Effects of tirapazamine on experimental colorectal liver metastases after radiofrequency ablation.

BACKGROUND: Radiofrequency ablation (RFA) is a common procedure for the management of colorectal liver metastases. RFA-generated lesions are surrounded by a rim of hypoxia that is associated with aggressive outgrowth of intrahepatic micrometastases. Hypoxia-activated prodrugs such as tirapazamine are designed selectively to induce apoptosis in tumour cells under hypoxic conditions. Therefore, it was hypothesized that tirapazamine may have therapeutic value in limiting hypoxia-associated tumour outgrowth following RFA. METHODS: Murine C26 and MC38 colorectal cancer cells were grown under hypoxia and normal oxygenation in vitro, and treated with different concentrations of tirapazamine. Apoptosis and cell cycle distribution were assessed by western blot and fluorescence-activated cell sorting analysis. Proliferative capacity was tested by means of colony-formation assays. Mice harbouring microscopic colorectal liver metastases were treated with RFA, followed by a single injection of tirapazamine (60 mg/kg) or saline. Tumour load was assessed morphometrically 7 days later. RESULTS: Tirapazamine induced apoptosis of colorectal tumour cells under hypoxia in vitro. Under normal oxygenation, tirapazamine caused a G2 cell cycle arrest from which cells recovered partly. This reduced, but did not abolish, colony-forming capacity. A single dose of tirapazamine largely prevented accelerated outgrowth of hypoxic micrometastases following RFA. Tirapazamine administration was associated with minimal toxicity. CONCLUSION: Tirapazamine induced apoptosis in colorectal cancer cells in a hypoxia-dependent manner and potently suppressed hypoxia-associated outgrowth of liver metastases with limited toxicity. This warrants further study to assess the potential value of tirapazamine, or other hypoxia-activated prodrugs, as adjuvant therapeutics following RFA treatment of colorectal liver metastases.

Evaluation of the appendicitis inflammatory response score for patients with acute appendicitis.

BACKGROUND: Acute appendicitis is still a difficult diagnosis. Scoring systems are designed to aid in the clinical assessment of patients with acute appendicitis. The Alvarado score is the most well known and best performing in validation studies. The purpose of the present study was to externally validate a recently developed appendicitis inflammatory response (AIR) score and compare it to the Alvarado score. METHODS: The present study selected consecutive patients who presented with suspicion of acute appendicitis between 2006 and 2009. Variables necessary to evaluate the scoring systems were registered. The diagnostic performance of the two scores was compared. RESULTS: The present study included 941 consecutive patients with suspicion of acute appendicitis. There were 410 male patients (44%) and 531 female patients (56%). The area under the receiver operating characteristic curve of the AIR score was 0.96 and significantly better than the area under the curve of 0.82 of the Alvarado score (p < 0.05). The AIR score also outperformed the Alvarado score when analyzing the more difficult patients, including women, children, and the elderly. CONCLUSIONS: This study externally validates the AIR Score for patients with acute appendicitis. The scoring system has a high discriminating power and outperforms the Alvarado score.

Costs of relaparotomy on-demand versus planned relaparotomy in patients with severe peritonitis: an economic evaluation within a randomized controlled trial.

INTRODUCTION: Results of the first randomized trial comparing on-demand versus planned-relaparotomy strategy in patients with severe peritonitis (RELAP trial) indicated no clear differences in primary outcomes. We now report the full economic evaluation for this trial, including detailed methods, nonmedical costs, further differentiated cost calculations, and robustness of different assumptions in sensitivity analyses. METHODS: An economic evaluation was conducted from a societal perspective alongside a randomized controlled trial in 229 patients with severe secondary peritonitis and an acute physiology and chronic health evaluation (APACHE)-II score >or=11 from two academic and five regional teaching hospitals in the Netherlands. After the index laparotomy, patients were randomly allocated to an on-demand or a planned-relaparotomy strategy. Primary resource-utilization data were used to estimate mean total costs per patient during the index admission and after discharge until 1 year after the index operation. Overall differences in costs between the on-demand relaparotomy strategy and the planned strategy, as well as relative differences across several clinical subgroups, were evaluated. RESULTS: Costs were substantially lower in the on-demand group (mean, 65,768 euro versus 83,450 euro per patient in the planned group; mean absolute difference, 17,682 euro; 95% CI, 5,062 euro to e29,004 euro). Relative differences in mean total costs per patient (approximately 21%) were robust to various alternative assumptions. Planned relaparotomy consistently generated more costs across the whole range of different courses of disease (quick recovery and few resources used on one end of the spectrum; slow recovery and many resources used on the other end). This difference in costs between the two surgical strategies also did not vary significantly across several clinical subgroups. CONCLUSIONS: The reduction in societal costs renders the on-demand strategy a more-efficient relaparotomy strategy in patients with severe peritonitis. These differences were found across the full range of healthcare resources as well as across patients with different courses of disease. TRIAL REGISTRATION: ISRCTN51729393.

Health related quality of life six months following surgical treatment for secondary peritonitis--using the EQ-5D questionnaire.

BACKGROUND: To compare health related quality of life (HR-QoL) in patients surgically treated for secondary peritonitis to that of a healthy population. And to prospectively identify factors associated with poorer (lower) HR-QoL. DESIGN: A prospective cohort of secondary peritonitis patients was mailed the EQ-5D and EQ-VAS 6-months following initial laparotomy. SETTING: Multicenter study in two academic and seven regional teaching hospitals. PATIENTS: 130 of the 155 eligible patients (84%) responded to the HR-QoL questionnaires. RESULTS: HR-QoL was significantly worse on all dimensions in peritonitis patients than in a healthy reference population. Peritonitis characteristics at initial presentation were not associated with HR-QoL at six months. A more complicated course of the disease leading to longer hospitalization times and patients with an enterostomy had a negative impact on the mobility (p = 0.02), self-care (p < 0.001) and daily activities: (p = 0.01). In a multivariate analysis for the EQ-VAS every doubling of hospital stay decreases the EQ-VAS by 3.8 points (p = 0.015). Morbidity during the six-month follow-up was not found to be predictive for the EQ-5D or EQ-VAS. CONCLUSION: Six months following initial surgery, patients with secondary peritonitis report more problems in HR-QoL than a healthy reference population. Unfavorable disease characteristics at initial presentation were not predictive for poorer HR-QoL, but a more complicated course of the disease was most predictive of HR-QoL at 6 months.

Comparison of on-demand vs planned relaparotomy strategy in patients with severe peritonitis: a randomized trial.

CONTEXT: In patients with severe secondary peritonitis, there are 2 surgical treatment strategies following an initial emergency laparotomy: planned relaparotomy and relaparotomy only when the patient's condition demands it ("on-demand"). The on-demand strategy may reduce mortality, morbidity, health care utilization, and costs. However, randomized trials have not been performed. OBJECTIVE: To compare patient outcome, health care utilization, and costs of on-demand and planned relaparotomy. DESIGN, SETTING, AND PATIENTS: Randomized, nonblinded clinical trial at 2 academic and 5 regional teaching hospitals in the Netherlands from November 2001 through February 2005. Patients had severe secondary peritonitis and an Acute Physiology and Chronic Health Evaluation (APACHE-II) score of 11 or greater. INTERVENTION: Random allocation to on-demand or planned relaparotomy strategy. MAIN OUTCOME MEASURES: The primary end point was death and/or peritonitis-related morbidity within a 12-month follow-up period. Secondary end points included health care utilization and costs. RESULTS: A total of 232 patients (116 on-demand and 116 planned) were randomized. One patient in the on-demand group was excluded due to an operative diagnosis of pancreatitis and 3 in each group withdrew or were lost to follow-up. There was no significant difference in primary end point (57% on-demand [n = 64] vs 65% planned [n = 73]; P = .25) or in mortality alone (29% on-demand [n = 32] vs 36% planned [n = 41]; P = .22) or morbidity alone (40% on-demand [n = 32] vs 44% planned [n = 32]; P = .58). A total of 42% of the on-demand patients had a relaparotomy vs 94% of the planned relaparotomy group. A total of 31% of first relaparotomies were negative in the on-demand group vs 66% in the planned group (P <.001). Patients in the on-demand group had shorter median intensive care unit stays (7 vs 11 days; P = .001) and shorter median hospital stays (27 vs 35 days; P = .008). Direct medical costs per patient were reduced by 23% using the on-demand strategy. CONCLUSION: Patients in the on-demand relaparotomy group did not have a significantly lower rate of death or major peritonitis-related morbidity compared with the planned relaparotomy group but did have a substantial reduction in relaparotomies, health care utilization, and medical costs. TRIAL REGISTRATION: http://isrctn.org Identifier: ISRCTN51729393.

[Granulomatous mastitis: a rare cause of breast swelling]. / Een zeldzame oorzaak van een mammagezwel: granulomateuze mastitis.

Three women, aged 37, 39 and 29 years, presented with unilateral painful swelling of the breast. Ultrasound revealed inflammation with abscess formation. Histological biopsies contained granulomatous tissue without necrosis. Corynebacterium species were cultured in the first two patients. All 3 patients were diagnosed with granulomatous mastitis and were successfully treated with doxycycline. Granulomatous mastitis is a rare disorder that may mimic breast carcinoma. It occurs most frequently in fertile women. Diagnosis is based on histological biopsy which shows granulomas without necrosis, while other causes of granulomatous inflammation, especially tuberculosis, have been excluded. The aetiology is not fully understood. It is hypothesised that the granulomatous mastitis is caused by a type IV allergic reaction. Recently an association with Corynebacterium species was suggested. Best practice treatment methods are unclear. Most patients are treated with surgical intervention and steroids, but the rate of recurrence is high (50%). Treatment with doxycycline must be considered in patients with cultured Corynebacterium species.

Augmentation of interleukin-2 immunotherapeutic effects by lymphokine-activated killer cells and allogeneic stimulation in murine tumor cells.

Interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells were used in intraperitoneal and pulmonary tumor models in C57BL/6 mice. To maintain the immunotherapeutic effects of IL-2 plus LAK treatment but reduce its toxicity, ways were sought to augment IL-2 effects. The investigation showed that the adoptive transfer of LAK cells was a prerequisite for successful therapy of intraperitoneal cancer. When LAK cells were given on consecutive days within one course of immunotherapy, antitumor efficacy was augmented with additional doses of LAK cells. However, with the reduction of 1 complete cycle of IL-2 + LAK cells, no further reduction in intraperitoneal tumor was observed as compared to the reduction after 2 or 4 cycles. LAK cells generated from splenocytes of mice that had received an allogeneic tumor challenge 1 week earlier exerted a highly increased cytotoxicity as compared to normal LAK cells. Furthermore, the potentiation effect of an allogeneic response of the host at the tumor site was demonstrated by decreased numbers of lung implants and improved survival in mice given mixtures of syngeneic and allogeneic tumor cell suspensions. An alloimmune response within the microenvironment of tumor tissue markedly enhanced the antitumor effect of IL-2 against the syngeneic tumor. It was concluded that there is a fundamental need to improve the recruitment of adoptively transferred LAK cells or LAK precursors into tumor tissue. This may be the next step required in the further development of IL-2 and LAK immunotherapy.

Fate of gamma-interferon-activated killer blood monocytes adoptively transferred into the abdominal cavity of patients with peritoneal carcinomatosis.

Five patients with colorectal cancer widely metastatic to peritoneal surfaces have been treated i.p. with infusions of autologous blood monocytes made cytotoxic by in vitro incubation with human gamma-interferon. The monocytes were purified by a combination of cytapheresis and counter-current centrifugal elutriation procedures; each week approximately 350 million activated monocytes were given to patients as adoptive immunotherapy by a single i.p. instillation. On the eighth cycle of treatment the trafficking of i.p. infused blood monocytes was studied in two patients by prelabeling the cells with 111In. These activated cells became distributed widely within the peritoneal cavity. Two and 5 days after infusion their position within the peritoneum had not changed. When peritoneal specimens were obtained 36 h after 111In-labeled monocyte infusion, labeled monocytes were demonstrated to be associated with the serosal surfaces by autoradiographic analysis. Scintiscanning structures outside the abdominal cavity revealed that 111In-labeled monocytes infused i.p. did not traffic to other organs during the 5 days of the study. We conclude that i.p. adoptive transfer of autologous killer blood monocytes is an effective way of delivering these cytotoxic cells to sites of tumor burden on peritoneal surfaces in these cancer patients.

Conservative treatment for closed fifth (small finger) metacarpal neck fractures.

BACKGROUND: Subcapital fractures of the fifth metacarpal bone, meaning fractures just below the knuckle of the little finger, account for approximately 20% of all hand fractures. Currently, there is no consensus concerning the optimal management of these fractures. Traditionally, treatment consists of closed reduction and external splinting in a neutral position using plaster of Paris (POP), involving the metacarpal joint, the proximal interphalangeal joint and the carpo-metacarpal joint. An alternative treatment strategy is functional treatment using taping or bracing that does not restrict movement. OBJECTIVES: To compare functional treatment with immobilization, and to compare different periods and types of immobilization, for the treatment of closed fifth metacarpal neck fractures in adults. SEARCH STRATEGY: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialized Register (July 2004), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2004), OVID OldMEDLINE (1951 to 1965), OVID MEDLINE (1966 to July 2004), OVID MEDLINE In-Process (July 2004), EMBASE (1988 to 2004, week 29), the Internet, and reference lists of articles. No language restrictions were applied. SELECTION CRITERIA: All randomized and quasi-randomized controlled trials which compare functional treatment with immobilization or different types of immobilization for closed fifth metacarpal neck fractures. DATA COLLECTION AND ANALYSIS: Two review authors assessed abstracts of all studies identified by the initial search, identified studies meeting the selection criteria, independently assessed the quality of the trial reports, and extracted and analysed the data. MAIN RESULTS: Five studies met the inclusion criteria including a total of 252 participants. Most studies were of poor quality. The primary outcome measure, function of the hand, was not used in any studies. There was no evidence that any of the treatment modalities was statistically significantly superior. AUTHORS' CONCLUSIONS: No included studies reported our primary outcome measure of interest, validated hand function. There was heterogeneity between the studies, which were of limited quality and size. No single non-operative treatment regimen for fracture of the neck of the fifth metacarpal can be recommended as superior to another in result. Further research is definitely warranted.

[Three men with breast cancer]. / Drie mannen met mammacarcinoom.

In three men, aged 81, 66 and 58 years, breast cancer was diagnosed. All three were treated by modified radical mastectomy and axillary-node dissection. They received tamoxifen and the first and the third patient also received radiotherapy. Presentation of these patients is usually delayed, because of the rarity of and unfamiliarity with the disease. Consequently, the disease is often in a more advanced stage at presentation and overall mortality is higher in comparison with women with breast cancer. However, survival of male patients is similar to survival of female patients when matched for age and stage. This stresses the importance of a timely diagnosis. As in women, of the known risk factors for male breast cancer, a positive family history is one of the most important ones. Modified radical mastectomy, combined with sentinel-node biopsy by experienced teams, is the standard treatment. Criteria for adjuvant systemic treatment are identical for men and women, although hormonal therapy (tamoxifen) has a more prominent place in the adjuvant setting because of the high percentage of positive hormone receptors in men.

Inhibition of dihydrofolate reductase. Structure-activity correlations of quinazolines.

A quantitative structure-activity relationship (QSAR) has been formulated for quinazolines causing 50% inhibition of liver dihydrofolate reductase. The QSAR for the quinazolines is compared with QSAR for triazine and pyrimidine inhibitors. The three QSAR suggest new possibilities for the design of inhibitors of mammalian dihydrofolate reductase.

Substituent constants for correlation analysis.

Constants for pi and omega ahve been measured for a miscellaneous group of aromatic substituents of interest to medicinal chemists. Swain and Lupton's gamma and kappa values have been calculated from the omego constants. Values for molar refractivity are also given for each of the substituents.

Quantitative structure-activity relationships in 1-aryl-2-(alkylamino)ethanol antimalarials.

A quantitative structure-activity relationship has been formulated for 646 antimalarials acting against P. berghei in mice. The equation developed has 14 terms, 9 of which are indicator variables. The correlation coefficient for the QSAR is 0.898 and the standard deviation is 0.309. The antimalarials are all arylcarbinols of the type X-ArCHOHCH2NR1R2. Sixty different aryl structures, including a variety of heterocyles, are contained in the study. The most important determinate of activity is found to be the electron-withdrawing ability of the substituents X; the hydrophobic character of X and R plays less important roles. Suggestions for more potent analogues are made and the lack of activity of about 100 additional analogues is also considered.

Laparotomy enhances intraperitoneal tumor growth and abrogates the antitumor effects of interleukin-2 and lymphokine-activated killer cells.

The interrelationship between host resistance to cancer and the trauma of a surgical procedure is the subject of much speculation. Extensive study of animal models and human subjects is required to define these effects and to provide a theoretical model by which to interpret these data. We used a murine model of intraperitoneal cancer to demonstrate the augmentation of tumor growth by surgical trauma. In this intraperitoneal tumor model, a surgical procedure that included entry into the abdominal cavity resulted in augmented tumor growth; a surgical incision on the skin of the animal's back did not promote tumor growth. The immunotherapeutic effects of interleukin-2 and lymphokine-activated killer cells were significantly reduced by the performance of a laparotomy. This abrogation of the effects of the immunotherapeutic regimen was observed for up to 14 days after laparotomy but was lost by days 35 to 42. Healing tissue may promote tumor growth, and these effects are dominant over immunotherapy with interleukin-2 plus lymphokine-activated killer cells.

A nonelemental versus an elemental diet for early postoperative enteral feeding by needle catheter jejunostomy.

In a prospective randomised study the use of an elemental versus a nonelemental diet for early postoperative enteral feeding by needle catheter jejunostomy was investigated. After extensive gastrointestinal surgery, 25 patients received an elemental and 24 patients a nonelemental diet. The incidence of diarrhoea, the effects of the feeding and the costs were evaluated. The occurrence of diarrhoea was observed more frequently in the elemental diet group (14 25 ) compared to the nonelemental diet group (7 24 ), although this difference was statistically not significant (p > 0.05). No difference was found between the two groups in postoperative restoration of total protein and serum albumin levels and the extent of the postoperative weight loss. The costs showed a clear difference: the nonelemental diet was three times cheaper than the elemental diet. For early postoperative enteral feeding by needle catheter jejunostomy we therefore recommend the use of a nonelemental diet.

Formulation of de novo substituent constants in correlation analysis: inhibition of dihydrofolate reductase by 2,4-diamino-5-(3,4-dichlorophenyl)-6-substituted pyrimidines.

A correlation equation based solely on de novo constants was formulated for 105 2,4-diamino-5-(3,4-dichlorophenyl)-6-substituted pyrimidines acting as inhibitors of dihydrofolate reductase. An equation with seven indicator variables gives a correlation with a correlation coefficient of 0.903 and a standard deviation of 0.229. The technique used is a modification of the Free-Wilson approach. The results indicate that correlation equations with fewer parameters than the theoretical required to account for all molecular changes may often be encountered. It is also shown that cross-product terms can be used to establish the significance of cooperative substituent effects.

[Sentinel node metastasis in the case of colorectal cancer. No role for sentinel node biopsy at present]. / Lymfklierstadiëring bij het colorectaal carcinoom; momenteel geen rol voor schildwachtklierbiopsie.

With sufficient experience, sentinel node biopsy has a high identification rate for several techniques in the case of colorectal cancer. However, the sensitivity of the procedure seems to be too low to justify the replacement of routine pathological examination of the whole mesentery by sentinel node biopsy. Unexpected lymphatic drainage patterns can be found in about 5% of the patients. Therefore, the role of sentinel node biopsy in determining the extension of the resection is minimal in the case of colorectal cancer. In contrast, sentinel node biopsy is helpful in identifying the lymph nodes with the highest risk of harbouring metastases and it facilitates the scrutinising of the lymph node by the pathologist. This will lead to more micrometastases being detected. The prognostic significance of micrometastases and the impact on survival of adjuvant systemic therapy in such patients should be investigated in randomised controlled trials. At present, sentinel node biopsy in colorectal cancer should be restricted to a research setting.