Correlation of DNA ploidy, histopathology, stage and clinical outcome in gastric carcinoma. The determination of nuclear DNA ploidy from paraffin-embedded specimens was performed by flow cytophotometry on 277 surgically resected primary gastric carcinomas to assess the relationship of various pathological findings and DNA content with survival. The preparation of samples was performed by a modification of Hedley's technique and the staining method of Vindelov. Eighty-nine (32%) carcinomas were DNA diploid, 69 (25%) were DNA tetraploid, and 119 (43%) were DNA aneuploid. DNA non-diploid patterns were significantly associated with macroscopic ulcerative appearance, location of the tumour in the proximal stomach, histological grade, and advanced stage of tumour. Patients with DNA non-diploid cancers, and specifically DNA aneuploid cancers, exhibited significantly poorer survival than patients with DNA diploid tumours. These data support the prognostic value of tumour DNA content in patients with resected gastric carcinoma.


The biological effects of immunosuppression on cellular immunotherapy. Cytoreductive chemotherapy and immunosuppression have been postulated as possible adjuncts to cancer immunotherapy in studies using murine tumour-infiltrating lymphocytes (TIL). Treatment of animals with cyclophosphamide (Cy) therapy alone caused two distinct biological activities that altered the relationship between host and tumour. These two in vivo activities were distinguished by altering the timing and dose of Cy administration relative to tumour implantation. Cy administered 3 days following tumour injection caused a significant decline in the number of pulmonary micrometastases and greater survival compared to untreated controls in proportion to the dose of Cy administered. Further reduction in pulmonary disease was observed when Cy-treated mice were given TIL therapy. The possible role(s) of Cy-induced immunosuppression was studied by injecting Cy 24 h prior to tumour injection. This treatment failed to cause the cytoreductive effect observed when Cy was administered 3 days after tumour since Cy-administration prior to tumour resulted in a significantly higher number of pulmonary metastases and diminished survival compared to untreated controls. Despite the increased number of pulmonary metastases and decreased survival in mice treated with Cy before administration of tumour, therapy with TIL significantly diminished pulmonary disease compared to animals treated with Cy alone. Immunosuppression (without concomitant cytoreductive therapy) prior to TIL treatment significantly prolonged survival. Additional studies with TIL therapy indicate that the survival of animals immunosuppressed prior to tumour injection was significantly longer than controls which received immunotherapy alone. These results suggest that the combustion of immunosuppression plus cellular immunotherapy, which leads to significant survival advantage in these murine tumour models, may possibly augment the clinical response in human TIL trials.


DNA ploidy in squamous oesophageal carcinoma. The role of DNA ploidy in the management of oesophageal carcinoma is unclear. Most studies have employed flow cytometry (FC) for DNA analysis but some have used image analysis (IA) of tissue sections. In this study aneuploidy rates in stage IIa squamous tumours were determined by both FC and IA of cell suspensions and results were compared with outcome in two patient subgroups. Group 1 (n = 15) were patients who died from tumour recurrence within 1 year of surgery while Group 2 (n = 21) were patients who survived tumour free for at least 1 year. Aneuploidy rates differed significantly between techniques; 29 of 36 tumours (81%) were aneuploid by IA compared with 19 of 34 (56%) by FC (P < 0.05). Aneuploidy rates differed significantly between groups 1 and 2 as determined by FC (79%) versus 40%) (P < 0.05) but not by IA (93% versus 71%) (P = ns). Euploid status was a good prognostic indicator; 6 of 7 (86%) patients with euploid tumours by IA and 12 of 15 (80%) by FC (P < 0.05) survived more than 1 year. The sensitivity and specificity of euploidy was 93% and 28.6% for IA compared with 78.6% and 60% for FC. Since 33 (92%) of these tumours exhibited a marked peritumoral desmoplastic or chronic inflammatory reaction IA, being more sensitive to subtle nuclear change, may be a more appropriate technique than FC for evaluation of the role of ploidy in such tumours.


The effect of lowering faecal pH on the rate of proliferation of the normal colonic mucosa. Epidemiological and animal studies suggest that faecal pH may be a risk factor for colorectal cancer with low faecal pH associated with a lower incidence of the disease. The aim of this study was to determine whether faecal pH (or dietary fibre) affects the short-term risk factors for colon cancer. Sixty-nine normal volunteers were randomized into three equal groups (A-C). They provided food records, faecal specimens and submitted to rectal biopsy for thymidine labelling studies before and after a 2-week intervention. Group A received a placebo of fruit juice. Group B, approximately 3.0 g d-1 sodium sulphate in juice. Group C, 30 g d-1 supplementary dietary fibre as wheat bran in bread. Age, sex, weight, height and intake of macronutrients and minerals were similar in the groups prior to intervention. Faecal pH was similar for the three groups before and was reduced in Group B after intervention (P = 0.001) with a relative reduction of 0.5 pH units. The labelling index for the three groups was similar prior to intervention; after, it was lowest in Group B with a relative reduction of 0.5% points, although this difference was not statistically significant. The results thus do not support the hypothesis that an acidification of faecal pH leads to a reduction in risk markers for colon cancer.


Autocrine growth stimulation by transforming growth factor-alpha in human non-small cell lung cancer. We studied the biological response to and production of transforming growth factor-alpha (TGF-alpha) by the non-small cell lung carcinoma (NSCLC) clonal cell lines H226b, H322a, H460a, H596b. Each of these cell lines expressed epidermal growth factor receptor (EGFR) as determined by [125I]EGF competitive binding and Scatchard analysis and by phosphorylation. The receptors were functionally active as determined in immune complex kinase assays. H322a, H226b, H460a, and H596b cells showed stimulated [3H]thymidine (Thd) uptake in response to TGF-alpha. Exogenously added TGF-alpha increased colony formation in soft agar for three of the cell lines in media containing serum. All cell lines expressed TGF-alpha detected by immunohistochemistry and TGF-alpha mRNA, although to differing degrees. Cell lysates and spent media competed for EGFR binding with EGF, thus demonstrating production of TGF-alpha-like activity. The anti-TGF-alpha monoclonal antibody AB-3 inhibited the uptake of [3H]Thd by proliferating H322a and H226b cells but not H460a and H596b cells. No inhibition occurred with MOPC21 antibody and inhibition was completely reversed by addition of TGF-alpha to the culture. Suramin inhibited cell proliferation and [3H]Thd uptake by all cell lines. Inhibition of H460a and H596b cells was reversed with exogenous TGF-alpha but not PDGF. Our data suggests that TGF-alpha is a mediator of autocrine growth stimulation for NSCLC cells, and that for some NSCLC cells cytoplasmic binding of receptor and ligand is the primary mechanism for autocrine growth stimulation.


Alcohol injection: a treatment for ruptured hepatocellular carcinoma. Nine patients with bleeding from a ruptured hepatocellular carcinoma had absolute alcohol injection. Laparotomy and alcohol injection stopped the bleeding in seven patients. Injection under laparoscopic visualization was attempted in two patients and in one patient haemostatis was achieved initially. He rebled, however, 4 h later and laparotomy failed to control the bleeding. He died 2 days later because of coagulopathy and renal failure. In the second patient, bleeding was not controlled laparoscopically and immediate laparotomy and alcohol injection stopped the bleeding. The eight patients who survived left hospital between 8 and 21 days after surgery (median 10 days). In our experience, laparotomy and alcohol injection achieved good results in bleeding hepatocellular carcinoma.


Tumour location influences local cytokine production and host metabolism. To determine whether the location of tumour growth influences host cytokine and metabolic responses, experimental subcutaneous (SQ) and liver (LIV) tumours were compared in Buffalo rats. An LIV tumour that was only 1 +/- 1% (P < 0.05 versus SQ) of body weight produced similar anorexia, weight loss, acute phase response, and systemic cytokine responses as are SQ tumour that was 10 +/- 2% of body weight. Neither tumour-bearing group had abnormal liver function tests or evidence of obstructive biliary pathology. Tumour necrosis factor (TNF) was detected by western analysis in both tumour as well as histologically normal liver remote from the tumour in the LIV group but not in livers of animals in freely fed and SQ groups. The proximity of the tumour to competent tissue macrophage populations, such as hepatic Kupffer cells, may be sufficient to induce cachexia. Hence, tumour location may be as important as tumour burden in determining the host's response to cancer.


Treatment of neck nodes in oral cancer.

Treatment of neck nodes in oral cancer. In a review of 98 patients who were operated upon for squamous oral cancer, a high proportion of them (48%) developed recurrence after a minimum follow-up of 2 years. Nodal status significantly affected the nodal recurrence rate and survival. For N0, N1, N3 tumours, the 2-year nodal recurrence-free rates were 79, 83, 18%, and the 2-year survival rates were 58, 59 and 10%. For small tumours with N0 neck, the group with elective neck dissection and the observed group did not have statistically different nodal recurrence-free rate and overall survival. The 2-year nodal recurrence-free rate was 92% versus 77% (P value > 0.3) and the 2-year survival rate was 56% versus 72% (P value > 0.6). In patients with N1 neck, radical neck dissection was reasonably effective in controlling neck metastasis. Radical neck dissection in an attempt to treat fixed neck nodes (N3) was not successful in controlling the neck disease.


Effects of cyclosporine on human B-cell lymphoma development in vivo. Cyclosporine (CsA) is a potent immunosuppressive agent primarily affecting T-lymphocyte function. Patients receive CsA following organ transplantation to prevent rejection. These patients are at high risk for developing Epstein-Barr virus (EBV)-induced lymphoproliferative disease (LPD) or B-cell lymphoma (BCL). Severe Combined Immunodeficient (SCID) mice reconstituted with human peripheral blood leukocytes (PBL) develop fatal B-cell lymphomas of human origin following latent or active infection with EBV. This model was utilized to determine the role of CsA in the development of human BCL. SCID mice were reconstituted with PBL, latently or actively infected with EBV, and treated with CsA. Following active EBV infection, mice developed human BCL with or without CsA treatment. In contrast, treatment with CsA prevented the development of BCL in mice latently infected with EBV. This suggests a T-cell interaction with latently infected B-cells which is perturbed by CsA. Further understanding of this interaction and the occurrence of human BCL may allow the development of strategies to prevent, detect, or treat malignancies associated with immunosuppression.


Adjuvant chemotherapy for colorectal hepatic metastases: role of route of administration and timing. Improved results in the adjuvant and therapeutic treatment of colon cancer has led to renewed interest in the role of adjuvant chemotherapy following liver resection for colorectal hepatic metastases. However, little is known about the most effective method or timing of delivery of adjuvant chemotherapy. Sixty-nine BD-IX rats underwent a right hepatic lobectomy following tumour inoculation via a splenic injection of 10(7) K12/TRb colon cancer cells. The rats were then randomized to receive systemic FUdR (1 mg kg-1 d-1 for 7 d) or regional (hepatic artery or portal vein) FUdR (2 mg kg-1 d-1 for 7 d) immediately or 72 h following tumour injection. On Day 28, a laprotomy was performed, and tumour nodules in the liver were counted. The animals were followed to death, and at autopsy the cause of death from hepatic or extrahepatic metastases was determined. All methods of FUdR infusion were superior to no treatment. Immediate portal vein (PV) FUdR infusion delayed the appearance of hepatic tumour (P = 0.003), changed the cause of death from hepatic to extrahepatic disease (P = 0.019), and prolonged survival (P < 0.05). Infusion of FUdR via the PV 72 h later did not delay the appearance of hepatic tumours nor prolong survival. In contrast, delayed HA FUdR infusion controlled hepatic metastases (P = 0.04) and improved survival (P < 0.05).


Clinical relevance of tumour markers CA 19-9 and CA-50 in sera from patients with pancreatic duct carcinoma. Serum levels of the tumour antigens CA 19-9 and CA-50 and their relation to the extent of the disease were studied in 97 patients with carcinoma of the pancreas. Of 13 patients with normal serum concentrations of CA 19-9, 11 (84.6%) had irresectable disease, whereas 87.5% of the patients with resectable disease expressed antigen levels above cut-off. Following attempted radical surgery, preoperatively elevated serum levels decreased in eight patients (50%). Unchanged and high levels were associated with residual disease and early death. Clinical signs of recurrence were preceded by elevated serum levels of both tumour antigens.


Inhibition of the growth of human melanoma metastases in nude mice by melanoma-specific murine monoclonal antibody. The administration of anti-melanoma murine monoclonal antibody (MAB) 16.C8 (IgG2a) to nude mice bearing established human melanoma lung or liver metastases resulted in a significant inhibition of tumour growth. A total dose of 2 mg of affinity purified 16.C8 caused complete inhibition of tumour growth in 89 and 100% of animals in the liver and lung model, respectively. In contrast, a significant tumour growth was found in most control animals which received an irrelevant IgG2a MAB or 2% human serum albumin in Hanks Balanced Salt Solution (HBSS). The MAB was most effective when treatment was started on day 1 or 4 following tumour inoculation. When the 16.C8 MAB treatment was delayed 7 or 14 days, 33 and 67% of 16.C8 treated animals, respectively, developed tumours. The MAB-mediated anti-tumour activity appeared to be dose dependent, and the effect of a suboptimal dose was potentiated by the concomitant administration of recombinant interleukin 2 (rIL-2). Recombinant IL-2 alone in a similar dose did not elicit comparable anti-tumour activity. Moreover, the MAB 16.C8 inhibited tumour growth in irradiated animals which may suggest the involvement of host-radioresistant cellular elements in the 16.C8 antibody-mediated anti-tumour activities in nude mice. These results suggest that MAB 16.C8 alone or combined with rIL-2 may prove useful in the immunotherapy of metastatic melanoma.


Neurotensin stimulates growth of colon cancer. Neurotensin (NT), a peptide from the distal gut that is released by fat ingestion, stimulates the growth of normal small bowel and colonic mucosa. The purpose of this study was to determine whether chronic administration of NT would affect the growth of a mouse colon cancer (MC-26) and a human colon cancer (LoVo) in vivo. In experiment 1, male Balb/c mice were inoculated with MC-26 cells (5 x 10(4)) and then randomized to four treatment groups receiving either saline (control) or NT (150, 300 or 600 micrograms kg-1) administered subcutaneously (s.c.) every 8 h for 21 days. In experiment 2, 60 mice with MC-26 tumours were randomized to receive saline (control) or NT (300 or 600 micrograms kg-1) for 28 days, and survival was then assessed. In experiment 3, 16 athymic nude mice with LoVo tumour xenografts were randomized to receive either saline (control) or NT (600 micrograms kg-1). We found that administration of NT (300 and 600 micrograms kg-1) significantly stimulated mean tumour area, weight and DNA, RNA and protein content of MC-26 tumours. In addition, the survival rate of mice bearing MC-26 tumours and treated with either dose of NT was significantly decreased compared with the control group given saline injections. Similarly, NT (600 micrograms kg-1) stimulated growth (tumour area, weight and nucleic acid contents) of the human colon cancer, LoVo. We conclude that NT acts as a tropic factor for the colon cancer cell lines MC-26 and LoVo in vivo. NT may play an important role in growth regulation of certain colon cancers.


Independent prognostic factors in T2/T3 transitional cell bladder tumours with special reference to histoquantitative methods. A cohort of 233 T2/T3 transitional cell carcinomas were followed up for over 10 years. Five nuclear factors, two mitotic indices, DNA ploidy and S-phase fraction (SPF) were related to progression and survival of TCCs during that time period. SPF predicted pelvic lymph node involvement at diagnosis (P = 0.064). Progression in T-category was related to T-category (P = 0.035), DNA ploidy (P = 0.0180), papillary status (P = 0.0021), mitotic activity index (MAI) (P = 0.0011), volume corrected mitotic index (M/V index) (P = 0.0017), WHO grade (P = 0.0003) and S-phase fraction (P = 0.0002). Progression in N and M-categories was related to the same variables. Independent predictors of progression in T-category were SPF (P = 0.0161) and WHO grade (P = 0.0236), whereas progression in M-category was independently related to MAI (P = 0.0012) and T-category (P = 0.0004). The SPF (P < 0.0001), M/V index (P < 0.0001), MAI (P < 0.0001), WHO grade (P < 0.0001) and papillary status (P < 0.0001) were the most important predictors of survival in univariate analysis. In a multivariate analysis SPF and M/V index (P < 0.0001) were the best predictors of survival followed by papillary status and T-category. The results show that the proliferation rate of T2/T3 TCCs as determined by flow cytometric SPF or M/V index are equally powerful predictors. They are clearly better than nuclear morphometry, DNA ploidy or WHO grading as prognostic factors.


Preservation of fertility following doxorubicin administration in the rat. Several hundred thousand men receive chemotherapy each year; many are sterilized by this treatment. Testicular circulatory isolation (TCI), a regional drug exclusion approach to circumvent chemotherapy-related infertility, lessens doxorubicin-induced testicular injury in the rat. We evaluated the effect of TCI on doxorubicin-induced infertility in this study. Thirty-two eight-week-old male Sprague-Dawley rats were used. Eight rats received TCI for 45 min. Eight received doxorubicin (i.v. bolus) plus sham surgery. Eight received i.v. doxorubicin given immediately after institution of TCI. Eight controls received sham surgery alone. Mating studies began 2 months later. Six of the 8 males receiving TCI alone were fertile. In the doxorubicin-treated, sham-operated group, 0 of 7 animals were fertile. In the doxorubicin-treated group which also received TCI, 2 of 7 males were fertile. In the sham-operated group, all 8 rats were fertile. This is the first evidence that regional drug exclusion technique can improve fertility in this model.


Early results of follow-up after radical resection for colorectal cancer. Preliminary results of a prospective randomized trial. One-hundred and six consecutive patients were included in a prospective study of intensive monitoring after radical resection for colorectal cancer, 54 being randomized into a conventional follow-up group (Group I) and 52 into an intensified follow-up group (Group II). After a median follow-up of 2 years the overall rate of detection recurrence in Group I was 24% (13/54) and in Group II 25% (13/52). The recurrence rates among those followed up for at least 2 years were 36% (10/28) and 30% (9/30), respectively. Of the recurrences in Group I, one was local, five regional and six distant, and the corresponding figures in Group II were three, four and five. One radical extirpation of a local perineal recurrence has been performed in Group I, whereas two intestinal reresections for local anastomotic recurrences and two hepatic resections for solitary hepatic metastases have been performed in Group II. Mortality to date is 13% (7/54) in Group I and 8% (4/52) in Group II. Two adenomatous polyps have been removed from the colon in Group I during endoscopic surveillance and seven in Group II. These preliminary results encourage us to continue the trial up to 5 years after primary surgery.


Secondary cytokine production by lymphoid cells used in cellular immunotherapy. Interleukin-2 (IL-2) has been used extensively in cellular immunotherapy trials as a systemic activator of the immune system as well as an ex vivo stimulant for lymphoid cell function. Despite the measurement of several in vitro and in vivo immunologic parameters related to cellular immunotherapy, determinants of successful cellular immunotherapy remain unknown. To further delineate the consequences of exposing peripheral blood lymphocytes to high concentrations of IL-2, we assessed the supernatants of IL-2-activated peripheral blood lymphocytes for production of tumour necrosis factor (TNF) and interferon-gamma (IFN-gamma). Exposure of normal monocyte-depleted peripheral blood mononuclear cells (PBMC) to IL-2 caused a dose-dependent increase in secretion of TNF and IFN-gamma which increased linearly after 48 h in culture. Analysis of positively selected, highly purified PBMC subpopulations exposed to IL-2 revealed that TNF-alpha and TNF-beta were produced by both CD3+ and CD16+ subpopulations but not by CD22+ cells. These studies were extended to supernatants obtained from PBMC cultures used in the adoptive cellular immunotherapy of patients with advanced cancer. Patients treated with lymphokine-activated killer (LAK) cell immunotherapy were classified as responders (N = 14) or non-responders (N = 17) to therapy. We found no significant difference in the production of TNF between responders and nonresponders (22 +/- 9 U ml-1 vs. 20 +/- 6 U ml-1), P > 0.05. However, LAK cell supernatants harvested from non-responders contained a significantly higher level of IFN-gamma (232 +/- 94 U ml-1) compared with responders (42 +/- 14), P < 0.05. Furthermore, the linear association between IFN-gamma and TNF-alpha production was different between these two response groups (rs = -0.19 for non-responders and rs = 0.48 for responders). These results suggest that secondary cytokine production by adoptively transferred lymphocytesmay play an important role in the host response to cellular immunotherapy.


Mechanisms of accelerated hepatic glutamine efflux in the tumour-bearing rat. The mechanisms potentially controlling the net release of glutamine by the liver that occurs in tumour-bearing rats were investigated. Studies were undertaken when the tumour comprised approximately 7% (15 +/- 2 g) of total body weight. Hepatic glutamine gradient ratios were calculated by dividing hepatic glutamine content by arterial blood glutamine concentration. Both sodium-dependent and sodium-independent hepatocyte carrier-mediated glutamine transport were evaluated employing hepatic plasma membrane vesicles (HPMVs). In TBR the hepatic glutamine gradient ratio doubled (P < 0.001) secondary to a 52% increase in hepatic content (P < 0.005) and a 16% decrease in circulating glutamine (P < 0.001). Sodium-dependent glutamine transport was increased in HPMVs from TBR secondary to a 24 +/- 4% increase in the maximal velocity of transport (Vmax; P < 0.01) without alteration in apparent transporter affinity (Km). Saturable sodium-independent carrier-mediated glutamine transport was increased in HPMVs from TBR over CONT to a much greater relative degree owing to a 2.7-fold increase in transport Vmax (P < 0.05) without a change in transport Km. The accelerated hepatic efflux of glutamine which characterizes malignant growth appears to be the result of both mass-action gradient phenomena and alterations at the level of hepatocyte membrane transport activity.


Detection of squamous cell cancer and pre-cancerous lesions by imaging of tissue autofluorescence in the hamster cheek pouch model. Early detection of invasive and pre-invasive neoplasms of the aerodigestive tract will ultimately improve the management of patients with these lesions. This paper describes the use of quantitative fluorescence imaging of early squamous cell carcinomas in an animal model. Dysplasia, carcinoma in situ and invasive cancers were imaged exploiting tumour autofluorescence. Mapped biopsies were obtained from areas imaged determining a sensitivity of 100% and specificity of 80%. Autofluorescence imaging is an excellent method of detecting neoplasms of the aerodigestive tract.


Intraluminal ultrasound of rectal tumours: a prerequisite in decision making. The use of intraluminal ultrasound (IUS) as a staging technique was evaluated in 58 patients with a rectal tumour. Thirty-four patients had a rectal carcinoma, four had a local recurrence after a previous anterior resection and 20 other patients had a villous adenoma. IUS assessment of rectal wall invasion, infiltration into adjacent organs, and the presence of perirectal lymph node involvement was compared with the definitive histological findings. In 90% of all patients the pre-operative local tumour staging was predicted correctly. In 38 patients with a rectal carcinoma the overall accuracy for the T grade was 84%. The sensitivity for the detection of perirectal fat infiltration was 91%, with a specificity of 70% and a negative predictive value of 78%. The accuracy in predicting direct infiltration into adjacent organs was 100% (n = 5). In the four patients with a local recurrence, the diagnosis was suspected by means of IUS and confirmed by biopsies. Extraluminal tumour growth was predicted correctly in all cases, with extension into the coccygeal bone in one patient. IUS identified lymph nodes in 29 of 38 cases, with a sensitivity of 57% and a specificity of 76%. All 20 villous adenomas were correctly staged as non-infiltrative tumours. After transmural excision, three adenomas proved to contain a completely removed T1 carcinoma. IUS is the most accurate tool in predicting the depth of local tumour invasion and needs a place in the preoperative screening programme in patients with a rectal tumour, as well as in the postoperative follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)


A novel role for autologous tumour cell vaccination in the immunotherapy of the poorly immunogenic B16-BL6 melanoma. The growth of immunogenic tumours stimulates the generation of tumour-sensitized, but not functional, pre-effector T cells in the draining lymph nodes. These pre-effector cells can mature into effector cells upon in-vitro stimulation with anti-CD3 and IL-2. In the current study, using a defined, poorly immunogenic tumour, B16-BL6 melanoma, the pre-effector cell response was not evident during progressive tumour growth but was elicited by vaccination with irradiated tumour cells admixed with Corynebacterium parvum. After anti-CD3/IL-2 activation, these cells were capable of mediating the regression of established pulmonary metastases. The efficacy of the vaccine depended on the doses of both tumour cells and the adjuvant. While higher numbers of tumour cells were more effective, an optimal dose (12.5 micrograms) of C. parvum was required. The dose of irradiation was not a critical factor. After vaccination, kinetic studies revealed that the pre-effector cell response was evident 4 days later and declined after 14 days. These observations illustrate the potential role of active immunization in the cellular therapy of cancer.


Is the new UICC staging system of gastric cancer reasonable? (Comparison of 5-year survival rate of gastric cancer by old and new UICC stage classification). In the new UICC TNM system for gastric cancer approved in 1985, a T1 lesion with lymph node (LN) metastasis is classified as stage, Ib; in the old TNM system this was classified as stage III. This is contradictory to a general rule of the UICC TNM system, whereby cancer with LN metastasis is classified as stage II or III. Two thousand and sixty-three patients with less than T4 gastric cancer who were treated at Seoul National University Hospital from 1970 to 1986 were analysed for significant prognostic factors. Survival curves were subsequently analysed according to the number of LN metastases and the depth of invasion. As a result of multivariate study for clinical and pathological features such as age, tumour location, gross appearance, histological type, depth of tumour invasion and regional lymph node metastasis, we confirmed that only two factors--regional lymph node metastasis and depth of gastric wall invasion--are significant. We showed that when the LN variable is classified according to the number of LN metastases (0 group, 1-3 group, > 3 group) like the UICC TNM classification of colorectal cancer, the survival curves are similar to those reported by the Japanese Research Society for Gastric Cancer. The authors propose the modification of the UICC TNM classification system according to depth of invasion and the number of LN metastases, whereby a T1 lesion with LN metastasis is classified as stage IIa instead of stage 1b.


Activities of thymidylate synthetase and thymidine kinase in gastric cancer. In a previous clinical study, sequential methotrexate and 5-fluorouracil has shown improved efficacy for treating advanced gastric cancer of the poorly differentiated type. In this study, we investigated whether difference in the levels of thymidylate synthetase (TS) and thymidine kinase (TK) activities in gastric cancer tissue account for selectivity of the treatment. Activity of TS was higher in 19 cases of the poorly differentiated type than in 16 cases of the well differentiated type (P < 0.02), whereas TK activity was lower in the poorly differentiated type than in the well differentiated type (P < 0.01). Thus, the TS/TK ratio was significantly higher in poorly differentiated gastric cancers than in well differentiated cancers (P < 0.001). These results suggest that a greater dependence upon the de novo pathway of pyrimidine synthesis in poorly differentiated gastric carcinomas may enhance the efficacy of sequential methotrexate and 5-fluorouracil treatment.


Wide resection with latissimus dorsi muscle transposition in breast conserving surgery. In this study we evaluated whether the immediate transposition of the latissimus dorsi muscle (LDM) improves breast appearance and patient satisfaction after quadrantectomy. Twenty-three patients (transposed group) had the transposition of LDM immediately after quadrantectomy, but eight patients (non-transposed group) had quadrantectomy alone. For evaluation, breast size was classified as small (A or B cup) and large (C or D cup). Consequently, the cosmetic result was evaluated as excellent in 73% of the patients with transposed small breasts, but in only 25% of the patients with non-transposed small breasts and by none of the patients with transposed large breasts. On the other hand, all patients with transposed small breasts reported that they are satisfied with their operation, as opposed to 88% of the patients with transposed large breasts and 63% of the patients with transposed large breasts and 63% of the patients with non-transposed small breasts. It was concluded therefore, that the transposition of LDM is useful in correcting post-quadrantectomy breast deformity, especially in patients with small breasts.


Histopathological prediction of liver metastasis after curative resection of colorectal cancer. To estimate the risk of liver metastasis after curative resection of colorectal cancer, resected specimens from 290 patients (45 with metachronous liver metastasis) were examined and the relationships between 10 histopathological variables and liver metastasis were analysed using our application of the Akaike information criterion (AIC). Of the 10 variables examined, the depth of venous invasion (Vd) had the greatest prognostic value for metastasis, followed by the number of venous invasions, the number of lymphovascular invasions, lymph node metastasis and type of infiltration. The prediction of liver metastasis was further improved by combining Vd with lymphocyte infiltration, mucinous production, interstitial fibrosis or depth of penetration, although these four variables per se were minimally informative for metastasis. We conclude that the prediction of liver metastasis is best achieved by combining Vd with other variables. Our risk group classification, and the estimated probability of liver metastasis for each group, are shown.


Laparoscopic feeding jejunostomy tube in oncology patients. Laparoscopic-guided feeding jejunostomy tubes are being utilized in two specific groups of patients: (i) patients with resectable or locally advanced adenocarcinoma of the pancreas treated on a protocol of preoperative chemoradiation, who may require nutritional support, and (ii) patients with metastatic or obstructing foregut tumours who require a route for delivery of fluid and medication. The technique, rationale and results for our first 17 patients who underwent laparoscopic placement of a tube jejunostomy are described. Laparoscopic feeding tube placement is a safe and cost-effective method to gain enteral access and stage the oncology patient's disease. This procedure is less invasive than standard surgery for tumour staging and feeding tube placement, and facilitates formula advancement and the patient's early hospital release without morbidity or mortality.


Intra-rectal injection of tumour cells: a novel animal model of rectal cancer. The purpose of this study was to develop an animal model of rectal cancer. Three murine-derived cell lines, B16 melanoma, CT26 and MCA38 colon carcinoma, as well as the human colon cancer cell line LS174T were injected into the submucosa of the mouse rectum. Subcutaneous CT26 anbd B16 tumours and intra-caecal CT26 tumours served as controls for tumourigenicity of the cell lines. B16 melanoma produced a locally aggressive rectal tumour as well as skin and para-aortic lymph node metastases. CT26 produced local tumour when injected intra-rectally and colon tumours and liver metastases when injected into the caecum. MCA38 and LS174T intra-rectal injections resulted in large rectal carcinomas without metastases. We believe that growth of a colon cancer cell line in the rectum approximates the human disease more closely than other models of colorectal cancer. We would expect that the model could similarly be utilized to assess the effects of novel adjuvant treatments for rectal cancer as well as in the study of the tumour biology of rectal cancer.


The effect of insulin on glucose and protein metabolism in the forearm of cancer patients. This study was designed to study the effect of systemic hyperinsulinaemia (INS) on glucose and protein metabolism in cancer patients. Sixteen cancer patients (8 > 10% weight loss (WL); 8 < 10% weight loss (NWL)) were compared with 12 healthy controls. Glucose uptake (GU) and phenylalanine (PHE) exchange kinetics were measured across the forearm in the postabsorptive state (PA) and in response to INS (71 +/- 5 microU ml-1). At steady state in response to INS, the negative PA PHE net balance became significantly positive, and GU significantly increased, for cancer and control groups, with no significant differences between the two groups. Subset analysis of NWL cancer vs. WL cancer found no difference between WL and NWL for the change in PHE balance from PA and INS, however GU increased significantly only for the NWL group between PA and INS. These data indicate that cancer patients are not resistant to the anabolic effect of INS on protein metabolism, regardless of weight loss, but are resistant to the effect of INS on glucose metabolism when further along in the disease process as evident by more significant weight loss. This differential response to the effect of INS can be exploited in an attempt to promote protein accrual in weight-losing cancer patients.


K-ras gene mutation in colorectal adenomas and carcinomas from familial adenomatous polyposis patients. Colorectal adenomas and carcinomas from familial adenomatous polyposis (FAP) patients were screened for the presence of K-ras gene mutations at codon 12 using an in vitro amplification step (polymerase chain reaction) followed by dot blot analysis using oligonucleotide probes specific for different mutations at codon 12. We examined 28 colorectal adenomas and two colorectal carcinomas from 12 FAP patients and observed a mutation at codon 12 in seven adenomas and in both carcinomas. The frequency of K-ras gene mutations in colorectal tumours from FAP patients is similar to those in cases of sporadic adenomas and sporadic colorectal carcinomas indicating that the mechanisms involved in their development may be similar.


K-ras gene mutations in adenomas and carcinomas of the colon. DNA extracted from 29 colorectal carcinomas and 40 sporadic adenomas was amplified by the polymerase chain reaction (PCR) and analysed for the presence of K-ras gene mutations at codon 12 using a panel of synthetic oligonucleotide probes specific for normal and mutated sequences. The presence of mutations was correlated with various histopathological and clinical data. Ten carcinomas (34.5%) and 14 sporadic adenomas (35%) showed K-ras mutations at codon 12. In the carcinoma group, no apparent correlation was found between the presence of mutant oncogenes and the degree of histological differentiation, Dukes' staging or the development of distant metastasis. In the adenoma group, the frequency of mutations increased with the size of the adenoma and the severity of the dysplastic changes. This study confirms that ras gene mutations are common and early events in colon carcinogenesis. They appear to give a selective growth advantage to those polyps with mutations which leads to their increase in size and thus possibly prepare the ground for malignant transformation.


Intraoperative radiotherapy for unresectable cholangiocarcinoma--the Mayo Clinic experience. Thirteen patients with unresectable cholangiocarcinomas were treated with external beam radiation therapy (ERT) and intraoperative radiation therapy (IORT) in combination with biliary stenting. Local treatment failure occurred in 50% of the patients treated with curative intent and an additional two patients developed distant recurrent disease. Patient morbidity was primarily related to biliary sepsis and gastrointestinal complications. There was minimal morbidity related to the IORT. Although the median survival of 16.5 months seemed to be an improvement over our previous results for ERT alone or ERT with 5-fluorouracil, the survival data are still discouraging. Further improvements in treatment will require better means of biliary bypass and increased tumour response perhaps by the use of radiosensitizers or hyperthermia in conjunction with radiation therapy.


Effective regional therapy of experimental cancer with paralesional administration of tumour necrosis factor-alpha + interferon-gamma. Systemically administered tumour necrosis factor (TNF) has anti-tumour effects in animal tumour models but its clinical application is limited by severe toxicity. Interferon-gamma(IFN-gamma) has been shown to augment the anti-tumour effect of TNF. We evaluated the effect of paralesional (p.I.) injections of TNF plus IFN-gamma in a murine tumour model and compared the toxicity and anti-tumour effect with that seen with systemic administration. C57BL6 mice with 10-day subcutaneous MCA sarcomas were treated with daily p.I. injections of recombinant huTNF +/- IFN-gamma for 5 days. Optimal mean survival and 30-day cure rate was seen with doses of 5 micrograms TNF-alpha + 5000 U IFN-gamma (P < 0.05 vs. control or IFN-gamma alone). Tumour response after a single i.v. injection of 0-15 micrograms TNF + 5000 U IFN-gamma was then compared with five daily p.I. injections of the same dose of TNF-alpha and IFN-gamma. All animals with p.I. injections of > 5 micrograms TNF had initial complete necrosis of tumour with a variable degree of surrounding tissue necrosis, with rapid regrowth of tumour seen in some animals. Although treatment-related mortality was similar between i.v. and p.I. therapy, there was a higher percentage of animals cured with p.I. injections with overall cure rates in treated animals at 30 days of 17% vs. 72% (i.v. vs. p.I., P < 0.01) and 13% vs. 67% (P < 0.04) in a repeat study. 2+ clinical applications.


Adoptive transfer of bryostatin 1-activated T cells provides long-term protection from tumour metastases. Treatment of human cancer with tumour-specific T lymphocytes is limited by the frequent unavailability of autologous tumour to stimulate T-cell growth and by the toxicity associated with high-dose interleukin-2 (IL-2) treatment. In the present study we demonstrate that Bryostatin 1 (B) plus ionomycin (I) can substitute for tumour antigen and activate tumour-bearing hosts' T-cells which provide long-term protection against tumour challenge after adoptive transfer. Lymphocytes obtained from the popliteal lymph nodes (DLN) draining an MCA-105 footpad sarcoma were stimulated with B/I, and then cultured for 7 days with 20 U ml-1 IL-2. This in vitro stimulation protocol consistently expanded cell numbers greater than 20-fold during 7 days. Mice given B/I-stimulated draining lymph node (DLN) cells were protected from specific i.v. tumour challenge for at least 15 weeks after adoptive transfer, even in the absence of IL-2 treatment. Tumour immunity conferred by B/I-activated DLN cells was systemic and independent of host T-cells. However, resistance to tumour challenge was lost when either CD4+ or CD8+ T-cells were depleted in vivo. These studies indicate that DLN cells activated with bryostatin 1 and ionomycin persist long-term in vivo as functional memory cells after adoptive transfer.


Expression polymerase chain reaction: a sensitive method for analysis of gene expression in human tumours. To analyse the expression of individual genes in small tumour samples, we have used the method of RNA polymerase chain reaction (PCR) to develop a technique which we have termed expression PCR. With this technique, specific cDNA sequences of a target gene are amplified, analysed by gel electrophoresis, and semi-quantitated using laser densitometry. Alpha-actin is amplified as a reference gene to control for template RNA and each target gene is analysed at several cycle numbers to optimize PCR dynamics. In this study, we have demonstrated expression PCR by analysing the levels of expression of tyrosine kinase genes in a panel of human tumours. We have compared expression PCR with Northern analysis to show that these techniques provide equivalent information on relative levels of gene transcription, with expression PCR requiring 100-fold less RNA. This technique is sufficiently sensitive to detect and compare the levels of expression of genes not seen on Northern analysis and is ideally suited for analysing the expression of multiple genes within the same portion of a tumour.


Sodium butyrate stimulates polyamine biosynthesis in colon cancer cells. Differentiation inducers act through polyamine-dependent and independent pathways. Sodium butyrate (NaB) inhibits proliferation and induces terminal differentiation in human and murine cancer cell lines. An effect of this agent on polyamine biosynthesis has not been demonstrated previously. In the present study, we examined the effects of NaB on polyamine biosynthesis in mouse colon cancer (MC-26) cells. All studies were performed on exponentially growing cells, and ODC and polyamine transport measurements were performed as described previously. NaB inhibited the growth of MC-26 cells in a dose-dependent manner. Cell shape was significantly altered by treatment with NaB (development of dendritic-like processes and flattening and spreading out of cells on culture dishes). NaB stimulated ODC activity in a dose-dependent manner. The activity was elevated by 8 h after treatment, and at 48 h there was a ten-fold increase in activity (compared with control activity). The increase in ODC activity led to an increase in polyamine biosynthesis; putrescine, spermidine, and spermine levels in MC-26 cells were significantly elevated by 24 h after treatment with NaB. Polyamine uptake was similar in control cells and cells treated with NaB alone. Our finding of significant stimulation of polyamine uptake by NaB after inhibition of endogenous synthesis (by an ODC-dependent pathway) in DFMO-treated cells suggests that cellular requirements are increased for polyamines in NaB-treated cells. We conclude that polyamine-dependent processes are important in the mechanism of action of NaB in colon cancer cells.


Characterization of GRO alpha, beta and gamma expression in human colonic tumours: potential significance of cytokine involvement. The GRO genes, isolated from transformed fibroblasts, belong to a superfamily of genes such as platelet factor 4 and neutrophil activating peptide/IL-8. Three related GRO genes are described which are closely linked on chromosome 4: GRO alpha, GRO beta, and GRO gamma: GRO beta and GRO gamma share 90 and 86% sequence homology with GRO alpha. The GRO alpha gene product shares homology with, and is melanocyte growth stimulatory activity (MGSA). The MGSA/GRO alpha has potent chemotactic, growth regulatory and transformative functions. The function of GRO beta and gamma is unknown. Expression of GRO alpha is well characterized in vitro; studies in actual human tissues are not reported. We chose to determine the specific expression of GRO alpha, beta and gamma in both normal and transformed human colonic tissues and to assess the role of exogenous cytokines on their induction. Tissues from ten patients with colonic neoplasia were obtained at the time of colectomy. All specimens underwent Northern analysis for GRO gene expression, comparing normal colonic mucosa with neoplastic mucosa. Differential GRO alpha, beta and gamma expressions were determined by polymerase chain reaction (PCR). GRO alpha expression was evaluated in the tumour specimens compared with normal, while there was constitutive expression of GRO gamma in both normal and neoplastic colonic mucosa. Expression of GRO beta was minimal in all tissue specimens. In addition, HT29 colon carcinoma cells stimulated with IL-1 beta and TNF alpha demonstrated induction of GRO alpha and IL-8. Thus, GRO alpha is differently elevated in in vivo colon carcinoma specimens. GRO gamma was constitutively expressed in colonic tissues; GRO beta was not similarly expressed.


Loco-regional nodal relapse in melanoma. Two-hundred and seven patients without evidence of disease following lymph node dissection (LND) were stratified into three groups: Group A, lymph node relapse within the site of prior LND; Group B, lymph node relapse in a different, but regional, lymph node group; Group C, no lymph node relapse. Decreased survival was noted in both Groups A and B versus Group C. Prognostic factors were identified as: (i) axial or subungal/volar (subvolar) location and the number of positive lymph nodes at initial LND for nodal relapse within the same lymph node group; (ii) male gender, axial/subvolar location, and the number of histologically positive lymph nodes at initial LND for nodal relapse in a different, but regional lymph node group; (iii) relapse within the initial LND site for a decreased survival. Six of 10 patients with both axial/subvolar primaries and four or more positive lymph nodes developed a relapse within the dissection site post-LND. These prognostic factors describe a subset of patients who would be candidates for postoperative adjuvant local/regional and systemic therapy trials.


Risk factors which predict pattern of recurrence after curative surgery for patients with advanced gastric cancer. The objective of the study was to define risk factors for peritoneal dissemination and haematogenous metastasis after curative resection of patients with an advanced gastric cancer. In retrospective analyses of 405 patients, 168 died of a tumour recurrence. Patients who died of gastric cancer were more likely to have large, invasive tumours which had spread throughout the stomach, metastasized to lymph nodes, and vessel invasion by gastric cancerous cells (P < 0.01 or P < 0.05). Of the 168 deaths, 60 (35.7%) were secondary to haematogenous recurrence, 53 (31.5%) were related to peritoneal dissemination, and 19 (11.3%) were related to a local recurrence. To determine the independent risk factors related to peritoneal dissemination and haematogenous metastasis, multivariate analyses using a stepwise logistic model suggested that serosal invasion (P < 0.01, relative risk = 2.57) and Borrmann type 4 (P < 0.01, relative risk = 1.95) were the greatest risk factors for peritoneal dissemination. The presence of lymph node metastasis (P < 0.01, relative risk = 2.62) and presence of vessel invasion by cancerous cells (P < 0.05, relative risk = 1.59) were the greatest risk factors for a haematogenous metastasis.


Factors affecting outcome in locally advanced breast cancer. Patients presenting with locally advanced breast cancer (LABC) constitute a diverse group for which a variety of treatment modalities have been instituted. To assess which factors have a direct impact on outcome, we reviewed the medical records of 104 patients diagnosed with stage IIIA, stage IIIB and T3N0M0 breast carcinoma. When considered individually (univariate analysis), clinical stage, pathological stage, oestrogen receptor status and type of therapy were significant predictors for disease-free survival (DFS) and overall survival (OS). However, in a multivariate analysis, only clinical stage was a significant predictor for both DFS and OS, while ER status was a significant predictor for OS. There was a high degree of correlation between clinical and pathological staging. Nearly two-thirds of the patients developed a recurrence by 5 years. Loco-regional recurrence was the site of first recurrence in one-third of the patients by 5 years. The prognosis for patients presenting with LABC is poor, and they should be treated aggressively with loco-regional and systemic multimodality therapy. Although groups of patients with improved outcome could be identified by clinical or pathological staging, no group demonstrated an outcome good enough to be spared from multimodality therapy.


Gastroduodenal polyps in familial adenomatous polyposis. A retrospective review of the medical records of 30 patients with familial adenomatous polyposis who underwent oesophagogastroduodenoscopy was performed to evaluate the spectrum of gastroduodenal polyps. Twenty-five patients (83%) had gastroduodenal polyps. Eighteen patients (60%) had gastric polyps and 21 patients (70%) had duodenal polyps. Five patients (17%) had gastric and 20 patients (67%) had duodenal adenomatous polyps. Three patients (10%) died from an upper gastrointestinal tract adenocarcinoma. Three of nine patients with periampullary adenomas had a normal-appearing papilla of Vater. Since gastroduodenal polyps are common in familial adenomatous polyposis, oesophagogastroduodenoscopy should be performed at the time of diagnosis. Biopsy of polyps as well as biopsy of a normal-appearing papilla of Vater should be performed. Due to their malignant potential, if identified, gastroduodenal adenomatous polyps should be destroyed.


Significance of local recurrence after mastectomy for breast cancer. In a retrospective study 678 patients who underwent (modified) radical mastectomy between 1970 and 1986 were analysed. By comparing the groups of patients who experienced local recurrence, regional recurrence or distant metastasis during follow-up with patients who remained free of disease, we have tried to gain some insight into the significance of local recurrence. By looking at the prognostic factors and the disease-free period there is hardly any difference between the patients with either a local, regional or distant recurrence. Actuarial survival of patients with local recurrence is slightly better than the survival of patients with distant metastasis (P = 0.009). From our results and from the literature we conclude that an isolated local recurrence after mastectomy for breast cancer is, in most cases, a first manifestation of metastatic disease. Probably only a minority of the local recurrences is caused by tumour cells left behind in the operation field.


A simplified technique to resect abnormal bony radiolocalizations using a gamma counter. A simplified technique for localizing and verifying the correct biopsy site of lesions identified on a bone scan has been utilized. A hand-held gamma counter was used for localization of incision placement, determination of extent of bone to be resected, and verification that appropriate tissue was resected. This technique was used to guide biopsy of bony lesions in five patients and to guide resection of a pubic ramus chondrosarcoma. We conclude that intraoperative use of a gamma counter to guide biopsy of bony lesions minimizes surgery time, increases the confidence of obtaining correct tissue, and makes a frequently frustrating procedure very simple. In addition, the probe may assist with determining adequate margins at definitive resection of tumours which accumulate technetium-99m MDP.


The effectiveness of skin cancer screening and continuing medical education programs toward increasing the survival of patients with malignant melanoma. The 5-year survival rate for malignant melanoma has increased 40% over the last 50 years. During this same time period, the treatment for the disease has not changed significantly, and consists of wide excision of the primary tumour and perhaps regional node dissection. The purpose of this study was to investigate the possible impact of screening/education programs on melanoma survival. In 1987, a multimodality University-based Melanoma Treatment Center was established and programs were instituted for skin cancer screening and Continuing Medical Education (CME) of health care providers. During the last 5 years, 594 patients with newly diagnosed melanoma have been registered at the clinic. The number of patients with localized (stage 1 or 2, negative regional nodes) disease was 516 (85%). For all stages of disease, the 3-year actuarial survival for this screened population was 85%. From the National Cancer Database of 9879 patients registered with melanoma for 1988, 75% had localized disease and the 3-year survival was 76%. There were significant differences noted between the screened Florida population and the nationwide database using an odds ratio statistic. This involved a higher frequency of patients diagnosed with localized disease (odds ratio = 1.89 (1.49-2.40)) and a better survival (odds ratio = 1.79 (1.41-2.27)) in the screened population served by CME-educated community physicians.


Amiloride inhibits the growth of human colon cancer cells in vitro. Cytoplasmic alkalinization induced by activation of the Na+/H+ antiport plays an essential role in the initiation of cell proliferation. In the present study we examined the effects of amiloride, a specific and reversible inhibitor of Na+/H+ antiporter, on the growth of human colon cancer cells (HT-29). Amiloride (50-800 microM) inhibited the growth of HT-29 cells in a dose-dependent fashion. Forty-three percent inhibition of growth was found at an amiloride concentration of 400 microM after 4 days of treatment. The inhibitory effect of amiloride on growth of HT-29 cells was reversible since removal of amiloride by a media change after 48 h treatment lead to rapid regrowth to control levels. The reversibility of growth inhibition suggests that amiloride is not a non-specific cytotoxin for HT-29 cells. We examined the possible mechanisms for the inhibitory effects of amiloride. Amiloride (400 microM) completely abolished serum-stimulated ODC activity and inhibited difluoromethylornithine (DMFO)-stimulated putrescine uptake by 56%. We conclude that amiloride inhibits the in vitro growth of human colon cancer cells; since ODC-activity and polyamine transport were both inhibited, the inhibitory effects may be mediated in part by polyamine-dependent processes. Amiloride may be a useful agent in the treatment of colon cancer.


Use of radiolabelled monoclonal antibodies in patients with primary and metastatic large bowel cancer. Accurate assessment of the extent of primary and metastatic large bowel cancer is critical to surgical decision making and to providing reliable prognostic information. This prospective study compared external gamma camera images and an intraoperative hand-held gamma detecting probe for detection of radiolabelled monoclonal antibody (B72.3) in 28 patients with primary and metastatic large bowel cancer. Fourteen patients received 0.2 to 20 mg (2 or 5 mCi) 111indium-labelled monoclonal antibody B72.3 followed by whole body imaging scan with an external gamma detector/camera on two occasions 24 h apart within 7 days after injection. Fourteen patients received 1.0 mg (2.0 mCi) 125iodine-B72.3 followed by intraoperative probe evaluation 2-3 weeks postinjection. Mean patient ages for the two groups were 60 years (range 28-75 years) and 63 years (range 43-77 years), respectively. Disease sites were primary in the large bowel in six patients and primary as well as metastatic in 22 patients. External scanning detected 111indium-B72.3 uptake in 1/5 primary lesions, 1/7 hepatic and 1/3 extrahepatic sites. The intraoperative gamma probe localized disease in 1/3 primary lesions, 7/11 hepatic and 3/3 extrahepatic sites. The intraoperative gamma probe had a sensitivity of 71% for detection of metastases compared with a 20% sensitivity using the external gamma scan method (P = 0.03). 125iodine-labelled B72.3 influenced the extent of the operative procedure in 4/14 (29%) patients; immunolocalization with external gamma detection did not alter the operative procedure in the 14 patients studied.(ABSTRACT TRUNCATED AT 250 WORDS)


Resection of hepatic and pulmonary metastases from colorectal cancer. Resection of hepatic metastases of colorectal origin has gained wide acceptance, but when patients have synchronous or metachronous pulmonary metastases, they are often considered incurable and are offered systemic therapy only. We performed a retrospective review of the patients at Memorial Sloan-Kettering Cancer Center who underwent resection of both hepatic and pulmonary metastases of colorectal origin between 1970 and 1990. Ten patients were identified who met the above criteria. Median survival after hepatic and pulmonary resections were 34 and 18 months, respectively. Actuarial 1-, 3- and 5-year survivals are 89%, 78% and 52%, respectively. With a median of 18 months after second operation, three patients have no evidence of disease (NED), four are alive with disease (AWD) and three are dead of disease (DOD). In the absence of effective chemotherapy, selected patients with hepatic and pulmonary metastases of colorectal origin should be considered for resection as it offers the only possibility for long-term survival.


Analysis of ras oncogene mutations in human squamous cell carcinoma of the head and neck. The presence of proto-oncogene mutations at codons 12, 13 and 61 of the Ha-, Ki-, and N-ras in primary head and neck squamous cell carcinoma are analysed in this study. Oncogene ras-specific sequences were amplified by the polymerase chain reaction and probed with mutation specific oligonucleotide probes. Mutations were detected in 8 of 22 samples (36.3%). No mutations were detected on patients' peripheral blood DNA. We found that histologically and clinically, squamous cell carcinomas with or without a ras mutation do not differ significantly from each other.


Testicular circulatory isolation: a phase I study. Antineoplastic agents may damage germinal epithelium. Testicular circulatory isolation (TCI) is a regional drug exclusion technique designed to minimize this. We evaluated the technical and anaesthetic aspects of TCI in 10 patients who underwent bilateral orchiectomy immediately thereafter. A modified aortic clamp was placed trans-scrotally across the left testicular pedicle without pre-medication or anaesthesia and left in place for 1 h, occluding testicular blood flow. Minimal pain and anxiety were reported during the procedure. There were no complications related to TCI in any patient. This study supports the institution of trials of TCI in young men about to receive fertility-threatening chemotherapy.


Results in surgery of pulmonary metastases. Nowadays surgical treatment of pulmonary metastases is a generally accepted therapeutic concept. Between 1973 and 1991 surgical resection was indicated in 655 patients, and 752 thoracotomies were carried out including 65 laser resections. Median sternotomy has become the preferred access, as the preoperative staging is not exact enough concerning the number of the metastases. This access offers the possibility to examine both lungs during the operation. In 521 operations, wedge resections were carried out, in 199 operations, a lobectomy was necessary. Overall 30-day mortality amounted to 2.8%. The probability to survive 1 year amounted to 71%, to survive 3 years to 42% and to survive 5 years to 31%. Irrespective of the primary tumour, the radicality of the operation is a statistically prognostic factor. Carcinomas showed better prognosis than sarcomas. The isolated examination of the different groups of primary tumors (mammary carcinomas, testicular carcinomas, hypernephromas, melanomas, colorectal carcinomas, osteosarcomas and soft tissue sarcomas) revealed a different influence of various prognostic factors, e.g. the number of metastases and the disease-free interval. Surgery of pulmonary metastases is part of an interdisciplinary concept of oncological therapy, which offers a prolongation of life to most patients and cure to some. If a prolongation of life cannot be achieved, an improvement of life quality can be obtained by surgical treatment.


[Contribution of surgical endoscopy and extrahydraulic lithotripsy in complex biliopancreatic lithiasis]. Surgical endoscopy combined with electro-hydraulic lithotripsy was done on 17 patients selected for complex multiple bilio-pancreatic lithiasis. In the biliary tract (7 patients), per operatory lithotripsy was performed on 3 patients (impacted main duct stones n = 2, impacted left hepatic stones n = 1); it was done through a T-tube in 1 young patient with an impacted stone in the ampulla and percutaneously in 3 patients (1 gall bladder and 2 intra hepatic lithiasis, one of them with biliary cirrhosis and portal hypertension). Four of this patients had had iterative surgery, extracorporeal lithotripsy or retrograde endoscopy. Complete desobstruction was obtained in all patients with minimal morbidity (minor hemobilia n = 2, hemorrhage from oesophageal varicose n = 1). In the pancreas, the technique was performed on 10 patients with impacted stones in the Wirsung duct and cephalic obstruction. Mean duct diameter was 7 mm. Complete desobstruction was obtained in 9 cases and endoscopic maneuvers were associated with "double stream" operation: sphincterotomy and cephalic desobstruction plus latero-lateral wirsungo-jejunostomy. Morbidity was small (minor hemorrhage n = 3). To conclude, endoluminal electro-hydraulic lithotripsy is an interesting adjuvant technique for the treatment of obstruction from stones in complex bilio-pancreatic lithiasis, either during open surgery or trans-cutaneously.


Advances in the surgical management of anal incontinence. Standard procedures for anal incontinence due to trauma (obstetric lesions, iatrogenic lesions in connection with anal surgery) have been overlapping suture of the external anal sphincter and, for idiopathic incontinence, postnatal repair according to Parks. In cases where these operations fail, or if a pronounced sphincter destruction is found, transposition of striated muscles (primarily the gracilis and the gluteus maximus) may be performed. In patients where the incontinence is due to a primary neurological disease, implantation of an artificial sphincter or a neurostimulator may be the only alternatives. The technique and the results of these newer operations for anal incontinence are presented.


[Rebound hyperglycemia and peroperative normalization of insulinemia. Complete excision of insulinoma?]. Clinical usefulness of the hyperglycemic rebound and the normalization of plasma insulin level as intraoperative markers of complete removal of insulinoma was assessed. Surgical removal was curative (no clinical or biological recurrence) in six patients harboring a single adenoma (mean follow-up = 32.2 months). In these patients plasma glucose increased an average of 32 mg/dl 30 minutes after resection, 68 mg/dl after 60 minutes, and 91 mg/dl after 90 minutes. Sensitivity of hyperglycemic rebound (defined as a plasma glucose increment of at least 30 mg/dl after tumor removal) as a marker of complete resection of the insulinoma was 40% at 30 min and 83% at 60 minutes after resection. Preresectional values of plasma immunoreactive insulin were elevated in 3 out of 4 patients with adenoma. All postresectional values were within normal ranges. Two patients operated on because of malignant insulinoma, underwent partial tumor resection; hyperglycemic rebound was also present, and high preresectional insulin values became normal 30 minutes after partial tumor removal. We conclude that information provided by intraoperative monitoring of both plasma glucose and insulin cannot be used as the only markers of complete resection of all insulinomas. Only long term clinical and biological follow-up can guarantee the complete resection of an insulinoma.


A clinico-pathological study of the origin of adeno-carcinoma of the mid-thoracic oesophagus and results of surgical resection. Adenocarcinomas of the mid-thoracic oesophagus are rare, and in a recent review were found to be 93 in 1099 (8.5%) in our series of carcinoma of the oesophagus and cardia. Study was planned to establish the origins of adeno carcinoma in the mid-thoracic oesophagus and to carry out a comparative evaluation of the results of surgery of such tumours derived from different origins. 58 patients with adeno carcinoma in the mid-thoracic oesophagus undergoing surgical resection (10% of all resected patients). Protocol of the study: clinical, radiological, endoscopic and intra-operative study together with serial histopathological examination of all resected specimens, follow-up check. Four types of adenocarcinoma were identified according to their origin judged by the study results. Type 1: in 29 patients (20 males, 9 females) the tumour had risen from the cardia and had extended upwards in one continuous sheet. Type 2: in 16 cases (8 males, 8 females) adeno carcinoma had originated from the stomach within a hiatal hernia and had extended to the "mid" oesophagus. Type 3: 2 patients (1 male, 1 female) had adeno carcinoma in the mid-oesophagus surrounded by squamous epithelium and presumably originated from oesophageal glands. Type 4: in 11 patients (10 males, 1 female) the tumour had clearly risen from columnar epithelial lined oesophagus (Barrett). SURGICAL RESULTS: 2 patients died in hospital and one at home 25 days after operation (total mortality just over 5%). There was no serious morbidity. The long-term results per type were: Type 1: 4 survived 5 years or more, the remainder survived 14 months on average. Type 2: 2 survived 5 years or more, the remainder survived 16 months on average. Type 3: None survived 5 years, 2 survived 10 and 18 months. Type 4: None survived 5 years, 2 average survived was 11 months. Only 20% of the adeno carcinoma of the mid-oesophagus are associated with Barrett and these have the worst prognosis after surgical resection.


Use of mini-invasive procedures in esophageal surgery. The authors have applied the advantages of mini-invasive surgery to the treatment of esophageal diseases. The technical possibilities of esophageal dissection have been investigated in patients with cancer of the intrathoracic esophagus. The mini-invasive techniques have been applied in the clinical setting to perform the esophagectomy through a trans-hiatal approach or by means of thoracoscopy. Performing the esophagectomy through the trans-hiatal approach allows an accurate mediastinal dissection and lymphadenectomy of the paraesophageal nodes. Performing the esophagectomy by means of thoracoscopy requires division of the azygos vein. In our experience better to divide the esophagus high in the chest. At present, trans-hiatal esophagectomy with mini-invasive procedures seems to be the technique of choice. However, the approach based on thoracoscopy will gain popularity with the development of more sophisticated instruments. In selected cases, it could be advantageous to use both techniques.


[Indications and early results of splenectomy in hematologic diseases]. In this retrospective study, we present 245 patients with various hematological diseases, who had undergone splenectomy for diagnostic or therapeutic purpose in our Department during the last 20-year period (1971-1991). There were 138 men (56%) and 107 women (44%), with a mean age of 49 years. The hematological diseases, for which the splenectomy had been performed, were according to the frequency of admittance: hemolytic anemia, complicated or not by gallstone formation, Werlhoff disease (thrombocytopenic purpura), Hodgkin's disease, hairy-cell leukemia, chronic lymphatic leukemia, non-Hodgkin lymphoma. A drain was placed in the splenic bed in all patients. All patients received anticoagulant therapy and antibiotics as well. Pneumococcal vaccination had been done systematically during the preoperative period. All patients received prophylaxis with a Penicillin for two years postoperatively. During the immediate postoperative period the mortality (1.2% OPSI: 1 case) and the morbidity (3.5% OPSI: 1 case) rates were very low. In conclusion, splenectomy in patients with hematological diseases is a safe procedure, even in high risk patients, but it requires a preoperative preparation and a close cooperation between surgeon and hematologist during the peri- and postoperative periods. Additionally, we have to notice that the possibility of an acute serious infection exists for any patient during the rest of his life.


Optical spectroscopic imaging for non-invasive evaluation of tissue oxygenation. Altered rates of oxygen delivery and uptake between and possibly within different organs occur during critical illness. The mechanisms governing this heterogeneity are as yet not fully understood and techniques directed at being able to map the course of oxygen to the mitochondria to produce ATP, the main molecule needed to drive energy requiring processes in the cell, would give valuable information about the mechanisms underlying organ dysfunction during disease. Oxidative phosphorylation occurring in the mitochondria is the main site for the production of ATP in mammalian cells. Metabolic substrates, ADP and Pi, and O2 are the ingredients needed to produce ATP. Due to the central role of oxidative phosphorylation in the metabolism of the cell, much attention has been directed at developing non-invasive techniques to measure intermediates of the oxidative phosphorylation in tissue as an indication of the metabolic state of tissue. One such method enables mapping the distribution of tissue hypoxia by use of a fluorescence technique based on the measurements reduced nicotine amide dinucleotide (NADH). NADH is situated at the high-energy side of the respiratory chain and during tissue hypoxia accumulates in concentration because less NADH is oxidized to NAD+. Excitation of NADH by 366 nm light produces, unlike NAD+, fluorescence at 460 nm light. Previously, however, producing images of NADH fluorescence distribution in tissue has been limited to saline perfused in vitro models. We recently undertook to develop an NADH videoflurometer sensitive enough to NADH fluorescence in vivo (Ince C, Bruining HA (1991) Optical Spectroscopy for the measurement of tissue hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)


Aspects of breast cancers.

Aspects of breast cancers. Breast cancer is the commonest killing malignant disease of women in the European Community. The average annual age standardised mortality rate among the 12 EEC countries ranges from 28.5 to 13.7 per 100,000 females. In Ireland, breast cancer is treated primarily by general surgeons. At our Breast Institute at St. Vincent's Hospital where we see 100 patients with breast diseases weekly it is policy to recommend quadrantectomy, total axillary dissection and radiotherapy (QU.A.R.T.) for patients with T1 and T2 tumours if they are peripherally placed within the breast. Complete axillary dissection in early breast cancer provides accurate staging and virtually eliminates axillary recurrence and the dissection is standardised and audited in our unit. Audit of axillary dissection improves the lymph node yield and enhances the completeness of the procedure. Sophisticated mammography improves the detection of small tumours but even excellent mammography may fail to identify malignant disease. Screening programmes for early breast cancer detection should be based on clinical examination in addition to mammography and some 15% of our patients with palpable breast cancer had falsely negative mammograms. Before operation, extensive scintigraphy and sonography is carried out before primary treatment is undertaken. After treatment, clinical and biochemical surveillance is carried out. We have found the lysosomal protease, Cathepsin D to be a useful marker of progressive disease and prognosis in patients with breast cancer. Routine postoperative CEA and CA15.3 are also valuable markers and a high or rising CA15.3 often precedes clinical or investigative evidence of recurrence. In addition, assay of c-erB-2 protein by ELISA is also a simple, rapid quantitative prognostic guide in patients with breast cancer.


[Unilateral anorchidism or monorchidism]. Monorchidism is a Testicular Regression Syndrome (Vanishing Testis Syndrome), defined as the unilateral or bilateral partial and complete absence of testicular tissue with or without rudimentary epididymal and spermatic cord remnants in the presence of normal duct development and normal external genitalia. In this paper we report the results of a personal series of 36 patients. We discuss the histopathology and try to answer the question whether protection of the solitary contralateral testis by orchidopexy is necessary in monorchidism. Our results suggest that a fixation of the contralateral testis is not necessary in children operated on for monorchidism. The histopathological findings provide a support for the concept of in utero torsion of the testis as the basis for the Testicular Regression Syndrome. These findings are characteristic, if non-specific. Vas deferens, epididymis, calcification or hemosiderin pigmentation was noted in almost 90% of the cases. In the absence of these remnants clinical and surgical findings and the presence of a richly vascular stroma supported the diagnosis.


[Obstruction caused by colorectal cancer. Surgical development]. The evolution of surgery for obstructed colon started at the turn of the century, and was guided by 3 main therapeutic principles: decompression (colostomy or internal derivation); tumour resection; reestablishment of function. These objectives were attained with various solutions and can be summarized in 3 approaches: the 3 stage operation, the 2 stage operation with initial resection of the tumour and finally the colonic resection with immediate reestablishment of function. The analysis and comparison of our personnel experience (n = 655), and the review of the literature lead us to the following conclusions: 1) the 3 stage operation, with a global mortality in our series of 27.6%, has been abandoned and is rarely dependable today; 2) the primary resection of the tumour, which should be an important objective, reduces mortality (18.8% in our experience); 3) of the methods including the primary resection of the tumour, those with immediate reconstruction of the digestive integrity and sub-total colectomy should be favoured, using the ileon as the proximal limb of the anastomosis (8.5% mortality in our series).


[Refractive surgery of the cornea. Classical operations]. The study discusses the refractive operations performed by means of classical surgery. Presented are briefly the keratophakia, epikeratophakia and keratomileusis; largely presented are: radial keratotomy, transversal keratotomy and Ruiz' operation. The two last methods are used for correction of astigmatism. The presented problems are illustrated by personal material.


[Refractive surgery of the cornea. II. Operations with excimer laser]. Discussed are the possibilities of application of excimer laser for the correction of myopia, astigmatism and hypermetropia, based on personal material and survey of the literature. The results obtained hitherto submit a considerable hope for utilization of the presented method in the future.


[Radial keratotomy--personal results].

[Radial keratotomy--personal results]. Operated were 20 eyes (19 persons); in 16 cases the indication for operation was anisometropia larger than 3 dioptres with existing intolerance against contact lenses. On 4 persons the operation was performed for cosmetic indications. The period of observation oscillated between 3 and 16 months. The authors obtained a reduction of the refraction error of about 5 dioptres, in individual cases the astigmatism was also corrected with a good result. There were no essential complications.


[Initial results of myopia correction with excimer laser]. The aim of the study was to demonstrate the efficacy of removal of the corneal tissue from the optical area by means of an excimer laser (Aesculap Meditec MEL-60) by the method of photo-ablation and by obtaining in that manner a change of refraction power of the optic system of a myopic eye. Fifty three corrections of myopia in 46 patients were performed from January 1991 to January 1992. Evaluated was the efficacy of this method i.e. the degree of the obtained correction in the relation to the expected one.


[Surgical treatment of acquired and congenital astigmatism]. Performed were 78 operations of correction of astigmatism by the method of linear incision of the cornea by means of an excimer laser. In dependence of the degree of the error two or four incisions were executed. The period of observation amounted 3 to 22 months. Improvement of refraction was obtained in the amount of 0.5 to 9.0 dioptres in relation to the initial one.


[Corneal astigmatism after cataract extraction: differences between the continuous x-shaped suture and the single knot stitch]. The author examined the postoperative astigmatism in 70 eyes of patients subjected to an extracapsular extraction with implantation of a posterior chamber lens in postoperative periods of 14 days, 3, 6 and 12 months. Compared were 2 groups of eyes with different methods of wound closure: by single knot stitches and by a continuous x-shaped suture. The degree of astigmatism showed to be higher in the 6 first postoperative months in the group of single knot stitches but after 6 months it became levelled with the degree of astigmatism detected in the group of continuous x-shaped suture.


[Diagnostic value of endothelial microscopy in surgery of the anterior segment]. The observation of the corneal endothelium was performed by means of an endothelial corneal microscope before the surgical operation of the anterior segment. Endothelial microscopy was executed in eyes in which one could expect changes caused by injuries, by previous operation or by already suffered inflammatory conditions of the anterior segment as well as in order to quality the corneae of the donors for transplantation.


[Corneal thickness after cataract extraction. Early observations]. The corneal thickness was measured after cataract extraction. In 36 patients the thickness was tested by an ultrasound pachymetry before the operation and on the 1, 3 and 7 day after surgery. The visual acuity and the clinical status of the cornea of the operated eye were also examined. The most pronounced oedema was seen on the first day in the neighbourhood of the incision. On the 7th postoperative day the corneal thickness approximated the status existing before the operation in the majority of patients. There was a dependence between the corneal thickness and its clinical status and the visual acuity.


[Examination of corneal endothelium after cataract extraction in children]. Examined were 39 eyes (23 children) after extraction of congenital cataract or a subluxated lens as well as after implantation of an anterior chamber lens; evaluated were changes of density of the corneal endothelial cells. The operation the least damaging the corneal endothelium showed to be the lensectomy through the pars plana of the ciliary body.


[Diagnosis and treatment of acute keratoconus]. The discussion on this topic was considered as advisable because of frequent diagnostic faults and an incorrect treatment of keratoconus. The authors presents the diagnosis, foundations of the general and topical treatment of keratoconus.


[Keratoconus and coexisting diseases in monozygotic twins]. The study presents conditions mostly described as co-existing with the keratoconus in 7 patients (from among 300 examined) born from an uni-ovular twin pregnancy. Only one pair of twins showed keratoconus of both eyes and developing identically in both eyes.


[Preliminary report on the use of excimer laser in treating keratoconus]. Operations for the reduction of astigmatism in cases of keratoconus were performed on 10 eyes in 8 patients. Disruption of the continuity of the posterior limitans lamina of the cornea was not observed in either case. In 4 cases the intervention had to be repeated. The period of observation amounts presently 1-3 months.


[Many years of personal observation on the effect of timolol for arresting development of keratoconus]. On examining about 300 patients with keratoconus in the period of 20 years the authors detected in a number of cases variations of the intraocular pressure. By means of a pneumo-tonometer Digilab 30R periodic variations of the IOP were measured in 76 patients and daily variations in 42. The statistical analysis showed that the application of Timolol and reduction of the IOP variations has a decisive influence on the improvement of objective changes and the visual acuity without correction. Presently in our Department Timolol is used successfully in 160 patients. There was no deterioration in either patient at that time and many patients showed an improvement of the condition of keratoconus.


[The technique of stitching a corneal patch in corneal grafting]. One of the main problems of corneal transplantation is the postoperative astigmatism. In the last period the intraoperative application of the kerato-scope, new type of needles and threads in stitching the corneal patch created a chance for solving this problem. The authors present the methods used for stitching of the corneal patch, their advantages and the defects with consideration of differences resulting from the thickness and kind of the thread, from the length and form of the needle. Basing on personal experience and data from the literature they propose the technique of the suture which they are using.


[Keratoprosthesis from a personal collection 15-year old material]. The study presents the analysis of a 15-years material concerning the keratoprosthesis in severe corneal leukoma of various aetiology. The material comprises 82 cases of corneal leukoma of the 5th category (hopeless leukoma) caused in the majority of cases by chemical burns as well as post-inflammatory leukoma, on the background of pemphigus, after opacified corneal grafting. The authors discuss the characteristic complications of keratoprosthesis and present their personal results.


[A triple operation of perforating corneal transplantation, cataract extraction and implantation of an intraocular lens]. The triple operation was performed in 7 patients (4 men and 3 women). The age of the patients was 18-56 years, the period of hospitalization 3 to 5 days. The surgery was performed in a light intravenous anaesthesia (NLA) or topical anaesthesia. The diameter of the graft oscillated between 7.25 and 9.0 mm. In all the cases after an extracapsular cataract extraction (or removal of remnants) the lens was implanted in the capsule. The graft was sutured by means of 20 single stitches (10.0 nylon) or applying a continuous suture (11.0 nylon). From the complications one observed breaking of a stitch, vascular ingrowth from the periphery and glaucoma. In the postoperative period--from 9 months to 3 years the visual acuity of the patients improved up to 0.4-0.7 in 4 cases and up to 0.8-1.0 in the remaining 3 cases.


[Disintegration of the cornea requiring total grafting in a case of acute gonorrhea infection]. Presented is a case of an acute gonorrhea infection of the eye with disintegration of the cornea which required a nearly immediate operation of corneal transplantation "from limbus to limbus". The patient, aged 17 years was admitted to the hospital showing bilateral acute purulent conjunctivitis and central necrosis of the left cornea with suspicion of endophthalmitis. In spite of a massive pharmacological treatment (together with intravitreal cephazolin) the cornea disintegrated from hour to hour. In atypical conditions, in an eye with acute inflammation a corneal grafting was performed together with cataract extraction and anterior vitrectomy. The grafting was "from limbus to limbus". The visual acuity of the eye with transplantation improved--with correction of +10.0 Dsph up to 1.0 in the period of 3 months.


[Retransplantation of the cornea with use of material selected for HLA factor compatibility]. Eleven re-transplantations of the cornea were performed between October 1988 and October 1991. Utilized was the material selected according to a partial compatibility of the HLA factor in 11 men with opacified transplants performed previously without antigen selection in high risk leukoma (in 10 cases after severe eye burns). In 3 patients the transplant was the fifth one, in 1 patient the fourth, in two--the third and in 5 the second one. Favourable results (transparent and semi-transparent grafts) were obtained in 8 patients (72.7 p.c.).


[Methods of preserving material for corneal grafting]. The methods of preservation of the material for corneal grafting are developing already for many years. The method of conservation of the corneae is closely connected with the way of the collection of the material: the whole globe or only the cornea with a 2-3 mm strip of the sclera. The whole globe is put into a moisture chamber, instead the cornea with a strip of sclera is preserved in various preservation fluids.


Diverse effect of cytokine treatment of tumor cells on specific versus non-specific cytotoxicity. The effect of IFN-gamma and TNF-alpha treatment of an ovarian carcinoma line on the sensitivity to lysis by specific CTL clones and non-specific Tumor Associated Lymphocytes (TAL), isolated from the ascites fluid, was analyzed. The in vitro established TAL line displayed a non-specific lytic activity against the autologous tumor as well as against several allogeneic tumor lines. Pretreatment with IFN-gamma alone, or in combination with TNF-alpha, rendered the carcinoma line less susceptible to lysis by the autologous TAL line. Conversely, susceptibility to lysis by tumor specific T cell clones, isolated from the TAL line, was increased as a result of cytokine pretreatment. Several TCR-alpha/beta+, CD8+ T-cell clones showing a more specific pattern of lysis against the autologous tumor were isolated. Lysis of the autologous tumor by these clones involved the TCR-alpha/beta via a MHC-class I restricted mechanism dependent on the adhesion molecules ICAM-1 and LFA-3, as inferred from antibody blocking studies. The enhanced sensitivity to specific CTL clones seen after cytokine treatment may be related to the enhanced expression of ICAM-1 molecules on the ovarian carcinoma. These results have implications for cytokine based immunotherapy, where IFN-gamma may enhance the effects of tumor associated specific CTL while decreasing that of non-specific effector cells.


[Use of excimer laser in pterygium surgery]. Primary and recurrent pterygium were excised by means of excimer laser or by a combined method of surgical and laser excision in 45 eyes in 41 patients. In 88.8 p.c. of cases no recurrencies were observed in the period of a 3-12 months.


Production of prostaglandin E by squamous carcinoma of the head and neck and adenocarcinoma of gastrointestinal tissue. The production of prostaglandin E ex vivo was studied in samples of 31 squamous cell carcinomas of the head and neck (SCCHN) and 12 adenocarcinomas of gastrointestinal tract (ACGI). As a control, the PGE production was measured in 22 samples of noninvolved mucosa in patients with SCCHN and 12 samples of gastrointestinal mucosas. The mean PGE production by SCCHN was significantly higher than in normal mucosa. Furthermore, the PGE production by tumors which recurred or spread to regional lymph node within 18 months after surgery was higher than in tumors which did not recur within that interval. Also, production of PGE by noninvolved mucosa was significantly higher in patients in which tumor recurred after surgery than in patients which were tumor free. On the other hand, the mean production of PGE by ACGI was not different from that of normal mucosa. These data show that determination of PGE production might have prognostic significance in SCCHN.


[Keratoplasty with simultaneous cataract extraction and implantation of an intraocular lens]. In the period of 1985-1992 we performed in our centres 34 operations of a double procedure and 12 operations of a triple procedure. During the observation--from 2 months to 7 years--we obtained favourable results encouraging to connect the corneal grafting with cataract extraction in high myopia and with extracapsular cataract extraction with implantation of an artificial lens in emmetropic eyes. Presented is the appropriate technique of operation and the results obtained.


[Two year experience of treating inflammatory conditions of the cornea with the excimer laser]. Abrasion of the pathologically changed corneal epithelium by photo-ablation--by means of an excimer laser--was performed in 183 patients; among them were 55 patients with chronic keratitis, 36 with recurrent keratitis, 69 with corneal ulcerations and 23 cases of unsuccessful conservative treatment after thermal or chemical burns. The efficacy of the treatment was defined in dependence on the attained improvement of the visual acuity and the time of epithelialization of the pathological change.


Prognostic significance of cytochemical analysis of leukemic M2 blasts. Cytochemical analysis of leukemic blasts from 46 patients with acute myeloblastic M2 leukemia (according to the FAB classification) was performed before and after cytostatic therapy, and compared with findings obtained in 20 age- and sex-matched control subjects. Cytochemical findings for myeloperoxidase (MPO), Sudan black B, acid phosphatase and alpha-naphthyl-acetate esterase (ANAE) were related to the achievement of the first complete remission (CR), i.e. data were compared after the patients had been divided into CR and non-CR groups. The analysis clearly showed that a high proportion of myeloperoxidase- and, to a lesser extent, Sudan black B-positive blasts before treatment may have constituted a significantly unfavourable prognostic factor.


Leukemic progression as process of adaptation (theoretical model). On the basis of an assumption that leukemic progression is a process of adaptation of normal hemopoiesis to the effect of the leukemic clone, a theoretical model of leukemia development is built. General conclusions are as follows: the possibility of reaching remission depends upon suppression of normal hemopoiesis by cytostatics in a system of two cell populations: the duration of remission depends upon suppression of the leukemic clone; the quantity of blast cells of marrow in remission can exceed 5 per cent.


[Use of rigid gas permeable contact lenses]. By application of contact lenses destined for a extended wearing, for preservation of a normal structure and metabolism of the cornea a considerable permeability of the contact lens for oxygen is necessary (Dk/L 75-80). The actually most popular in the world soft contact lenses have no such parameters. The application of rigid lenses produced from materials of high permeability for oxygen enables the extended wearing without substantial disturbances of the corneal metabolism. The paper presents a new generation of fluoro-silicone acrylates used for the production of contact lenses permeable for oxygen. Discussed are the problems connected with the adjusting of these lenses, their tolerance and influence on the corneal metabolism.


Bone marrow cells in the DNA-synthesis-phase in the myelodysplastic syndrome and lymphome. The bromodeoxyuridine (BRDU) labelling of bone marrow cells was studied in 46 subjects. The labelling in 14 patients, mostly untreated, with the myelodysplastic syndrome (MDS) and four lymphoma patients was significantly (p = 0.043) higher (11.38 +/- SE 2.3% S-phase cells) than that of marrow cells (7.18 +/- SE 1.04%) from 14 apparently healthy normal controls and from nine patients with non hematologic disease. Six iron deficiency had numerically but not significantly increased values. Bone marrow samples from MDS-patients showing the highest numbers of cells in the DNA-synthesis phase had the lowest numbers of colonies and clusters in the CFU-C assay (p < 0.03). The data suggest that the DNA-synthesis period is longer in MDS than in controls.


The incidence of HPV in a Swedish series of invasive cervical carcinoma. The incidence of HPV was studied in 71 invasive squamous carcinomas of the cervix using PCR technique. We used primers, which presumably recognize all types of HPV (consensus primers), and also type-specific primers. In situ hybridization was carried out in 24 of the cases. The overall incidence of HPV was 53/71 (75%) of which 5 cases were positive with the consensus primers only. However, 21/71 cases (30%) were negative for the consensus primers but positive for one of the type-specific primer pairs. This finding indicates that subgenomic deletions may have occurred in the viral genome upon integration in the human DNA. In situ hybridization was positive in 14/24 cases (58%), showing excellent correlation with PCR results. The HPV types detected were, in descending order of frequency: type 16 (52%), 31 (23%), 18 (13%), 33 (12%). No cases of HPV type 6 or 11 were found in this series of invasive carcinomas.


The impact of surgery on the multidisciplinary treatment of bronchogenic small cell carcinoma (updated review including ongoing studies). Recent results of studies on patients with SCLC treated by surgery with curative intent followed by adjuvant chemotherapy demonstrate a definite progress in comparison to non-surgical-treatment programs for patients with comparable stage of disease. Of 186 randomized patients enrolled for the multicenter cooperative ISC-Study I and II, 76 patients with stage pT1-3N0M0 received surgery for cure followed by chemotherapy and selective radiotherapy to the brain. The projected 4 year crude survival rate by September 1991 was 57%. In 27 of 43 patients with stage pT1-3N2M0, the tumors were completely resected, resulting in a 4 year survival rate of 32%. The survival curve for both groups of patients shows a sharp bent at 27 months postoperatively, whereafter the survival curves take a plateau-like course. These promising results were confirmed by several other groups. They are in favour of initial surgery for resectable tumors, followed by postoperative chemotherapy, while patients on preoperative chemotherapy followed by adjuvant surgery showed less favourable results.


Abnormal regulation of the myc gene in myeloid leukemia. To study the regulation of expression of the myc protooncogene, cells from normal individuals and patients with acute myelogenous leukemia (AML), and chronic phase and blastic crisis of chronic myeloid leukemia (CML) cells were put in overnight culture in the presence or absence of fetal calf serum. Myc expression in normal marrow cells and chronic phase CML cells fell after culture in vitro. In contrast, myc expression was maintained or increased in a majority of the AML and blastic crisis CML specimens. These data demonstrate that the regulation of myc expression is disordered in many AML and blastic crisis specimens but not in chronic phase CML cells.


Case report: acute polymyositis in a patient with chronic graft vs. host disease. Chronic graft versus host disease (cGVHD) is a multisystemic condition which occurs in 25 to 40% of patients undergoing allogeneic bone marrow transplantation. A 31 year old male developed acute polymyositis one year in the setting of cGVHD etc. after allogeneic bone marrow transplantation. A viral etiology could not be proven. This presumably represented a manifestation of cGVHD. His clinical condition improved with immunosuppression and he remains asymptomatic, off therapy.


[The treatment of acute gastrointestinal hemorrhages at a specialized hospital]. A differential approach to surgical interventions corresponding to the system of treatment of patients with gastrointestinal bleedings developed by the authors gave considerably less lethality in patients with bleedings caused by acute gastric and duodenal ulcers and by the Mallory-Weiss syndrome. General lethality among these patients was 3.3% and 5.1% correspondingly. This system was most effective at large specialized centers for treatment of patients with acute gastrointestinal bleedings. However many of its principles are easy for a great number of practical surgeons.