscopic ulceration. Macrophages were in high concentration at the base of ulcerated areas, and were also diffusely dispersed within tumoral stroma. However, the pattern of macrophage COX-2 expression revealed two populations of macrophages--those deep within the tumour (negative for COX-2) and those at the base of ulcers (positive for COX-2). In all cases, the tumour epithelial cells expressed COX-2. MVD was higher at the base of ulcers, adjacent to COX-2+ macrophages, and was lower deep within the tumour. CONCLUSIONS: In colorectal cancers, macrophages may have a dual role. Those concentrated at the base of the ulcers, where there is an associated high MVD, may induce angiogenesis, but their function may be in a healing/repair process. The lack of COX-2+ macrophages and lower MVD deep within the tumour suggests that it may be the epithelial COX-2 component that is important in tumour progression.

Effects of a selective cyclo-oxygenase 2 inhibitor on colonic anastomotic and skin wound integrity.

BACKGROUND: Selective inhibitors of inducible cyclo-oxygenase (COX-2) are of potential benefit in the perioperative period for both their analgesic and, perhaps, antineoplastic actions. However, their effects on laparotomy and intestinal wound healing are unknown. METHODS: Forty adult Sprague-Dawley rats underwent laparotomy, descending colonic transection and handsewn reanastomosis. The animals were randomized to receive either a selective COX-2 inhibitor (rofecoxib, 10 mg/kg) or an equal volume of water by gavage before operation and then daily after surgery. Animals were killed after 3 or 7 days, and their wounds were evaluated by means of tensiometry (skin and colonic wounds) and bursting pressure measurement (colonic anastomoses). In addition, haematoxylin and eosin-stained intestinal sections were examined and scored by a blinded independent observer. RESULTS: Five animals that received rofecoxib had anastomotic leaks by day 7 compared with none in the control group (P = 0.048). Intact colonic suture lines were also significantly weaker in this group (tensile strength at day 3, P = 0.043; bursting pressure on days 3 and 7, both P = 0.019). Skin wound strengths were similar in the two groups at both time points. CONCLUSION: Although beneficial in the treatment of pathological inflammation, selective COX-2 inhibitors may adversely affect colonic anastomotic healing.

Cyclooxygenase-2 expression in primary human colorectal cancers and bone marrow micrometastases.

BACKGROUND: Both the expressions of the inducible form of cyclooxygenase-2 and the presence of bone marrow micrometastases are poor prognostic markers in patients with colorectal carcinoma. AIMS: As cyclooxygenase-2 expression in these tumours is associated with increased metastatic potential in vitro, our objectives were to determine the relationship between cyclooxygenase-2 and haematogenous spread to bone marrow. PATIENTS AND METHODS: Thirty-two patients with resection of colorectal carcinoma were evaluated (median age: 69.5 years). Bone marrow was obtained from all patients from both iliac crests before manipulation of the primary tumour. The tumours were of varying stages at diagnosis (5 Dukes' A, 14 Dukes' B, 11 Dukes' C and 2 Dukes' D). Tumour sections were stained for cyclooxygenase-2 using the avidin-biotin immunohistochemical technique. Extent of staining was graded depending on the percentage of epithelial cells staining positive for cyclooxygenase-2. Micrometastases were detected by staining contaminant cytokeratin-18 positive cells in the bone marrow aspirates by either immunohistochemical (ARAAP) or immunological (flow cytometry) methods. Fisher's exact probability test was used to calculate statistical significance. RESULTS: Cyclooxygenase-2 expression in the primary tumour was detected in 72% of the patients. Twelve (38%) patients had bone marrow micrometastases detected by either immunohistochemistry or flow cytometry. Of the 12 patients who had bone marrow micrometastases, 8 tumours demonstrated increased expression of cyclooxygenase-2 protein (66.6%). In contrast, 9 out of the 20 (45%) patients in whom micrometastases were not detected expressed increased levels of cyclooxygenase-2 (P = 0.29). When dividing the patients into subgroups of localised (Dukes' A and B) versus disseminated (Dukes' C and D) disease, there was no further association between cyclooxygenase-2 expression and bone marrow micrometastases (P = 0.179 and 1.0). CONCLUSION: In this pilot study, there was no association between cyclooxygenase-2 expression and bone marrow micrometastases in patients with otherwise localised or disseminated disease.

Recurrent aneurysmal fibrous histiocytoma.

Aneurysmal fibrous histiocytoma is a rare variant of cutaneous fibrous histiocytoma that results from blood vessel proliferation and haemorrhage into a fibrous histiocytoma. The resulting lesion has a very different clinical appearance, hence the potential confusion with other skin lesions. This report describes the case of a 48 year old woman with a recurrent fibrous histiocytoma with prominent vasculature, which over a three year period recurred on two occasions, showing more progressive features of the aneurysmal variant. In addition, squamous lined cysts were present within this tumour, a finding that has not been described previously. The histological features of this rare lesion and the importance of the differential diagnosis from other similar appearing malignant lesions will be discussed.

Helicobacter pylori induces cyclooxygenase-1 and cyclooxygenase-2 expression in vascular endothelial cells.

BACKGROUND: Helicobacter pylori induces cyclooxygenase activity in the stomach, although the COX isoform and cellular source are unclear. A potential source is the vascular endothelial cell, which plays a role in regulating mucosal blood flow and inflammatory cell infiltration. METHODS: We examined the effect of four strains (toxigenic and non-toxigenic) of H. pylori on COX isoform expression in vascular endothelial cells. Prostaglandin synthesis was measured by enzyme immunoassay and COX isozyme expression determined by Western blot and RT-PCR. Gene induction was examined using 5' deletion constructs of the COX-1 and COX-2 promoters coupled with luciferase. RESULTS: All H. pylori strains induced prostaglandin generation and expression of both COX-1 and COX-2 in HUVEC, although this was most pronounced with the highly toxigenic strain H. pylori 60190. Treatment of the cells with selective COX inhibitors demonstrated that COX-1 was predominantly responsible for the enhanced generation of prostacyclin induced by H. pylori 60190. Similar results were seen with H. pylori broth culture filtrates, suggesting that a secreted product was responsible. Induction of COX-2 reflected both enhanced gene expression and stabilization of the mRNA. CONCLUSIONS: H. pylori increased both COX-1 and COX-2 activity in vascular endothelial cells. This increased generation of endothelial cell prostacyclin may play a role in modulating mucosal blood flow, platelet function and inflammatory cell infiltration in response to H. pylori infection. The regulation of COX-1 at the transcriptional level by H. pylori described in this study is a novel finding and calls into question the traditional description of COX-1 as a purely constitutive, housekeeping gene.

The quality and value of sudden infant death necropsy reporting in Ireland.

BACKGROUND: Infant necropsies are important for identifying cause of death. Recently issued guidelines have recommended investigations to be performed following sudden unexpected death in infants. AIMS: To evaluate the quality and value of infant postmortem reporting. METHODS: Postmortem reports from 1994-1996 and 1998-2000 in Ireland were evaluated using the National Sudden Infant Death Register. Scoring was by a modification of the Rushton system based on the extent of the postmortem data. The finding of additional pathological information was also assessed. RESULTS: Of the 274 cases registered during the selection period, reports were available for 245. Overall quality of necropsy reporting was below the minimum accepted standard in 55.5%; 47% of the necropsies were performed in regional paediatric pathology centres. The quality of necropsies performed in regional centres was significantly higher than those performed elsewhere. Although 86% of the cases were defined as sudden infant death syndrome (SIDS; no cause of death found), the finding of additional pathological information was significantly related to the extent of the necropsy. There was a significant improvement in the quality of necropsies after the postmortem guidelines were issued. CONCLUSIONS: The overall quality of sudden unexpected infant death necropsies in Ireland is less than adequate. A minimum accepted standard of necropsy is required before a diagnosis of SIDS can be made. Although standards have improved recently, this study highlights the need to adhere to published guidelines and the importance of auditing the effect of introducing practice guidelines on clinical practice to complete the audit loop.

Well differentiated fetal adenocarcinoma of the lung in a 29 year old woman.

This report describes a case of well differentiated fetal adenocarcinoma of the lung in a 29 year old female smoker. The histological pattern and immunohistochemical profile were consistent with well differentiated fetal adenocarcinoma and the patient made an uneventful postoperative recovery with no recurrence after 18 months. This neoplasm is a rare lung tumour that is composed of glycogen rich neoplastic glands and tubules that resembles fetal lung at 10 to 15 weeks of gestation. It is important to identify this rare variant of adenocarcinoma because it is a low grade malignancy with low associated mortality.

Stimulation of adhesion molecule expression by Helicobacter pylori and increased neutrophil adhesion to human umbilical vein endothelial cells.

Helicobacter pylori upregulates endothelial adhesion molecules but the pattern is unclear. Human umbilical vein endothelial cells (HUVEC) were exposed to control medium or H. pylori 60190. Binding of monoclonal antibodies against P-selectin, E-selectin, vascular adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) was determined using enzyme-linked immunosorbent assay. Binding of polymorphonuclear leukocytes to HUVEC was determined on cells exposed as above. After 6 h exposure to H. pylori, there were 30%, 124%, 167% and 100% increases in P-selectin, E-selectin, VCAM-1 and ICAM-1 levels and a 400% increase in polymorphonuclear leukocyte adhesion in HUVEC exposed to H. pylori. Effects of incubation for other intervals between 0 and 18 h are also described. H. pylori exerts some of its effects on gastric mucosa via gastric vasculature. This study gives insight into the pattern of H. pylori-associated endothelial adhesion molecule upregulation.

Valuing educational scholarship at the Medical College of Wisconsin.

Since the late 1980s faculty and staff at the Medical College of Wisconsin (MCW) have actively sought to align their school's academic culture and promotional process with its mission of educational excellence and innovation. As one of the top 50 medical schools receiving NIH funds, MCW has well-established mechanisms to evaluate and recognize the scholarship of discovery. Understanding, evaluating, and recognizing the value of individuals engaged in the scholarship of teaching, however, required changes in individuals' beliefs and in the MCW's promotion processes and organizational infrastructure. Building on the successful introduction of the MCW's Educator's PortfolioCopyright, a tool for documenting educational scholarship, a multifaceted change strategy was implemented to influence underlying beliefs and values about clinician-educators. Retrospectively, this strategy was consistent with John Kotter's eight-step change model, which the authors apply as an organizing framework for this case report of educational evolution at the MCW. Through creating a guiding coalition, developing vision and strategy, generating short-term wins, and anchoring new approaches in the MCW's culture, the MCW has made substantive progress in recognizing and rewarding educational scholarship. Changing academic cultures to value education is itself an educational process, requiring persistence and the ability to teach others about educational scholarship and its associated criteria.

Injury prevention education using pictorial information.

BACKGROUND: Written materials used in pediatric public health settings often exceed the reading skills of caretakers. OBJECTIVE: To compare a pictorial anticipatory guidance (PAG) sheet requiring limited reading skills to a TIPP (The Injury Prevention Program) sheet for providing injury prevention information to low-income urban families. DESIGN AND SETTING: A convenience sample of families with children treated at an urban pediatric clinic affiliated with a teaching hospital. Methods. Parents of children

The relationship between cyclooxygenase-2 expression and colorectal cancer.

CONTEXT: Epidemiological studies have implicated the inducible form of cyclooxygenase (COX-2) in the pathogenesis of colorectal cancer; however, its role is not fully understood. OBJECTIVE: To examine the relationship between the expression of COX-2 in human colorectal cancer and patient survival. DESIGN: Patients diagnosed as having colorectal cancer were evaluated and followed up for up to 9.4 years (median follow-up, 2.7 years). Tumor sections were stained for COX-2 using a rabbit polyclonal antibody raised against human COX-2. The extent of COX-2 staining was graded by 2 observers blinded to outcome. Preabsorption of the anti-COX-2 antibody with a COX-2 peptide abolished the staining, demonstrating the specificity of the assay. SETTING: Gastrointestinal unit of a large general teaching hospital in Dublin, Ireland. PARTICIPANTS: Seventy-six patients (median age, 66.5 years) with colorectal cancer (Dukes tumor stage A, n = 9; Dukes B, n = 30; Dukes C, n = 25; Dukes D, n = 12) whose diagnosis was made between 1988 and 1991. Fourteen normal colon biopsies were stained for COX-2 as controls. MAIN OUTCOME MEASURES: Survival in years following diagnosis compared by extent of COX-2 epithelial staining (grade 1, <1%; grade 2, 1%-19%; grade 3, 20%-49%; grade 4, > or = 50%), Dukes stage, tumor size, and lymph mode metastasis. RESULTS: COX-2 was found in tumor epithelial cells, inflammatory cells, vascular endothelium, and/or fibroblasts. The extent of epithelial staining was heterogeneous, varying markedly among different tumors. Normal tissue adjacent to the tumors also stained weakly for COX-2. No COX-2 was detected in control tissue samples. The Kaplan-Meier survival estimate was 68% in patients who had grade 1 tumor epithelial staining compared with 35% in those with higher grades combined (log-rank chi2 = 5.7; P = .02). Greater expression of COX-2 correlated with more advanced Dukes stage (Kendall tau-b, 0.22; P = .03) and larger tumor size (Kendall tau-b, 0.21; P = .02) and was particularly evident in tumors with lymph node involvement (Kendall tau-b, 0.26; P = .02). CONCLUSIONS: Our data indicate that COX-2 expression in colorectal cancer may be related to survival. These data add to the growing epidemiological and experimental evidence that COX-2 may play a role in colorectal tumorigenesis.