Lymphogenous Spread Research Articles

Prognostic relevance of the AQP5 −1364C>A polymorphism in primary breast cancer

Besides known prognostic factors in breast cancer, disseminated tumor cells are regarded as a surrogate marker for minimal residual disease in breast cancer. Their prognostic significance is comparable to that of lymph node status. However, the mechanism by which the primary tumor directs cells to disseminate into lymph nodes or into blood vessels is unclear. Aquaporins (AQPs) are small integral membrane proteins that provide a major pathway for water transport throughout several organs, and have been shown to be of potential importance in various types of cancer. Here, we analyzed the single nucleotide polymorphism (SNP) A(-1364)C in AQP5 in 107 patients with early stage breast cancer in order to test the hypothesis that this polymorphism is associated with lymphogenous and hematogenous tumor cell dissemination and overall survival. Paraffin-embedded tumor tissue was dewaxed, and DNA was extracted from tumor tissues using the QIAamp Blood DNA Mini Kit. The quantification and quality of the extracted DNA were determined spectrophotometrically. Genotyping of the -1364A>C polymorphism was performed by Pyrosequencing. Cytokeratin-positive (CK+) bone marrow (BM) cells were isolated by density gradient centrifugation followed by immunocytochemistry, applying the pan CK antibody A45-B/B3. There was no evidence of an association between the AQP5C>A genotypes and an increased risk of developing breast cancer, nor between the genotypes and tumor size, lymph node involvement, distant metastasis, grade, histopathology, expression of estrogen receptor and HER2, or the dissemination of tumor cells to BM. In contrast, when comparing C-allele carriers with patients carrying the AA genotype, expression of the progesterone receptor differed significantly between these genotype groups (mean AA genotype 51%, mean AC and CC genotype 73%; p=0.039). Additionally, a significant correlation was found between progesterone receptor expression and adjuvant chemotherapy (p=0.021) and adjuvant endocrine therapy (p=0.017), respectively. SNPs in AQP5 are not associated with hematogenous or lymphogenous tumor cell spread. However, we observed for the first time an association between SNPs in AQP5 and progesterone receptor positivity, which might have implications for future adjuvant treatment. Further investigations must include more than one AQP as well as factors promoting angiogenesis to elucidate the different modes of tumor cell dissemination.

Epidermotropic scrotal metastasis of colorectal cancer

Dear Editor: Colorectal cancer is one of the most frequent malignancies in men and women, with an incidence around 50/100,000, counting for approximately 10% of all newly diagnosed cancer cases and for 10% of all cancer deaths. After total resection of the primary tumor, relapses occur mainly within the first 2–3 years of follow-up, with extramural local recurrences (e.g., peritoneum, pelvis) and metastases to the liver, lungs, and bone as the most common sites of tumor spread. Herein, we report the very unusual occurrence of epidermotropic cutaneous metastases of colorectal cancer at the scrotum as the first site of disseminated tumor spread. A 69-year-old man presented with an asymptomatic, rapidly developing erythematous soft plaque at the right scrotum measuring up to 2 cm in diameter. Five months previously, a colorectal adenocarcinoma (pT4, N0, G3, L1) had been surgically resected and combined radiochemotherapy with 5-fluorouracil and radiation of the pelvis was just completed. Therefore, the red plaque was first interpreted as an acute radiodermatitis. Within two weeks, a second lesion developed in the groin, which appeared as a dome-shaped nodule rather untypical for dermatitis. Histopathologic evaluation of the two tumors demonstrated islets of adenocarcinoma within the epidermis and dermis. The morphology of the tumor cells was similar to that of the tumor in the rectum. Staging at this time revealed no evidence of visceral metastases. Thereafter, the patient developed generalized lymphogenic spread of colorectal carcinoma and died 6 months later of a cerebral insult. Cutaneous metastases in colorectal cancer occur in approximately 4.4% of cases according to a survey on 413 patients with metastatic disease. The probability of these metastases being the first sign of extranodal spread is even lower with 3%. Skin involvement of colorectal carcinoma occurs predominantly at the abdominal wall or pelvis and seems to favor sites of previous incisions. The scrotum as the first site of cutaneous spread is very uncommon. Histopathologically, cutaneous metastases are usually confined to the dermis or subcutaneous fat without involvement of the epidermis. Epidermotropism as it occurred in the present case is exceedingly rare. The fact that the metastases evolved during and within the area of radiation indicates a highly aggressive biological behavior. Cutaneous metastases are usually known to signify widespread, terminal disease, with a discouraging life expectancy after diagnosis estimated as being between 4.4 and 18 months. Although a few The authors indicated no potential conflicts of interest.

Solitary and Multiple Isolated Metastases of Clear Cell Renal Carcinoma to the Pancreas: An Indication for Pancreatic Surgery

Isolated pancreatic metastases (isPMs) of clear cell renal carcinoma are rare. Most of them are solitary; some are multiple. The reported rates and the clinical implications of multiple isPMs from clear cell renal cancer vary. Therefore, the available literature was analyzed to shed light on the clinical significance of these extremely rare metastatic lesions. A literature search brought to light 236 cases of isPMs (both solitary and multiple) from renal cell carcinoma. These were analyzed. A total of 12% of the metastases were synchronous with the primary tumor, and 88% were metachronous, occurring 10.0 +/- 6.5 years (mean +/- SD) after nephrectomy. A predilection for a specific part of the pancreas was not identifiable. The localization of the renal cell cancer (left or right kidney) did not have any effect on the site of the metastases. Seventy-four (39%) of the metastases to the pancreas were multiple (3.2 +/- 1.5). Their epidemiology did not differ from that of solitary metastatic lesions. Actuarial 3- and 5-year survival rates after radical resection were 78% and 78%, respectively, for multiple versus 75% and 64% for solitary metastases. The epidemiological data do not support a direct local lymphogenous or venous spread from the primary tumor to the pancreas. They rather suggest a systemic spread. Because of the positive outcome, radical removal of both solitary and multiple metastases should be attempted in eligible patients.

Chemokine receptors in head and neck cancer: Association with metastatic spread and regulation during chemotherapy

Head and neck carcinomas are histologically and clinically heterogeneous. While squamous cell carcinomas (SCC) are characterized by lymphogenous spread, adenoid cystic carcinomas (ACC) disseminate preferentially hematogenously. To study cellular and molecular mechanisms of organ-specific metastasis, we used SCC and ACC cell lines and tumor tissues, obtained from patients with primary or metastatic disease. Comprehensive analysis at the mRNA and protein level of human chemokine receptors showed that SCC and ACC cells exhibited distinct and nonrandom expression profiles for these receptors. SCC predominantly expressed receptors for chemokines homeostatically expressed in lymph nodes, including CC chemokine receptor (CCR) 7 and CXC chemokine receptor (CXCR)5. No difference in expression of chemokine receptors was seen in primary SCC and corresponding lymph node metastases. In contrast to SCC, ACC cells primarily expressed CXCR4. In chemotaxis assays, ACC cells were responsive to CXCL12, the ligand for CXCR4. Exposure of ACC cells to cisplatin resulted in upregulation of CXCR4 on the cell surface, which was repressed by the transcriptional inhibitor, alpha-amanitin. Treatment of ACC cells with CXCL12 resulted in the activation of Akt and ERK1/2 pathways. Furthermore, CXCL12 suppressed the rate of apoptosis induced by cisplatin in ACC cells, suggesting that signaling via CXCR4 may be part of a tumor cell survival program. Discrimination of the chemokine receptor profile in SCC and ACC in vitro and in tissues provided insights into their distinct biologic and clinical characteristics as well as indications that chemokine receptors might serve as future therapeutic targets in these malignancies.

Wertigkeit der Sentinel-Lymphknotenbiopsie bei urologischen Tumoren

Gamma probe-guided lymphadenectomy of prostate cancer that is presumed to be localized furnishes evidence that lymphogenous spread of the disease is present considerably more often and earlier than previously assumed, even when the clinical stage is considered localized. Multiinstitutional trials have confirmed that in principle sentinel lymphadenectomy on its own is able to detect lymph node positive patients with minimal complications and a sufficient degree of certainty. Sentinel lymphadenectomy for penile cancer is an undemanding surgical procedure and in contrast to inguinal lymphadenectomy can be considered minimally invasive. Decisions on indication and necessity for an additional inguinal lymphadenectomy depending on tumor stage and local findings in the inguinal lymph nodes are handled quite differently in various centers and should be further standardized. The most recent studies on sentinel lymphadenectomy for urinary bladder and testicular cancer demonstrate that on principle the procedure is likely feasible also for these tumor entities. Whether it is possible to replace standard treatment methods with these procedures or at least have them serve an ancillary function remains to be determined in further investigations. Basically, the premise holds true that for all urological tumor entities before standard diagnostic techniques are abandoned, the value of exclusively performing sentinel lymphadenectomy must be adequately validated. It does not suffice to rely on the results from other working groups. It is in fact essential that the accuracy of the method - the feasibility of which can be influenced by numerous factors - be assessed by comparison with a standard lymphadenectomy performed in one's own center.

The Tumor Bed Effect: Increased Metastatic Dissemination from Hypoxia-Induced Up-regulation of Metastasis-Promoting Gene Products

Cancer patients with recurrent local disease after radiation therapy have increased probability of developing regional and distant metastases. The mechanisms behind this observation were studied in the present work by using D-12 and R-18 human melanoma xenografts growing in preirradiated beds in BALB/c-nu/nu mice as preclinical models of recurrent primary tumors in humans. D-12 tumors metastasize to the lungs, whereas R-18 tumors develop lymph node metastases. Based on earlier studies, we hypothesized that metastasis was governed primarily by the proangiogenic factor interleukin-8 (IL-8) in D-12 tumors and by the invasive growth-promoting receptor urokinase-type plasminogen activator receptor (uPAR) in R-18 tumors. Pimonidazole was used as a hypoxia marker, and hypoxia, microvascular hotspots, and the expression of IL-8 and uPAR were studied by immunohistochemistry. The metastatic frequency was significantly higher in tumors in preirradiated beds than in control tumors in unirradiated beds, and it increased with the preirradiation dose. D-12 tumors showed increased fraction of hypoxic cells, increased fraction of IL-8-positive cells, and increased density of microvascular hotspots in preirradiated beds, and R-18 tumors showed increased fraction of hypoxic cells and increased fraction of uPAR-positive cells in preirradiated beds. Strong correlations were found between these parameters and metastatic frequency. IL-8 was up-regulated in hypoxic regions of D-12 tumors, and uPAR was up-regulated in hypoxic regions of R-18 tumors. Daily treatment with anti-IL-8 antibody (D-12) or anti-uPAR antibody (R-18) suppressed metastasis significantly. Our preclinical study suggests that primary tumors recurring after inadequate radiation therapy may show increased metastatic propensity because of increased fraction of hypoxic cells and hypoxia-induced up-regulation of metastasis-promoting gene products. Two possible mechanisms were identified: hypoxia may enhance metastasis by inducing neoangiogenesis facilitating hematogenous spread and by promoting invasive growth facilitating lymphogenous spread. The aggressive behavior of postirradiation local recurrences suggests that they should be subjected to curative treatment as early as possible to prevent further metastatic dissemination. Moreover, the possibility that patients with a high probability of developing local recurrences after radiation therapy may benefit from postirradiation treatment with antiangiogenic and/or anti-invasive agents merits clinical investigation.

Determination of nodal status and treatment in early gastric cancer

Background In view of its low associated risk of metastatic spread, early gastric cancer has an excellent prognosis. The basis for the choice of treatment is the risk of lymphogenous metastatic spread together with the individual surgical risk. Methods The data collected from 279 patients in whom, between 01/1982 and 12/2001, a gastric resection or gastrectomy was carried out for early gastric cancer at the Surgical Department of the University Hospital, Erlangen, were analysed. A number of macroscopic and histopathological factors were examined by univariate and multivariate analysis for their effect on lymphogenous metastatic spread. Results In 33 patients (11.8%), regional lymph-node metastases were confirmed histologically. The grade of malignancy (high-grade, relative risk 9.9), diameter (>20 mm, relative risk 5.0) and lymphatic invasion (relative risk 3.5) all demonstrated a significant independent influence on the occurrence of regional lymph-node metastases. Seventy-three patients were identified as a low-risk group, with a risk of lymphogenous metastatic spread of only 1%. Conclusions Well differentiated or moderately differentiated carcinomas having a diameter of less than 2 cm can be treated by local intervention, such as local excision or endoscopic removal, without any increase in risk, provided that the tumour is reliably removed without residual tumour (histologically confirmed R0). In the presence of an elevated surgical risk, the choice of treatment must be made on an individual basis.

Determination of nodal status and treatment in early gastric cancer

Background In view of its low associated risk of metastatic spread, early gastric cancer has an excellent prognosis. The basis for the choice of treatment is the risk of lymphogenous metastatic spread together with the individual surgical risk. Methods The data collected from 279 patients in whom, between 01/1982 and 12/2001, a gastric resection or gastrectomy was carried out for early gastric cancer at the Surgical Department of the University Hospital, Erlangen, were analysed. A number of macroscopic and histopathological factors were examined by univariate and multivariate analysis for their effect on lymphogenous metastatic spread. Results In 33 patients (11.8%), regional lymph-node metastases were confirmed histologically. The grade of malignancy (high-grade, relative risk 9.9), diameter (>20 mm, relative risk 5.0) and lymphatic invasion (relative risk 3.5) all demonstrated a significant independent influence on the occurrence of regional lymph-node metastases. Seventy-three patients were identified as a low-risk group, with a risk of lymphogenous metastatic spread of only 1%. Conclusions Well differentiated or moderately differentiated carcinomas having a diameter of less than 2 cm can be treated by local intervention, such as local excision or endoscopic removal, without any increase in risk, provided that the tumour is reliably removed without residual tumour (histologically confirmed R0). In the presence of an elevated surgical risk, the choice of treatment must be made on an individual basis.

Contemporary insights into dissemination of primary non-Hodgkin's lymphomas of the spleen

6675 Background: The aim of current researches was to study the mode and the steps of dissemination of primary splenic non-Hodgkin's lymphomas (NHL) in regard with its histological types. Methods: A representative group of 155 patients (age range 15 - 82 years) with primary NHL of the spleen was analyzed in our study. According to the N.C.I. Working Formulation, low-grade (LG) NHL were identified in 110 (70.9%) cases, and those high-grade (HG) - in 45 (29.1%). Staging was realized by means of conventional physical and X-ray examinations, computerized tomography, ultrasound and nuclear isotope scannings, bone marrow aspiration and biopsy, laparoscopy, exploratory laparotomy with splenectomy and lymph node biopsy. Stage IV disease was diagnosed in 107 (97.3%) patients with LG NHL, and in 38 (84.6%) with HG NHL. Results: LG splenic NHL showed the prevalent bone marrow (BM) involvement (99.1%), which had been the only one site of tumour dissemination in 24.3% of cases. The liver involvement was revealed in 58.3% of patients. The abdominal lymph node (ALN) and the peripheral lymph node (PLN) affection was registered in 40.0% and 30.8% of cases, respectively. The following combinations of the multiple extrasplenic sites of lymphomatous involvement mainly occurred: BM, liver and ALN - 13.3%, those followed by PLN - 11.4%, BM, liver and PLN - 9.6%, BM and ALN - 8.7%. HG splenic NHL demonstrated the predominant ALN (68.3%) and liver (65.8%) involvement. The BM affection (52.6%) proved to be less frequent. The PLN involvement occurred only in 28.9% of cases. The following combinations of the extrasplenic sites of the tumor dissemination mostly were detected: ALN, liver and BM - 15.6%, ALN, PLN and liver - 13.3%, ALN and BM - 11.1%, ALN and liver - 6.7%. Conclusions:In primary LG NHL of the spleen, early hematogenous dissemination in the BM was common, followed by the consecutive liver, ALN and PLN involvement. In primary HG splenic NHL, initial lymphogenous spread in the ALN was typical, with the following successive liver, BM and PLN involvement. The histology-respecting dissemination features of primary splenic NHL should be taken into consideration in the process of diagnosis and treatment. No significant financial relationships to disclose.

Lymph node topography of the head and neck in New Zealand White rabbits.

Investigations of the lymphogenic metastatic spread of VX2 carcinomas in New Zealand White rabbits require an exact knowledge of the topography of cervical and facial lymph nodes. The topography of neck lymph nodes was evaluated from 16 rabbits macroscopically, histologically and by lymphographic investigations, and the possibility of their surgical removal (neck dissection) was examined. The upper aerodigestive tract and the ear of New Zealand White rabbits drain via four consistent groups of 12-18 lymph nodes. Except for the paratracheal lymph node, they are all easily accessible to surgery. The data presented in this study encourage the use of induced VX2 carcinomas in New Zealand White rabbits as an animal model to study the lymphogenic metastatic spread of squamous cell carcinomas of the head and neck. Such investigations could lead to an improvement of surgical and pharmaceutical treatment of this tumour entity.

Bacterial colonization and invasion in pigs experimentally exposed to Streptococcus suis serotype 2 in aerosol.

A recently developed porcine model for aerogenous infection with Streptococcus suis serotype 2 was applied in a study of the phases of bacterial colonization and initial invasion. Eighteen pigs were exposed to aerosolized S. suis serotype 2 after pre-exposure to mild acetic acid in aerosol. The animals were killed consecutively within the first six days after challenge. After death, all animals were necropsied and examined by bacteriology, histopathology, and immunohistochemistry. Systemic infection was established in four out of 18 animals exposed to S. suis serotype 2. All systemically infected animals developed clinical signs and lesions typical of the infection. In four additional animals, subclinical infection was demonstrated by re-isolation of S. suis from the palatine tonsil. However, in all 18 challenged animals, immunohistochemistry demonstrated S. suis serotype 2 antigen in the palatine and/or nasopharyngeal tonsils. In all four systemically infected animals, S. suis serotype 2 antigen was also found in the mandibular lymph node. These observations point towards the tonsils as possible portals of entry for S. suis serotype 2 with subsequent lymphogenous spread. Thus, the present findings parallel the proposed pathogenesis for S. suis serotype 1 infection in pigs.

Lymphogene Metastasierung operierter Rektumkarzinome

Lymphogenic Metastatic Spread of Operated Rectal Carcinomas The aim of this study was to determine the risks of local surgery of rectal carcinoma regarding lymphogenic metastatic spread. The appearance of lymphatic metastases in 290 patients suffering from rectal carcinoma was investigated retrospectively. 112 of 290 patients revealed secondary malignancies at the time of operation. 66 patients showed single lymphatic lesions (pN1: 35, pN2: 31), 17 patients had single hematogenous lesions, and 29 patients showed both lymphatic and hematogenous metastases (pN1: 11, pN2: 18). Proximally involved lymph nodes were preferably nodes located near the superior rectal artery and at the inferior mesenteric artery; furthermore, a small number of lateral-iliacal lymph nodes were positive. In 4 cases, lymphatic metastases along the superior rectal artery were found, whereas the local lymph nodes at the tumor were free of any lesions. Low-risk tumors (with little risk of lymphatic metastasis and possible local surgery) had the following features: 1. T-stage: (p)Tis; (p)T1; in case of G1 also (p)T2; 2. Grading: highly differentiated (G1), (G2 questionable); 3. No vessel infiltration; 4. M and N negative (no enlargement of lymph nodes); 5. Tumor size: length < 2 cm, width < 1 cm, deepth < 0.5 cm, diameter < 2 cm, volume < 1 cm³; 6. Normal preoperative CEA and CA 19-9; 7. Recommended safety distance of 5–10 mm in cases of local resection. Local surgical procedures are recommended at special indications as above. However, they bear the potential risk of nonradical surgery and an incomplete staging, and there is a need for careful follow-up examinations.

The sentinel node concept in head and neck squamous cell carcinoma--a critical analysis in 100 patients

The value of Sentinel Node (SN) concept is a current issue in clinical oncology. Few investigations deal with SN biopsy in head and neck squamous cell carcinomas (HNSCC). For this reason the SN concept was investigated based on the results of the so far largest group of 100 patients. Three groups of patients were investigated. Group 1: In 30 patients (6 x oral cavity, 24 x oropharynx) a dynamic lymphoscintigraphy was performed. Group 2: 60 previously untreated patients (12 x oral cavity, 23 x oropharynx, 16 x larynx, 9 x hypopharynx); neck lymph node status on ultrasound imaging: 39 x N0, 5 x N1, 16 x N2, intraoperative identification of the SN during neck dissection (ND) accomplished according to the extent of assumed lymphogenic metastatic spread; postoperative comparison of the histological result of the SN with the neck dissection specimen. Group 3: 10 previously treated patients (1 x oral cavity, 5 x oropharynx, 1 x larynx, 3 x hypopharynx) in whom an intraoperative SN biopsy was performed. Group 1: In 20/30 patients a cervical lymph drainage could be visualized on dynamic lymphscintigraphy and an activity enrichment above the mean metastatic region could be identified transcutaneously. Group 2: In 34 patients the tumorfree SN1 reflected the regional lymph node status. In 9 patients an isolated tumor metastasis (pN1) was found in the intraoperatively identified SN1 and in a further patient in the SN2 (pN1). The results of SN biopsy are encouraging in cases of clinical N0-necks. Nevertheless the data demonstrates that extensive investigations followed by a critical analysis of the results are required. The presented results suggest that the value of the SN concept seems to be of minor importance in cases of advanced lymphogenic metastatic spread.

Streptococcus suis Serotype 2 Infection in Pigs: New Diagnostic and Pathogenetic Aspects

In a study aimed at improving the diagnosis and elucidating the pathogenesis of Streptococcus suis serotype 2 infection in pigs, a combination of bacterial culture and histopathological and immunohistochemical examination was applied to a range of tissues from 42 naturally infected pigs with typical macroscopical lesions. By culture, 21 pigs (50%) were shown to be systemically infected with S. suis serotype 2; seven (17%) were infected withS. suis serotype 7, two with other bacteria, and 12 yielded no bacterial pathogens. The highest isolation rate for S. suis serotype 2 was obtained from the lateral cerebral ventricles and other regions of the brain, whereas the bacterium was only rarely isolated from the liver or spleen. Immunohistochemically, a diagnosis of S. suis serotype 2 infection was obtained in two of 12 (17%) animals from which no pathogens had been cultured. Moreover, immunohistochemistry differed from culture in revealing a greater number of positive tissue specimens. The microanatomical distribution of bacteria pointed toward the pharyngeal and palatine tonsils as principal portals of entry. Furthermore, S. suis serotype 2 bacteria were frequently identified immunohistochemically in the regional lymph nodes of the upper respiratory tract, possibly reflecting primary lymphogenous spread from the tonsils.

Artificial lymphogenous metastatic model using orthotopic implantation of human lung cancer

Background and Methods. We established a new, patientlike orthotopic model of lung cancer metastasis with human non–small cell lung cancer cell lines. In this report, we describe the progressive stages of development of lymphogenous mediastinal metastasis in the Ma44-3 cell line from day 3 to day 15 after implantation in severe combined immunodeficiency mice and the process of lymphogenous metastasis. Results. All mice killed after day 12 had perivascular and peribronchial tumor growth. Micrometastasis to the mediastinum was first observed on day 5. On days 5 through 9, 10 of 13 mice had metastasis to the mediastinum, and all mice had one by day 12. When perivascular and peribronchial tumor growth was present by day 5, metastasis to the mediastinum developed in all mice. Conclusions. This study demonstrates the lymphogenous spread of human lung cancer in severe combined immunodeficiency mouse using an orthotopic implantation model. Our model was thought to be an artificial lymphogenous metastasis model, owing to forced tumor inoculation into lymphatic vessels.

Microsatellite instability and loss of heterozygosity in prostatic carcinomas: comparison of primary tumors, and of corresponding recurrences after androgen-deprivation therapy and lymph-node metastases.

The molecular mechanisms leading to prostate cancer progression are poorly understood. In particular, those changes which are responsible for androgen-independent growth and metastatic spread in prostate cancer are an issue of current investigations. To gain more insight into these processes, paired microdissected samples from both untreated, locally advanced primary tumors (n = 20) and recurrences (n = 20) after conventional androgen-deprivation therapy (ADT) were analyzed retrospectively for microsatellite instability (MSI) and loss of heterozygosity (LOH) at nine loci on chromosomes 8, 18, and X by polymerase chain reaction. In parallel, 12 prostatic carcinomas treated by radical prostatectomy and nine corresponding lymph-node metastases were analyzed in the same way. The group treated with ADT showed a total of 10 MSI in 7 of the primary tumors (35%): 4 of these (20%) at one locus, and 3 of these (15%) at two loci. In the recurrences, MSI was observed in 4 cases (20%): 3 of these at one locus (15%), and 1 of these (5%) at two loci. LOH was found in 8 cases (40%) before as well as after ADT. In the radically resected carcinomas, MSI could be detected at two chromosomal loci in one of the primary tumors (8%) and in one of the metastases (11%); LOH was found in 2 primaries (16%) and 3 metastases (33%). Although MSI can be found in advanced prostatic carcinomas, it apparently does not play a major role in the progression of prostate cancer regarding androgen-independent growth or lymphogenous spread.

Margin of resection in the management of primary melanoma.

In the last 20 years, it has become evident that the continued use of 4 to 5 cm margins of resection around a primary melanoma is not justified. A prospective randomized trial by the World Health Organization (WHO) Melanoma Group showed that for melanomas up to 2 mm thick, a 1 cm margin provides local control similar to that observed after a 3 cm margin. Another prospective randomized trial by the Melanoma Intergroup Committee in the United States concluded that for melanomas 1 to 4 mm in thickness, a 2 cm margin of resection provides local control that is as good as a 4 cm margin. For melanomas thicker than 4 mm, the current evidence suggests that a 2 cm margin is adequate, the chief manifestation of recurrence for these thick lesions being hematogenous and lymphogenous spread. The adoption of the narrower surgical margins suggested above should reduce the morbidity caused by the radical margins of the past without compromising local control of the disease.

Gastrointestinal cancer metastasis and lymphogenous spread: viewpoint of animal models of lymphatic obstruction.

Primary gastrointestinal cancer frequently spreads to the mesentery, omentum and other parts of the peritoneum and these deposits are generally considered to be induced by intraperitoneal seeding from the primary lesion. In this work, we examined the spread of gastrointestinal cancer from the viewpoint of lymphogenous metastasis using a rat model of mesenteric lymph vessel obstruction. With these models, we carried out mesenteric lymphangiography on the fourth and sixth postoperative days (five animals each) to examine morphological changes in the lymph vessels and lymph flow. In model animals with mesenteric lymph vessel obstruction, re-celiotomy, performed on the fourth postoperative day, revealed marked mesenteric edema and enlargement of the mesenteric lymph nodes, suggestive of lymph retention. We also carried out mesenteric lymphangiography and obtained images of extensive mesenteric lymph vessels and reflux of lymph distal to the obstruction point in all five animals. On the sixth postoperative day, we obtained lymphangiographic images of lymphatico-venous communication in the mesentery in all five animals. Thus in animals with lymph vessel obstruction, the lymph flow appeared to change to lymphatico-venous communication or reverse lateral flow. In clinical cases, it is conceivable that lymph retention and reflux of lymph induced by lymph vessel obstruction sometimes play a role in the mechanism of intraperitoneal cancer dissemination and hematogenous metastasis.

Conservative treatment of vascular graft infections in the groin

Clinical implications of vascular graft infection vary according to the position of the implanted graft. The infected aortic bifurcation graft is associated with a high incidence of therapeutic failure and also a high mortality rate. 1-s In comparison, the mortality rate is low following infection of an infrainguinal bypass graft, but the risk of major amputation approaches 80%. 6'7 The close anatomical relation to the perineal area and the poor vascularisation of the subcutaneous tissue combined with a rich regional lymphatic supply predispose the groin to wound infection. Thus, not only local contamination, but also haematogenous and lymphogenic spread from other infectious sites may contribute to the high incidence of infectious complications in the groin. According to Herbst et al. s one out of three graft infections is caused by microorganisms originating from the patient's ischaemic ulcer, corroborating the observation by Lorentzen et al} that 20% of foot ulcers yield the same microorganism as isolated from the graft. Management of infected vascular prostheses is controversial. One approach is to remove the graft with a new extra-anatomic arterial reconstruction in one or two proceduresg; but it is associated with a high level of complications and bears a high mortality, especially with the involvement of an aortobifemoral graft, s'1°'1~ The other approach involves less extensive procedures in combination with administration of potent antibiotics.S,6,12 ~5 With this approach excellent results have been reported even in patients with aortic graft sepsis} 6 One such antibiotic is gentamicin applied to the region of the infection, e.g. the groin. 12'13 In our first reports on this treatment, results from 14 and 17 patients, respectively, were presented. 12'~3 In this report the number of patients has increased to 38 with a follow-up period of up to 6 years, mean 13 months.

K-ras Mutations and Prognosis in Large-Bowel Carcinomas

Background: Colorectal carcinogenesis is regarded as a multistep process involving several genetic alterations, with mutation in the K-ras gene in about half of the tumours. We aimed at clarifying the role of this genetic alteration related to survival and clinicopathologic variables. Methods: One hundred large-bowel carcinomas operated on between 1978 and 1982 were studied for the presence of point mutations in codons 12 and 13 of the K-ras gene, using enriched polymerase chain reaction amplification. restriction fragment length polymorphism analysis, and direct sequencing. Results: Forty mutations were found (40%); 31 in codon 12 and 9 in codon 13, 7 different types. There was no relationship between tumours with and without K-ras mutations with regard to Dukes' stages, age or sex of the patient, tumour localization, histologic grade, DNA ploidy pattern, HLA-DR staining pattern, or survival. Samples from 5 different localizations in 7 carcinomas showed identical K-ras mutation pattern, as did 19 recurrences/metastases originating from 11 carcinomas. Conclusions: When present, the primary tumour shows homogeneous distribution of K-ras mutation, and the mutation follows the carcinoma in the secondary deposit, regardless of lymphogenous or hematogenous spread. The presence of K-ras mutation does not seem to have prognostic significance for the patient, and the precise nucleotide change is furthermore not predictive of tumour behaviour.