C-reactive protein identifies patients at risk of postpancreatectomy hemorrhage.

BACKGROUND: Postpancreatectomy hemorrhage grade C (PPH C) is a dreaded complication after pancreaticoduodenectomy (PD) with high mortality rate. Concurrent risk factors for PPH C have been difficult to recognize. Connection between postoperative pancreatic fistulas (POPF) and PPH C is well known, but POPF is often unknown prior to the PPH. The aim of this retrospective study was to define potential predictive factors for PPH C. METHODS: Retrospectively, 517 patients who underwent PD between 2003 and 2018 were included in the study. Twenty-three patients with PPH C were identified, and a matched control group of 92 patients was randomly selected. Preoperative data (body mass index, cardiovascular disease, history of abdominal surgery, biliary stent, C-reactive protein (CRP), ASA-score), perioperative data (bleeding, pancreatic anastomosis, operation time), and postoperative data (CRP, drain amylase, POPF, biliary fistula) were analyzed as potential predictors of PPH C. RESULTS: High postoperative CRP (median 140 mg/L on day 5 or 6) correlated with the development of PPH C (p < 0.05). Postoperative drain amylase levels were not clinically relevant for occurrence of PPH C. Grade C POPF or biliary leak was observed in the majority of the PPH C patients, but the leaking anastomoses were not detected before the bleeding started. DISCUSSION: High postoperative CRP levels are related to an increased risk of PPH C.

Trends in cutaneous malignant melanoma in Sweden 1997-2011: thinner tumours and improved survival among men.

BACKGROUND: Both patient survival and the proportion of patients diagnosed with thin cutaneous malignant melanoma (CMM) have been steadily rising in Sweden as in most Western countries, although the rate of improvement in survival appears to have declined in Sweden at the end of the last millennium. OBJECTIVES: To analyse the most recent trends in the distribution of tumour thickness (T category) as well as CMM-specific survival in Swedish patients diagnosed during 1997-2011. METHODS: This nationwide population-based study included 30,590 patients registered in the Swedish Melanoma Register (SMR) and diagnosed with a first primary invasive CMM during 1997-2011. The patients were followed through 2012 in the national Cause of Death Register. RESULTS: Logistic and Cox regression analyses adjusting for age at diagnosis, tumour site and healthcare region were carried out. The odds ratio for being diagnosed with thicker tumours was significantly reduced (P < 0·001) and the CMM-specific survival significantly improved in men diagnosed during 2007-2011 compared with men diagnosed during 1997-2001 (hazard ratio = 0·81; 95% confidence interval 0·72-0·91; P < 0·001), while the corresponding differences for women were not significant. Women were diagnosed with significantly thicker tumours during 2002-2006 and a tendency towards decreased survival was observed compared with those diagnosed earlier (during 1997-2001) and later (during 2007-2011). CONCLUSIONS: In Sweden, the CMMs of men are detected earlier over time and this seems to be followed by an improved CMM-specific survival for men. Women are still diagnosed with considerably thinner tumours and they experience a better survival than men.

Prognostic subclassifications of T1 cutaneous melanomas based on ulceration, tumour thickness and Clark's level of invasion: results of a population-based study from the Swedish Melanoma Register.

BACKGROUND: Survival and prognostic factors for thin melanomas have been studied relatively little in population-based settings. This patient group accounts for the majority of melanomas diagnosed in western countries today, and better prognostic information is needed. OBJECTIVES: The aim of this study was to use established prognostic factors such as ulceration, tumour thickness and Clark's level of invasion for risk stratification of T1 cutaneous melanoma. METHODS: From 1990 to 2008, the Swedish Melanoma Register included 97% of all melanomas diagnosed in Sweden. Altogether, 13,026 patients with T1 melanomas in clinical stage I were used for estimating melanoma-specific 10- and 15-year mortality rates. The Cox regression model was used for further survival analysis on 11,165 patients with complete data. RESULTS: Ulceration, tumour thickness and Clark's level of invasion all showed significant, independent, long-term prognostic information. By combining these factors the patients could be subdivided into three risk groups: a low-risk group (67·9% of T1 cases) with a 10-year melanoma-specific mortality rate of 1·5% (1·2-1·9%); an intermediate-risk group (28·6% of T1 cases) with a 10-year mortality rate of 6·1% (5·0-7·3%); and a high-risk group (3·5% of T1 cases) with a 10-year mortality rate of 15·6% (11·2-21·4%). The high- and intermediate-risk groups accounted for 66% of melanoma deaths within T1. CONCLUSIONS: Using a population-based melanoma register, and combining ulceration, tumour thickness and Clark's level of invasion, three distinct prognostic subgroups were identified.

Patterns and resectability of colorectal cancer recurrences: outcome study within the COLOFOL trial.

BACKGROUND: Improvements in surgery, imaging, adjuvant treatment, and management of metastatic disease have led to modification of previous approaches regarding the risk of recurrence and prognosis in colorectal cancer. The aims of this study were to map patterns, risk factors, and the possibility of curative treatment of recurrent colorectal cancer in a multimodal setting. METHODS: This was a cohort study based on the COLOFOL trial population of patients who underwent radical resection of stage II or III colorectal cancer. The medical files of all patients with recurrence within 5 years after resection of the primary tumour were scrutinized. Follow-up time was 5 years after the first recurrence. Primary endpoints were cumulative incidence, site, timing, and risk factors for recurrence, and rate of potentially curative treatment. A secondary endpoint was survival. RESULTS: Of 2442 patients, 471 developed recurrences. The 5-year cumulative incidence was 21.4 (95 per cent c.i. 19.5 to 23.3) per cent. The median time to detection was 1.1 years after surgery and 87.3 per cent were detected within 3 years. Some 98.2 per cent of patients who had potentially curative treatment were assessed by a multidisciplinary tumour board. A total of 47.8 per cent of the recurrences were potentially curatively treated. The 5-year overall survival rate after detection was 32.0 (95 per cent c.i. 27.9 to 36.3) per cent for all patients with recurrence, 58.6 (51.9 to 64.7) per cent in the potentially curatively treated group and 7.7 (4.8 to 11.5) per cent in the palliatively treated group. CONCLUSION: Time to recurrence was similar to previous results, whereas the 21.4 per cent risk of recurrence was somewhat lower. The high proportion of patients who received potentially curative treatment, linked to a 5-year overall survival rate of 58.6 per cent, indicates that it is possible to achieve good results in recurrent colorectal cancer following multidisciplinary assessment.

Influence of primary tumour and patient factors on survival in patients undergoing curative resection and treatment for liver metastases from colorectal cancer.

BACKGROUND: Resection of the primary tumour is a prerequisite for cure in patients with colorectal cancer, but hepatic metastasectomy has been used increasingly with curative intent. This national registry study examined prognostic factors for radically treated primary tumours, including the subgroup of patients undergoing liver metastasectomy. METHODS: Patients who had radical resection of primary colorectal cancer in 2009-2013 were identified in a population-based Swedish colorectal registry and cross-checked in a registry of liver tumours. Data on primary tumour and patient characteristics were extracted and prognostic impact was analysed. RESULTS: Radical resection was registered in 20 853 patients; in 38·7 per cent of those registered with liver metastases, surgery or ablation was performed. The age-standardized relative 5-year survival rate after radical resection of colorectal cancer was 80·9 (95 per cent c.i. 80·2 to 81·6) per cent, and the rate after surgery for colorectal liver metastases was 49·6 (46·0 to 53·2) per cent. Multivariable analysis identified lymph node status, multiple sites of metastasis, high ASA grade and postoperative complications after resection of the primary tumour as strong risk factors after primary resection and following subsequent liver resection or ablation. Age, sex and primary tumour location had no prognostic impact on mortality after liver resection. CONCLUSION: Lymph node status and complications have a negative impact on outcome after both primary resection and liver surgery. Older age and female sex were underrepresented in the liver surgical cohort, but these factors did not influence prognosis significantly.

ANTECEDENTES: Para curar el cáncer colorrectal es necesaria la resección del tumor primario, pero cada día es más frecuente la realización de una metastasectomía hepática con intención curativa. Este estudio basado en un registro nacional analizó los factores pronósticos para los tumores primarios tratados con intención curativa, incluido un subgrupo de pacientes a los que se realizó una metastasectomía hepática. MÉTODOS: En el registro poblacional sueco de cáncer colorrectal se identificaron los pacientes a los que se realizó una resección primaria radical entre 2009-2013 y se cotejaron con un registro de tumores hepáticos. Se obtuvieron los datos sobre el tumor primario y las características del paciente, y se analizó su influencia en el pronóstico. RESULTADOS: Se identificaron 20.853 pacientes con resección radical, de los que en un 38,9% se realizó la resección o ablación de metástasis hepáticas. La supervivencia relativa a 5 años, estandarizada por edad, después de la resección radical del cáncer colorrectal y después de la cirugía de las metástasis hepáticas colorrectales fue del 80,6% (i.c. del 95% 79,8-81,3) y del 49,6% (i.c. del 95%: 46,0-53,2), respectivamente. El análisis multivariable identificó la invasión ganglionar, las metástasis en varias localizaciones, una puntuación ASA alta y las complicaciones postoperatorias después de la resección del tumor primario como factores de riesgo tanto de la resección primaria como de la resección o ablación hepática. No tuvieron influencia sobre la mortalidad tras de la resección hepática ni la edad, el sexo o la ubicación del tumor primario. CONCLUSIÓN: El grado de invasión linfática y las complicaciones después de la resección primaria tuvieron un impacto negativo en los resultados tanto de la cirugía primaria, como de la cirugía hepática. Si bien la edad avanzada y el sexo femenino estaban infrarrepresentados en la cohorte de cirugía hepática, estos factores no influyeron significativamente en el pronóstico.

Type IV collagen is a tumour stroma-derived biomarker for pancreas cancer.

BACKGROUND: Pancreas cancer is a dreaded disease with high mortality, despite progress in surgical and oncological treatments in recent years. The field is hampered by a lack of good prognostic and predictive tumour biomarkers to be used during follow-up of patients. METHODS: The circulating level of type IV collagen was measured by ELISA in pancreas cancer patients and controls. The expression pattern of type IV collagen in normal pancreas, pancreas cancer tissue and in pancreas cancer cell lines was studied by immunofluorescence and Western blot techniques. RESULTS: Patients with pancreas cancer have significantly increased circulating levels of type IV collagen. In pancreas cancer tissue high levels of type IV collagen expression was found in close proximity to cancer cells in the tumour stroma. Furthermore, pancreas cancer cells were found to produce and secrete type IV collagen in vitro, which in part can explain the high type IV collagen expression observed in pancreas cancer tissue, and the increased circulating levels in pancreas cancer patients. Of clinical importance, our results show that the circulating level of type IV collagen after surgery is strongly related to prognosis in patients treated for pancreas cancer by pancreatico-duodenectomy with curative intent. Persisting high levels of circulating type IV collagen after surgery indicates a quick relapse in disease and poor survival. CONCLUSION: Our results most importantly show that stroma related substances can be evaluated as potential cancer biomarkers, and thereby underline the importance of the tumour microenvironment also in this context.

Centers of excellence or excellence networks: The surgical challenge and quality issues in rare cancers.

There are several suggestions that centralization of care improves outcome for rare cancers, particularly when optimal treatment requires complex surgery or high-technology radiotherapy equipment. Diagnosis and treatment in reference centers are expected to be more accurate because they benefit from large numbers of cases discussed in a multidisciplinary tumor board with a well-run pathway. However, centralization is sometimes moderately perceived by oncologists as a solution to be endorsed for rare cancer patients; disadvantages of centralization are the need for patients to move and the risk of a longer waiting list, with discomfort and possible negative effects on outcome. It is difficult to find single experts on rare cancers: all the more it will be difficult to find a multidisciplinary panel of experts, and the role of the surgeon is to be a functional part of it. On the other side, from a surgical point of view, the quality of the initial management of many rare cancers directly impacts the final outcome; surgery of rare cancers may not necessarily be more demanding than the average from a technical point of view, but the lack of cultural knowledge about the disease can well lead to inappropriateness even in the lack of major technical challenges. Care for rare cancer patients must be organized in pathways that cover the patient's journey from their point of view rather than that of the healthcare system, and pathways must follow the best evidence on diagnosis, treatment and follow-up.

Cross-resistance between cisplatin, antimony potassium tartrate, and arsenite in human tumor cells.

Cross-resistance between cisplatin (DDP) and metalloid salts in human cells was sought on the basis that mechanisms that mediate metalloid salt cross-resistance in prokaryotes are evolutionarily conserved. Two ovarian and two head and neck carcinoma cell lines selected for DDP resistance were found to be cross-resistant to antimony potassium tartrate, which contains trivalent antimony. The DDP-resistant variant 2008/A was also cross-resistant to arsenite but not to stibogluconate, which contains pentavalent antimony. A variant selected for resistance to antimony potassium tartrate was cross-resistant to DDP and arsenite. Resistance to antimony potassium tartrate and arsenite was of a similar magnitude (3-7-fold), whereas the level of resistance to DDP was greater (17-fold), irrespective of whether the cells were selected by exposure to DDP or to antimony potassium tartrate. In the resistant sublines, uptake of [3H]-dichloro(ethylenediamine) platinum(II) was reduced to 41-52% of control, and a similar deficit was observed in the accumulation of arsenite. We conclude that DDP, antimony potassium tartrate, and arsenite all share a common mechanism of resistance in human cells and that this is due in part to an accumulation defect.

Results of a multicenter randomized study to evaluate the safety and efficacy of combined immunotherapy with interleukin-2, interferon-{alpha}2b and histamine dihydrochloride versus dacarbazine in patients with stage IV melanoma.

BACKGROUND: The safety and efficacy of immunotherapy with histamine dihydrochloride (HDC), interleukin-2 (IL-2) and interferon-alpha2b (IFN) compared with dacarbazine (DTIC) in adult patients with stage IV melanoma was evaluated. PATIENTS AND METHODS: Two hundred and forty-one patients were randomized to either receive repeated 4-week cycles of IFN [3 MIU, s.c., once daily for 7 days], IL-2 (2.4 MIU/m(2), s.c., twice a day for 5 days) and HDC (1 mg, s.c., twice a day for 5 days) or DTIC 850 mg/m(2) i.v. every 3 weeks. The primary endpoint was overall survival. RESULTS: Median survival was longer for patients receiving HDC/IL-2/IFN (271 days) than for patients receiving DTIC (231 days), but this did not achieve statistical significance. Four patients receiving HDC/IL-2/IFN and nine receiving DTIC experienced at least one grade 4 adverse event. Striking differences in overall survival were observed between countries participating in the study. CONCLUSION: Treatment with HDC/IL-2/IFN was safely administered on an outpatient basis, but this immunotherapeutic regimen did not improve upon the response rate and overall survival seen with DTIC.

Cross-resistance between cisplatin and antimony in a human ovarian carcinoma cell line.

The metal compound cisplatin (DDP) is a widely used anticancer agent but naturally occurring and acquired resistance to DDP limits its effectiveness. Resistance is associated with a decreased accumulation of DDP and increased levels of glutathione and metallothioneins. Such changes also serve as protective and detoxification mechanisms for other metal salts in prokaryotes and lower eukaryotes. The aim of this study was to find metal salts for which the cross-resistance profile was the same as for DDP in sublines of the parental 2008 human ovarian carcinoma cells selected with either DDP (2008/C13*5.25) or CdCl2 and ZnCl2 (2008/MT). Among the metal salts tested the resistance profile of trivalent antimony most closely resembled that of DDP. DDP-selected cells were 15-fold resistant to DDP and 4.4-fold cross-resistant to antimony potassium tartrate, whereas of the cations tested (Cd2+, Zn2+, Ni2+ and Co2+) cross-resistance was observed only for Cd2+ (2.4-fold). When 2008 cells were selected for resistance to antimony (6.6-fold) they were found to be 16-fold cross-resistant to DDP. Accumulation of the DDP analogue cis-[3H]dichloro(ethylenediamine)platinum(II) was 59% lower in the DDP-selected subline and 48% lower in the antimony-selected variant than in the parental cell line. We conclude from the mutual cross-resistance to DDP and antimony potassium tartrate and from the impaired uptake of [3H]DEP in both the DDP and antimony-selected variants that DDP and antimony share a common mechanism of resistance. The significance of this observation lies in the fact that several evolutionarily conserved mechanisms for antimony detoxification are already known in lower organisms which may point the way to identification of additional DDP resistance mechanisms in mammalian cells.

Phase I/II trial of intraperitoneal 5-Fluorouracil with and without intravenous vasopressin in non-resectable pancreas cancer.

BACKGROUND: Systemic palliative treatment with chemotherapy against advanced pancreas cancer has low effectiveness despite considerable toxicity. AIM: To investigate the safety, toxicity and tumour response of intraperitoneal 5-Fluorouracil (5-FU) with intravenous Leucovorin and to monitor 5-FU pharmacokinetics in plasma during intraperitoneal instillation with and without vasopressin in patients with non-resectable pancreas cancer. PATIENTS/METHODS: Between 1994 and 2003, 68 patients with non-resectable pancreas cancer TNM stage III and IV, were enrolled to receive intraperitoneal5-FU instillation 750-1500 mg/m2 and intravenous Leucovorin 100 mg/m2 for two days every third week. Tumour response, performance status and toxicity were recorded. Seventeen patients were also treated with intravenous vasopressin 0.1 IU/minute for 180 minutes, during intraperitoneal 5-FU instillation. Area under the curve (AUC) and peak concentration (Cmax) of 5-FU in plasma were analysed. RESULTS: The treatment was well tolerated with minor toxicity. One complete response (54.1+ months) and 2 partial responses were observed. Time to progression was 4.4 months (0.8-54.1+), and median survival was 8.0 months (0.8-54.1+). There was a significant reduction of 5-FU Cmax in plasma the second day of treatment if vasopressin was used (3.4+/-2.5 and 6.1+/-5.4 mumol/l, respectively, p<0.05). 5-FU AUC in plasma was not significantly affected by vasopressin either day of treatment. CONCLUSION: Intraperitoneal 5-FU is a safe treatment with low toxicity to patients with non-resectable pancreas cancer. Tumour response was 4.4% and median survival time 8.0 months. Addition of vasopressin did not significantly decrease plasma 5-FU AUC but reduced Cmax on day 2 of treatment.

Vasopressin modulation of peritoneal, lymphatic, and plasma drug exposure following intraperitoneal administration.

i.p. administration of cytotoxic drugs for the treatment of regionally confined cancers results in a greater total drug exposure [area under the concentration x time curve (AUC)] for the peritoneal fluid and regional lymphatics than for plasma. We sought to augment the relative advantage of i.p. administration further through modulation of peritoneal clearance by reduction in splanchnic blood flow. Pigs were treated with 5-fluorouracil, etoposide (VP-16), and carboplatin (CBDCA) alone by the i.p. route or with the same drugs in combination with i.v. lypressin, a synthetic vasopressin analogue, which reduces splanchnic blood flow. Drug concentrations in peritoneal fluid, plasma, and thoracic duct lymph were monitored over the ensuing 6 h. The pharmacokinetics of 5-fluorouracil were not altered by vasopressin; however, vasopressin increased the peritoneal fluid:plasma AUC ratio for CBDCA from 30.6 +/- 5.6 to 70. 6 +/- 7.4 (P < 0.01) and increased the lymph:plasma AUC ratio from 1.1 +/- 0.4 to 2.6 +/- 0.22 (P < 0.05). In the case of VP-16, vasopressin increased the peritoneal fluid:plasma AUC ratio from 129 +/- 35 to 350 +/- 76 (P < 0.05) and the lymph:plasma AUC ratio from 2.1 +/- 0.6 to 10.6 +/- 3.5 (P < 0.05). Concurrent i.v. administration of vasopressin can increase the pharmacokinetic advantage of the i.p. route of administration of CBDCA and VP-16 markedly in the pig model. These data suggest that the strategy of concurrent i.p. administration of CBDCA or VP-16 plus an agent that reduces splanchnic blood flow may increase the dose intensity in the abdominal cavity and intraabdominal lymphatic tissue substantially without increasing systemic toxicity.

Histamine protects T cells and natural killer cells against oxidative stress.

Oxidative stress inflicted by monocytes/macrophages (MO) is recognized as an important immunosuppressive mechanism in human neoplastic disease. We report that two types of lymphocytes of relevance for protection against malignant cells, T cells and natural killer (NK) cells, became anergic to the T cell and NK cell activator interleukin-2 (IL-2) after exposure to MO-derived reactive oxygen metabolites and subsequently acquired features characteristic of apoptosis. The MO-induced anergy and apoptosis in T cells and NK cells were reversed by histamine, an inhibitor of reactive oxygen metabolite synthesis in MO. We propose that strategies to circumvent oxidative inhibition of lymphocytes may be of benefit in immunotherapy of neoplastic disease.

Immunohistochemical analysis of the distribution of the human ATPase (hASNA-I) in normal tissues and its overexpression in breast adenomas and carcinomas.

Human ATPase (hASNA-I) is a novel human gene recently cloned on the basis of homology to the arsA gene of bacteria. Its protein product is an ATPase that is free in the cytoplasm and bound in the perinuclear area and nucleolus in human cells. We prepared the hASNA-I-specific 5G8 monoclonal antibody and used it to investigate the expression of hASNA-I in normal human tissues and breast cancers. hASNA-I was detected immunohistochemically only in the epithelial cells of the liver, kidney, and stomach wall, in the adrenal medulla, in the islet cells of the pancreas, in the red pulp of the spleen, and in cardiac and skeletal muscle. No staining was observed in the uterus, testis, lung, thyroid, cerebellum, and large intestine. Although no staining was also observed in normal breast tissue, all four cases of breast fibroadenomas and all 15 cases of either primary or metastatic breast carcinoma demonstrated increased staining. No embryological or functional common denominator is readily apparent. However, the increased expression in malignant breast cells is of particular interest with respect to the use of this antibody for screening of cytological specimens.

Synergy between cisplatin and an inhibitor of S-adenosylmethionine dependent transmethylation in human ovarian adenocarcinoma cells.

Selection of cells for resistance to cisplatin results in resistance to arsenite and selenite. Mammalian cells detoxify arsenite and selenite by S-adenosylmethionine dependent methylation. We aimed to investigate whether S-adenosylmethionine dependent methylation is involved in the cellular metabolism of cisplatin. Treatment of human ovarian cancer cells 2008 and the cisplatin-resistant subline 2008/C13*5.25 with the S-adenosylhomocysteine hydrolase inhibitor adenosine-dialdehyde, an indirect inhibitor of transmethylation, resulted in a significant elevation (16-fold in 2008, 6-fold in 2008/C13*5.25) in the cellular content of S-adenosylhomocysteine without changing S-adenosylmethionine. Adenosine dialdehyde synergistically enhanced the cytotoxicity of cisplatin and carboplatin as evidenced by combination indices <1 using the combination index-isobologram method in clonogenic assays with 2008 human ovarian adenocarcinoma cells. However, the cellular accumulation, efflux, steady state content, and the formation of DNA adducts of the cisplatin [H-3]-DEP were not affected by adenosine-dialdehyde. Sodium arsenite was significantly more toxic in mice pretreated with adenosine-dialdehyde, whereas the toxicity of cisplatin remained unchanged. These studies suggest that inhibition of S-adenosylmethionine dependent transmethylation enhanced the toxicity of cisplatin and carboplatin to human ovarian carcinoma cells in vitro without directly affecting the metabolism of either platinum drug.

Influence of zymosan (a non-specific macrophage stimulator) and of indomethacin on liver tumours--an experimental study in rats.

Zymosan--a non-specific macrophage-stimulating agent--reduces tumour take in the liver. The mechanism for this effect is not clear, but it may be mediated via the Kupffer cells and prostaglandins. On the other hand, the Prostaglandin-synthesis inhibitor, indomethacin, inhibits tumour growth. Pretreatment with zymosan (3 mg 100 g-1) for 3 days of two different strains of rats, inoculated in the liver with a hepatoma or an adenocarcinoma cell suspension respectively, reduced tumour take and also initial tumour growth. The effect on tumour take and initial growth was inhibited by concomitant administration of indomethacin (0.2 mg 100 g-1). When zymosan was administered after tumour cell inoculation the growth rate of the hepatoma was retarded, but this effect was not abrogated by indomethacin. Pretreatment with indomethacin had no significant effect on tumour take or initial growth. When given after the tumour was established in the liver, indomethacin reduced the growth rate of the hepatoma, but not of the adenocarcinoma. These results suggest that there are different mechanisms for the effects of zymosan on tumour take and on growth of an established tumour. In immunoincompetent nude mice the effect on the hepatoma was similar to the effect in the rat. In vitro both tumours were insensitive to zymosan and indomethacin. This study confirms that pretreatment with a non-specific macrophage stimulator (zymosan) diminishes tumour take and growth in the liver, that the effect of zymosan on tumour take in the liver is abrogated by indomethacin and that the zymosan effect on tumour take in the liver is at least partly mediated by the Kupffer cells and prostaglandins.

Effect of carcinomatosis and intraperitoneal 5-fluorouracil on peritoneal blood flow modulated by vasopressin in the rat as measured with the 133Xe-clearance technique.

PURPOSE: Intraperitoneal administration of 5-fluorouracil for the treatment of gastrointestinal malignancies results in a greater total drug exposure in the peritoneal fluid than in plasma. Drugs are eliminated from the peritoneal cavity mainly by capillaries leading to the portal venous system and to a lesser extent by lymphatics. The drug itself and the presence of peritoneal carcinomatosis may affect elimination of the drug. The 133Xe-clearance technique allows the influence of a vasoactive agent on the peritoneal blood flow to be estimated with minimal invasiveness. The aim of the present study was to explore whether intraperitoneal 5-FU or peritoneal carcinomatosis affects the peritoneal blood flow and its reactivity to intravenous vasopressin, as measured indirectly with the 133Xe-clearance technique. METHODS: The animals used in this study were 63 Wistar-Fu (W-Fu) rats and 67 Lister-Hooded (LH) rats. On day 0, either 5-FU at 25 mg/kg body weight in 25 ml/kg isotonic saline was instilled intraperitoneally, or 1 x 10(5) syngeneic tumour cells were inoculated intraperitoneally. On days 1, 2 and 3 in the 5-FU-treated rats, and on days 12-16 in rats inoculated with tumour cells, peritoneal blood flow was analysed with the 133Xe-clearance technique, before and during intravenous infusion of vasopressin at 0.07 IU/min/kg body weight. RESULTS: The basal 133Xe-clearance before administration of vasopressin was similar in all groups except in the LH rats treated with 5-FU in which it was significantly lower. Infusion of vasopressin induced a significant decrease in 133Xe-clearance of the same magnitude in controls and in tumour-bearing rats. In the rats given intraperitoneal 5-FU, vasopressin did not reduce the 133Xe-clearance the first day after administration of 5-FU. CONCLUSIONS: Intravenous vasopressin at 0.07 IU/min/kg decreased peritoneal blood flow as measured indirectly with the 133Xe-clearance method. Intraperitoneal 5-FU abrogated the reduction in peritoneal blood flow with intravenous vasopressin the first day after treatment. In contrast, the presence of peritoneal carcinomatosis did not influence peritoneal blood flow, nor the effect of vasopressin

Digitonin enhances the efficacy of carboplatin in liver tumour after intra-arterial administration.

Platinum-containing drugs enter the cell slowly and have a poor tissue penetration. Increasing the permeability of the cell membrane might increase the intracellular drug concentration. Digitonin, a detergent that increases cell permeability by binding to cholesterol molecules in the cell membrane, can increase cisplatin accumulation and reduce tumour growth in vitro. The aim of this study was to determine whether digitonin could increase the efficacy of carboplatin (CBDCA) in vivo. In LH rats, a hepatoma was implanted in the liver. At 7 days after implantation, digitonin (or saline in the control group) was infused via the hepatic artery and, 10 min later, CBDCA was injected. Biopsies from the tumour and liver parenchyma were obtained after 1 h. The concentration of platinum measured in the liver tumours was higher in the digitonin group than in the control groups. In the liver parenchyma the concentrations were of the same magnitude. Measured with the 133Xe-clearance technique, digitonin did not alter the tumour blood flow. Digitonin enhanced the tumour-growth-retarding effect of CBDCA given intra-arterially at 5 mg/kg but not at 25 mg/kg. No increase in toxicity was observed for digitonin given together with CBDCA at 5 mg/kg. Systemic administration of CBDCA was not influenced by digitonin. These findings demonstrate that pretreatment with digitonin increases the tumour uptake of CBDCA and potentiates the cytotoxic effect of CBDCA.