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.

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.

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.

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.

Experts reviews of the multidisciplinary consensus conference colon and rectal cancer 2012: science, opinions and experiences from the experts of surgery.

The first multidisciplinary consensus conference on colon and rectal cancer was held in December 2012, achieving a majority of consensus for diagnostic and treatment decisions using the Delphi Method. This article will give a critical appraisal of the topics discussed during the meeting and in the consensus document by well-known leaders in surgery that were involved in this multidisciplinary consensus process. Scientific evidence, experience and opinions are collected to support multidisciplinary teams (MDT) with arguments for medical decision-making in diagnosis, staging and treatment strategies for patients with colon or rectal cancer. Surgery is the cornerstone of curative treatment for colon and rectal cancer. Standardizing treatment is an effective instrument to improve outcome of multidisciplinary cancer care for patients with colon and rectal cancer. In this article, a review of the following focuses; Perioperative care, age and colorectal surgery, obstructive colorectal cancer, stenting, surgical anatomical considerations, total mesorectal excision (TME) surgery and training, surgical considerations for locally advanced rectal cancer (LARC) and local recurrent rectal cancer (LRRC), surgery in stage IV colorectal cancer, definitions of quality of surgery, transanal endoscopic microsurgery (TEM), laparoscopic colon and rectal surgery, preoperative radiotherapy and chemoradiotherapy, and how about functional outcome after surgery?

Low level of education is associated with later stage at diagnosis and reduced survival in cutaneous malignant melanoma: a nationwide population-based study in Sweden.

BACKGROUND: A worse outcome has been reported for cutaneous malignant melanoma (CMM) patients with low socioeconomic status. We have investigated the association between level of education, clinical stage at diagnosis (stage at diagnosis) and CMM-specific survival in Sweden. METHODS: We identified 27,235 patients from the Swedish Melanoma Register diagnosed with a primary invasive CMM between 1990 and 2007 and linked data to nationwide, population-based, health and census registers with a follow-up to 2010. RESULTS: The odds ratio (OR) of higher disease stage at diagnosis was significantly increased in lower education groups (OR stage II versus I=1.6; 95% confidence interval (CI)=1.5-1.7. OR stage III-IV versus I=2.3; 95% CI=1.8-2.9). The risk of dying of CMM, was significantly increased in patients with low (hazard ratio (HR) low versus high=2.02; 95% CI=1.80-2.26; p<0.0001) and intermediate (HR intermediate versus high=1.35; 95% CI=1.20-1.51; p<0.0001) level of education. After adjustment for age, gender, stage at diagnosis and other known prognostic factors, the HRs remained significant for low versus high (HR=1.13; 95% CI=1.01-1.27; p=0.04) but not for intermediate versus high (HR=1.11; 95% CI=0.99-1.24; p=0.08) education. The HR associated with low level of education was significantly higher among female patients, patients <55 years, patients with truncal tumours and during the first 5 years after diagnosis. CONCLUSION: Lower level of education is associated with reduced CMM-specific survival, which may at least partially be attributed to a more advanced stage at diagnosis. These results emphasise the need for improved early detection strategies.

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.

Type IV collagen as a tumour marker for colorectal liver metastases.

BACKGROUND: About 50% of patients with primary colorectal cancer (CRC) will develop liver metastases (CLM). Currently, carcinoembryonic antigen (CEA) is the most common tumour marker for CRC and CLM. However, the sensitivity and specificity of this marker is not optimal, as almost 50% of patients have tumours that do not produce CEA. Therefore there is a need for better markers for CRC and CLM. METHODS: The circulating levels of type IV collagen were measured in patients with CLM, primary CRC and in healthy controls. The expression pattern of type IV collagen was studied by immunofluorescence in CLM and normal liver tissue. The metastatic volume of CLM in the liver was estimated from CT. RESULTS: In CLM tissue type IV collagen is highly expressed in the areas of desmoplasia. Patients with primary CRC (Dukes' A-C) did not show any increase in circulating type IV collagen compared to healthy controls. However, patients with CLM have significantly elevated levels of circulating type IV collagen when compared to patients with primary CRC and healthy controls. The levels of type IV collagen decreased during chemotherapy and increased at the time of disease progression. The circulating levels of type IV collagen seem to reflect the tumour burden in the liver. CONCLUSIONS: Type IV collagen has the potential to be used as tumour associated biomarker for CLM. These results indicate the importance of interaction between cancer cells and the stroma in the tumour microenvironment.

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.

ASNA1, an ATPase targeting tail-anchored proteins, regulates melanoma cell growth and sensitivity to cisplatin and arsenite.

PURPOSE: ASNA1 is homologous to E. coli ArsA, a well characterized ATPase involved in efflux of arsenite and antimonite. Cells resistant to arsenite and antimonite are cross-resistant to the chemotherapeutic drug cisplatin. ASNA1 is also an essential ATPase for the insertion of tail-anchored proteins into ER membranes and a novel regulator of insulin secretion. The aim of this study was to determine if altered ASNA1 levels influenced growth and sensitivity to arsenite and cisplatin in human melanoma cells. METHODS: Cultured melanoma T289 cells were transfected with plasmids containing sense or antisense ASNA1. Cells were exposed to cisplatin, arsenite and zinc. Cell growth and chemosensitivity were evaluated by the MTT assay and apoptosis by a TUNEL assay. RESULTS: ASNA1 expression was necessary for growth. T289 clones with decreased ASNA1 expression exhibited 51 +/- 5% longer doubling times than wildtype T289 (P = 0.0091). After exposure to cisplatin, ASNA1 downregulated cells displayed a significant increase in apoptosis. The cisplatin IC(50) in ASNA1 underexpressing cells was 41.7 +/- 1.8% compared to wildtype (P = 0.00097) and the arsenite IC(50) was 59.9 +/- 3.2% of wildtype IC(50) (P = 0.0067). CONCLUSIONS: Reduced ASNA1 expression is associated with significant inhibition of cell growth, increased apoptosis and increased sensitivity to cisplatin and arsenite.

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.

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.

133Xe clearance estimates the effect of vasopressin on peritoneal blood flow in rats.

BACKGROUND/AIMS: When assessing the peritoneal microcirculation with invasive methods, interference with the mechanisms of vaso-regulation may occur. The 133Xe clearance technique renders the possibility, by minimal invasiveness, to estimate the influence of a vasoactive agent on the peritoneal microcirculation. METHODOLOGY: Ten to 15MBq of 133Xe were injected in the abdominal cavity in thirty-eight Wistar-FU (W-FU) rats and 35 Lister-Hooded (LH) rats. A NaI (Tl)-scintillation detector registered activity before and during vasopressin infusion. Gamma camera imaging confirmed the washout from the abdominal cavity. The laser Doppler flowmetry technique was used as a comparison. RESULTS: Vasopressin at 0.07 IU/kg/min IV significantly reduced 133Xe-clearance by 37% (p = 0.029) and 52% (p=0.036) and laser Doppler flowmetry by 69% (p=0.0019) and 44% (p=0.0039) in W-FU and LH rats, respectively. A linear correlation between dose of vasopressin and relative decrease in 133Xe clearance was demonstrated in the W-FU rat model (r2=0.98, p=0.023). The 133Xe clearance from the abdominal cavity in rat using a single-compartment model or the slow compartment in a double-compartment model gave reproducible information. CONCLUSIONS: The usefulness of this mini-invasive technique for sequential measurements before and during intervention will render the 133Xe clearance suitable for assessment of blood flow changes in the abdominal cavity.

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

Blood flow in liver tumors--effects of vasoactive drugs estimated with xenon (133Xe) clearance.

BACKGROUND/AIMS: The aim of the present study was to identify in a standardized experimental rat liver tumor system the drugs which are most appropriate in influencing the relationship between liver tumor and normal liver parenchyma blood flow as estimated with 133Xe washout clearance method, and thereby positively influencing the kinetics of chemotherapeutic drugs. A battery of vasoactive drugs, which according to a literature review were considered to be active, were tested. METHODOLOGY: Twelve drugs were administered intravenously on 113 Wistar-Fu rats with an experimental adenocarcinoma in the liver (weight 0.62 g). 133Xe was applied in the tumor and in normal parenchyma with and without administration of a vasoactive drug. The pulses were registered with a NaI (Tl)-scintillation detector connected to a multichannel analyzer. The disappearance rate of the isotope was calculated according to a single compartment model. Four recordings were performed in each rat randomly in tumor and liver parenchyma with and without a drug (series A) and one series twice in tumor and twice in parenchyma with a drug (series B). RESULTS: In unaffected animals the tumor to liver quotient was 0.57+/-0.35. This quotient was higher in tumors less than 0.53 g. Angiotensin-II 8 mg i.v. increased the quotient to 0.95+/-0.20. No other drug significantly influenced the quotient. CONCLUSIONS: In an experimental adenocarcinoma in the liver this study has investigated the possibility of increasing the tumor to normal liver parenchyma blood flow quotient by a variety of vasoactive substances for the beneficial modification of tumor blood flow. Angiotensin II 8 mg i.v. was the only drug, which increased the quotient. None of the other tested drugs were supporting previous presented results on influencing tumor blood flow.

A comparison between hepatic artery ligation and portal 5-Fu infusion versus 5-Fu intra arterial infusion for colorectal liver metastases.

AIM: A prospective randomized study was executed comparing two regimens of regional therapy for liver metastases from colorectal cancer. METHODS: Eighteen patients were allocated to hepatic artery occlusion for 16 h followed by intraportal 5-fluorouracil (5-Fu) infusion (1000 mg/m(2)) for 5 days every sixth week (HAO). Twenty-one patients received intra-arterial 5-Fu infusion+Leucovorin (100 mg) i.v. for 2 days every second week (HAI). The follow up every third month included CT and CEA. Thirteen patients had limited extrahepatic cancer. At tumor progression regional therapy was stopped and systemic chemotherapy or the best supportive care was administered. RESULTS: The study was discontinued after randomization of 39 patients. No significant difference in survival within patients with and without extrahepatic cancer was present. The mean survival was longer in the HAI group than for the HAO group (19 months versus 13 months, p=0.0147) (median 18 (8-37) versus 12 (2-26). PR and SD were registered in 8/18 in the HAO group and 17/21 patients in HAI group. The median time to progress was 4 (1-22) months versus 7 (1-23) months for the HAO and HAI group, respectively. CONCLUSION: Regional intraarterial infusion with 5-Fu gives significantly better survival than hepatic artery occlusion followed by portal infusion. A limited amount of extrahepatic cancer does not influence survival time. A trial comparing hepatic artery 5-FU infusion and Leucovorin versus the most effective systemic therapy is warranted.

Intratumoural and peripheral blood lymphocyte subsets in patients with metastatic renal cell carcinoma undergoing interleukin-2 based immunotherapy: association to objective response and survival.

The aim of the present study was to analyse lymphocyte subsets in consecutive peripheral blood samples and consecutive tumour tissue core needle biopsies performed before and during interleukin-2 based immunotherapy, and to correlate the findings with objective response and survival. Twenty-six patients with metastatic renal cell carcinoma were treated with low dose s.c. interleukin-2, interferon-alpha and histamine. A total of 250 blood samples and 62 core needle biopsies from 23 and 19 of these patients, respectively, were analysed. After 2 weeks of treatment, a significant positive correlation between absolute number of peripheral blood lymphocytes (P=0.028), CD3 (P=0.017), CD57 (P=0.041) and objective response was demonstrated. There was no correlation between any peripheral blood leukocyte subsets and survival. Cytotoxicity of peripheral blood mononuclear cells was not correlated to objective response or survival. Within the tumour tissue at baseline, a significant positive correlation between CD4 (P=0.027), CD8 (P=0.028), CD57 (P=0.007) and objective response was demonstrated. After one month of immunotherapy, a significant positive correlation between intratumoral CD3 (P=0.026), CD8 (P=0.015), CD57 (P=0.009) and objective response was demonstrated. A significant positive correlation between intratumoral baseline CD4 (P=0.047), baseline CD57 (P=0.035), CD3 at one month (P=0.049) and survival was demonstrated. These data provide novel in vivo evidence of the possible contribution of lymphocyte subsets in the tumour reduction in responding patients during interleukin-2 based immunotherapy. Confirmation of the results requires further studies including a larger number of patients.

Outpatient treatment with subcutaneous histamine dihydrochloride in combination with interleukin-2 and interferon-alpha in patients with metastatic renal cell carcinoma: results of an open single-armed multicentre phase II study.

OBJECTIVES: Histamine inhibits formation and release of monocyte/macrophage-derived reactive oxygen metabolites and thereby protects natural killer (NK) and T cells against oxidative inhibition. Efficacy and safety of histamine, when given in combination with interleukin-2 (IL-2) and interferon-alpha (IFN-alpha), were evaluated in patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Forty-eight mRCC patients were included. The self-administered, outpatient regimen included IFN-alpha, 3 MIU s.c., once daily for 1 week, followed by up to nine 4 week cycles of IFN-alpha, 3 MIU s.c., days 1-7, weeks 1-4; interleukin-2, 2.4 MIU/m2 s.c., b.i.d., days 1-5, weeks 1 and 2; and histamine dihydrochloride, 1 mg s.c., b.i.d. days 1-5, weeks 1-4. RESULTS: Forty-six patients were eligible. Forty-two patients were evaluable for response with four partial responses (9% of eligible patients, 10% of evaluable patients). Fifteen patients (36%) had stable disease. After subsequent surgery of residual tumours, three patients (7%) had no evidence of disease at 14+, 21+ and 21+ months. Median survival time for all patients was 16.3 months. One grade 4 toxicity (thrombocytopenia) was observed. Most frequent grade 3 toxicities were fatigue/malaise (26%), dyspnoe (11%), nausea (9%) and stomatitis (9%). Four patients discontinued due to treatment-related toxicity. There were no treatment-related deaths. CONCLUSIONS: The present combination of histamine with IL-2 and IFN-alpha. as self-administered outpatient therapy is a safe and well-tolerated regimen. However, histamine does not appear to add efficacy with respect to response in this low-dose schedule of IL-2 and IFN-alpha. Whether histamine might improve efficacy with higher doses of IL-2 and IFN-alpha requires further investigation.