Christophe R. Berney

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.

Genetic Markers of Survival and Liver Recurrence after Resection of Liver Metastases from Colorectal Cancer

A significant number of patients with liver metastases from colorectal cancer (CRC) achieve 5-year survival after liver resection. Increased expression of genetic markers in the primary tumor are known to predict outcome after colonic resection, but the predictive value of such markers after resection of hepatic metastases is unknown. The objective of this study was to evaluate whether DNA content and multiple genetic markers, separately or expressed together, can predict patient outcome (liver recurrence and survival) after resection of hepatic metastases. We studied the paraffin-embedded liver tissue of 71 consecutive patients who had undergone a potentially curative resection of hepatic metastases from CRC. Using DNA flow cytometry and immunohistochemical staining techniques we determined the DNA content and the level of co-expression of seven tumor-associated proteins: proliferating cellular nuclear antigen (PCNA), epidermal growth factor receptor (EGFr), p53, c-erbB-2, H-ras, c-myc, and nm23. Three endpoints (liver recurrence, cancer specific, overall survival) were correlated with these tumor markers. The 5-year overall survival of the group was 31.2%. There was no correlation detected between the DNA aneuploidy and overall or cancer-specific survival. Similarly, expression of the individual tumor-associated proteins did not predict survival. Patients whose tumors co-expressed multiple markers had survivals similar to those whose tumors expressed fewer markers. However, a significant difference in hepatic recurrence was found between the p53-positive and p53-negative patients (p= 0.007), with marker-negative tumors having decreased recurrence. In conclusion, this study demonstrates that the DNA content and genetic markers c-myc, c-erbB-2, EGFr, H-ras, p53, PCNA, and nm23 do not predict survival after potentially curative resection of hepatic metastases from CRC. However, the immunoreactivity of p53 may be an important marker of local recurrence in the liver, which may be useful if re-resection of metastatic liver tumors is considered a viable management option in this disease.

Intra-arterial chemotherapy in locally advanced or recurrent carcinomas of the penis and anal canal: an active treatment modality with curative potential

The prognosis of locally advanced or recurrent carcinomas of the penis (PE) and of the anal canal (AC) after conventional treatment is dismal. We report 16 patients (eight with AC carcinomas and eight with PE cancers) treated by intra-arterial (IA) chemotherapy. Fifteen of them were treated for locally advanced or recurrent disease and one in an adjuvant setting. The chemotherapy was administered via a femoral IA catheter with its tip located above the aortic bifurcation, under the inferior mesenteric artery. It consisted of eight push injections, given over a 48-h period, of the following drug combination: cisplatin 8.5 mg m–2, 5-FU 275 mg m–2, methotrexate 27.5 mg m–2, mitomycin C 1.2 mg m–2, and bleomycin 4 mg m–2. Leucovorin was given po, 4 × 15 mg day–1, during the chemotherapy and for 3 days thereafter. A total of 52 cycles of treatment were administered. Of the 15 patients evaluable for response, six obtained a CR (three PE, three AC) and eight a PR. Among the complete responders, four are alive and disease-free 2–15 years after treatment. The other patients enjoyed an objective response lasting 3–25 months (median 7 months). Four patients developed grade III/IV haematological toxicity with three episodes of febrile neutropenia, one of them with a fatal outcome due to patients failure to obtain medical attention at the onset of his fever, one a grade III mucositis of the glans, and four a grade III/IV cutaneous toxicity, the latter caused by the IA administration of bleomycin. In conclusion, IA chemotherapy is effective and potentially curative in locoregionally advanced or recurrent carcinomas of the penis and of the anus. Its contribution in the primary management of advanced penile or anal carcinoma should be prospectively investigated.

Totally extraperitoneal repair of inguinal hernia: techniques and pitfalls of a challenging procedure

Inguinal hernia repair is the most common procedure performed worldwide in general surgery. Since the turn of the 21st century, the minimally invasive approach and in particular totally extraperitoneal (TEP) repair has gained in popularity. The concept of the TEP approach combines the advantages of anterior tension-free mesh repair (Lichtenstein repair) and the open preperitoneal approach championed by Stoppa. TEP repair uses a prosthetic mesh significantly bigger than in open herniorrhaphy, offering a complete overlap of the myopectineal orifice. TEP repair is a challenging technique with unfamiliar anatomy, a limited operative field, and long learning curve. This article provides an experienced opinion on the practical aspects of the TEP approach. Some of these steps have already been discussed in the surgical literature, while others are the fruit of a personal expertise grasped over the years with more than 1,000 TEP repairs performed.

Overexpression of nm23 Protein Assessed by Color Video Image Analysis in Metastatic Colorectal Cancer: Correlation with Reduced Patient Survival

The function and prognostic significance of the nm23 gene is controversial in colorectal cancer (CRC). The aim of this study was to determine if nm23 protein expression correlated with the subsequent development of liver metastasis. Paraffin-embedded sections of 30 metastasizing CRC primaries and their subsequently resected liver secondaries were compared with those of 28 nonmetastasizing CRCs, 20 adenomas, and 20 cases of normal colonic mucosa. Expression of nm23 protein, assayed by immunohistochemistry, was measured using a standard semiquantitative scaling system and compared with a microcomputer-based color video image analysis (VIA). There was good correlation between color VIA and semiquantitative evaluation of nm23 immunoreactivity, confirming the validity of quantitative analysis (Pearson’s r= 0.88; p < 0.001). Metastasizing CRC primaries and secondaries overexpressed nm23 protein when compared with the other clinical groups, particularly nonmetastasizing CRC (Student’st-test, p < 0.001). Furthermore, more nm23 immunoreactivity was associated with a higher risk of death from CRC (log-rank test, p= 0.002). These results suggest that overexpression of nm23 is highly associated with liver metastases from CRC and reduced survival.

Evidence for post-transcriptional down-regulation of the apoptosis-related gene bcl-2 in human colorectal cancer

This retrospective study was undertaken to investigate the expression of bcl‐2 protein and messenger RNA in colorectal cancer (CRC). Immunohistochemical analysis using a monoclonal mouse antibody to the bcl‐2 protein and in situ hybridization using a digoxigenin‐labelled bcl‐2 cRNA probe were carried out on formalin‐fixed and paraffin‐embedded specimens from 53 colorectal adenocarcinomas, 27 liver secondaries, and 60 adenomas with various degrees of dysplasia. Normal human tonsil sections were used as positive controls. Expression of bcl‐2 protein and of messenger RNA was evaluated semiquantitatively. The expression of bcl‐2 protein was gradually and significantly lost during the progression from moderately dysplastic adenoma to primary CRC (moderate/severe dysplasia: Mann–Whitney U‐test, p=0.0001; severe dysplasia/primary CRC: p=0.027), whereas the cellular expression of bcl‐2 mRNA was gradually increased during the dysplasia/adenoma–carcinoma neoplastic sequence. These observations suggest that in a proportion of colorectal cancer cases, the bcl‐2 proto‐oncogene expression may be down‐regulated at a post‐transcriptional level. Copyright

The role of fibrin glue in decreasing chronic pain in laparoscopic totally extraperitoneal (TEP) inguinal hernia repair: a Single surgeon's experience

Background:  Chronic pain is a disturbing severe complication of mesh inguinal hernia repair. Its risk, incidence, severity and its aetiologies vary widely in the literatures. It is well established that laparoscopic repair has decreased the incidence of chronic pain, but only to a certain degree. The main source of pain with this approach is staple fixation. Different ways of fixation were sought to avoid this problem.

Traumatic lumbar hernia repair: a laparoscopic technique for mesh fixation with an iliac crest suture anchor

Traumatic lumbar hernia (TLH) is a rare presentation. Traditionally, these have been repaired via an open approach. Recurrence can be a problem due to the often limited tissue available for mesh fixation at the inferior aspect of the hernia defect. We report the successful use of bone suture anchors placed in the iliac crest during transperitoneal laparoscopy for mesh fixation to repair a recurrent TLH. This technique may be particularly useful after previous failed attempts at open TLH repair.

Carolinas Comfort Scale for mesh repair of inguinal hernia

Professor Mellick is to be complimented for his biographical sketch of Sir Kenelm Digby, the exceptionally talented 17th-century polymath who dabbled in medicine among many other things. Digby lived in a tumultuous time when science as we now know had begun to emerge. Much has been written about Digby and his extraordinary accomplishments. He was the subject of the Wilkinson Lecture at Worcester College, Oxford, in 2005. This was given by Lesley Le Claire, the scholarly former college librarian. Le Claire had access to the treasure trove of Digbiana in the college. The college holds nearly all of Digby’s publications and many of them are first editions. The erudite lecture added some further insights into the life of this man for most (?all) seasons. As a Catholic, Digby could not become either a full member of Oxford or of one of its colleges. Neither could he take a degree. However, in the early 17th century, provisions were made for Catholics to attend Gloucester Hall, Oxford, an organization with a chequered Benedictine-linked history and which later evolved into Worcester College. It was at Gloucester Hall that Digby came under the influence of the mathematician Thomas Allen who dubbed him ‘the Mirandola of his age’, an extraordinary anointment for the intellectually precocious 15-year-old. Le Claire records that Digby was far from alone in his contention that the Powder of Sympathy was efficacious in promoting wound healing. He also stated, ‘The fact that healing often did occur has a simple explanation. Digby insisted that the wound itself should be kept absolutely clean with no application of the extremely dubious ointments in current use. Unwittingly, he was aiming at asepsis – a lesson that our modern hospitals are having to re-learn’. Le Claire makes a notable point in his observation that ‘Perhaps his greatest legacy is to the world of literature – not only at the material level of his generosity to libraries and his patronage of contemporary writers – but also in a more subtle sense: his vivid personality caught the imagination of writers long after his death’. It is well recorded that Digby more than dabbled in epicurean delights of the table and this may well have contributed to his eventually fatal trouble with ‘the stone’. Nevertheless, the Englishspeaking world is, perhaps unknowingly, forever indebted to this bon vivant for it was he who was ‘the first to recommend bacon and eggs for breakfast’ – still the unbeatable, gustatory quinella with which to start the day. References

Spontaneous Retroperitoneal Hemorrhage due to Adrenal Metastasis for Non-Small Cell Lung Cancer Treated by Radiation Therapy

Adrenal hemmorhage is not a rare event. It is mostly bilateral, consecutive to anticoagulation therapy, bleeding diathesis and trauma ( I ) . and also observed in severe stress situations with excessive adrenocortical stimulation, such as acute myocardial infarction, congestive heart failure, and specticemia (2). Massive unilateral hemorrhage is uncommon, but is a recognized complication of primary adrenal tumors, among which pheochromocytoma is most commonly encountered (3, 4). Adrenal involvement by metastatic neoplasms is a frequent occurence in some malignancies such as carcinoma of the lung (2, 5). These lesions are usually discovered incidentally during routine cancer work-ups or in postmortem studies (6). Hemorrhagic complications are exceedingly rare, but can be dramatic and are mostly managed surgically. We report here one case of retroperitoneal hemorrhage secondary to metastatic involvement of the left adrenal by a non-small cell carcinoma of the lung, which was successfully treated by transfusion and radiation therapy. Case repor/. A 56-year-old woman was admitted in June 1993 for investigation of unexplained weight loss and development of paresthesia and pains in her left arm and leg. Clinical examination was positive for a right axillary adenopathy and hypoesthesia of her left lower and upper limbs with a homolateral Babinski sign. Routine laboratory test was within normal ranges. Chest x-ray and thoracic CT-scan revealed a left upper lobe nodule (2 cm in diameter). Bronchoscopy showed a stenosis of a segmentary apical bronchus in the left lung and biopsy was positive for a poorly differentiated squamous cell carcinoma. A left adrenal mass of 5.4 cm in diameter was present on abdominal CT-scan being consistent with metastasis (Fig. la). A cerebral CT-scan showed 3 right hemispheric lesions. During her stay at hospital the patient suddenly presented with diffuse abdominal pain and nausea complicated by an abrupt hemoglobin drop on July 5th (Table 1). requiring transfusion of 4 blood units on the same day. On clinical examination, left upper abdominal tenderness and fever ( 38.4-C) were recorded. A second abdominal CT-scan revealed a change in radiodensity on the left adrenal mass with massive bilateral retroperitoneal infiltration predominating on the left side compatible with hemorrhage (Fig. I b and c). The diagnosis of spontaneous hemorrhage from the left adrenal metastasis was made and was coroborated by a transient rise of the platelets and the bilirubin over the following days (Table). No abnormality in prothrombin time, partial thromboplastin time and fibrinogen level was recorded. A radiation treatment of the adrenal was promptly started with a total dose of 30 G y in 10 daily fractions. The patient’s condition improved and she did not require further blood transfusion. She was discharged shortly thereafter and treated as an outpatient by radiotherapy and corticosteroi‘ds for her cerebral metastasis. Her condition deteriorated progressively and she died at home 2 months later. A postmortem examination was not performed Discussion. Spontaneous massive hemorrhage from neoplastic lesions is a relatively uncommon problem. It can arise from tumors, primary or metastatic, infiltrating the mucosa of the gastro-intestinal, genito-urinary and respiratory tracts (7). Spontaneous bleeding from an extraluminal lesion is an infrequent event, which has been described in metastatic melanoma, hepatoma, glioblastoma and, more rarely, in the context of hepatic metastasis from various tumors (8, 9). Although the hemorrhage in an extraluminal site is often self-contained it can induce acute symptoms because of the compression of the surrounding normal tissues, such as convulsions in cases of cerebral lesions (10). The retroperitoneum is an expandable space which can easily accomodate large amounts of blood, leading to significant blood loss and shock. The clinical manifestations of spontaneous retroperitoneal hemorrhage (SRH) are variable and nonspecific, the most frequently presenting features being abdominal pain, a tender flank mass and signs of hemorrhagic shock (Lenk’s triad) ( 1 I ). Among the many causes of SRH. tumors come far behind ruptured vascular aneurysms (1). Benign as well as primary malignant tumors have been reported to cause SRH (12, 13). Renal cell carcinoma (RCC) is admitted to be the first renal cause of SRH although the occurrence of such an event is still rare. A large review involving 309 cases of RCC reported only one case of SRH ( I ) . Benign angiomyolipomas of the kidney areconsidered to be thesecond most frequent tumoral cause of SRH (14). In the adrenals, pheochromocytomas, which are highly vascular tumors, are known to cause SRH. However, SRH due to retroperitoneal metastatic disease as in our patient is exceedingly rare. In the English medical literature