Timothy G. Allen-Mersh

Serum tryptophan decrease correlates with immune activation and impaired quality of life in colorectal cancer

Cancer-related indoleamine (2,3)-dioxygenase up-regulation by interferon-γ might influence quality of life by depleting serum tryptophan. We correlated serum tryptophan levels with immune activation and quality of life in patients with colorectal liver metastases. Venous blood was sampled from patients with primary colorectal cancer and from patients with metachronous colorectal liver metastases who completed quality of life and psychological questionnaires. Serum tryptophan, kynurenine, neopterin, interleukin 2 soluble receptor α (IL-2 sRα), soluble tumour necrosis factor receptor I (sTNF RI), interleukin 6, and C-reactive protein were measured. Liver metastasis volume was estimated by computerised tomography, and survival from blood sampling was noted. Sixty-six patients with colorectal cancer were studied (39 males; median age 66 years) of whom 25 had colorectal liver metastases only (17 males; median age 62 years; median liver metastasis volume 208 ml; median survival 234 days). Reduced serum tryptophan was significantly associated with Rotterdam Symptom Checklist physical symptom (r=−0.51, P=0.01) and Sickness Impact Profile (r=−0.42, P=0.04) scores, and correlated with increased serum neopterin (r=−0.36, P=0.003), IL-2 sRα (r=−0.51, P=0.01) and sTNF RI (r=−0.45, P=0.02) levels. Stepwise regression analyses suggested that serum tryptophan was an independent predictor of Rotterdam Symptom Checklist physical symptom (regression coefficient −20.78, P=0.01) and Sickness Impact Profile (regression coefficient −109.09, P=0.04) scores. The results supported a role for interferon-γ-mediated serum tryptophan decrease in cancer-induced quality of life deterioration.

Detection of colorectal cancer cells in peripheral blood by reverse-transcriptase polymerase chain reaction for cytokeratin 20

The staging of colorectal cancer currently depends on pathological examination of the surgical specimen and regional lymph nodes, accompanied by imaging tests such as computed tomography (CT) scanning. However, alternative molecular methods to detect circulating tumour cells in blood or bone marrow may provide additional information about the extent of disease and prognosis. We have previously reported the development of a reverse‐transcriptase polymerase chain reaction (RT‐PCR) for cytokeratin 20 (CK 20) mRNA to detect circulating epithelial tumour cells. In this study, we report on the application of this method for detecting circulating tumour cells in patients with colorectal cancer. Using this method, CK 20 mRNA was detected in 8/8 human colorectal cancer cell lines, in 8/9 biopsies from primary colorectal tumours and in 9/10 biopsies of liver metastasis in patients with metastatic colorectal cancer, suggesting that CK 20 may be a useful target for the detection of circulating tumour cells in this patient group. In spiking experiments, 10 cells were consistently identified in 2 ml of whole blood (1 × 106–1 × 107mononuclear cells). In 12/25 (48%) peripheral blood samples from patients with known metastatic colorectal cancer, CK 20 mRNA was detected. However, there was no correlation between the detection of CK 20 mRNA in the peripheral blood and disease progression and survival in this group of patients. CK 20 mRNA was detected in 1/12 normal blood samples, which raises questions about the absolute specificity of CK 20 expression. Int. J. Cancer (Pred. Oncol.) 79:288–293, 1998.© 1998 Wiley‐Liss, Inc.

Epidural analgesia in gastrointestinal surgery

The ideal perioperative analgesia should provide effective pain relief, avoid the detrimental effects of the stress response, be simple to administer without the need for intensive monitoring, and have a low risk of complications.

Pelvic connective tissue resilience decreases with vaginal delivery, menopause and uterine prolapse.

The late onset of pelvic visceral prolapse and incontinence after childbirth injury could be explained by menopause‐associated connective tissue weakening. Uterosacral ligament resilience (UsR) was assessed to determine whether it influenced uterine or pelvic floor mobility, or varied with age, vaginal delivery, menopause or histological variations in the ligament.

Clearance of Circulating Tumor Cells After Excision of Primary Colorectal Cancer

ObjectiveTo establish whether the prevalence of positive reverse transcriptase–polymerase chain reaction (RT-PCR) results decreased during the first 3 months after colorectal cancer excision, and to assess whether persistence of RT-PCR positivity after primary colorectal cancer excision was related to tumor stage or locally advanced and metastatic disease. MethodsSystemic venous blood was collected from patients with colorectal cancer before and at intervals up to 12 weeks after surgery. RNA was extracted from the mononuclear cell fraction of the blood samples and subjected to RT-PCR using specific primers for carcinoembryonic antigen mRNA and cytokeratin-20 mRNA. Healthy individuals with no history of cancer were used as controls. ResultsThe results of RT-PCR were positive in 81 of 116 patients with colorectal cancer before surgery, with no significant differences in preoperative prevalence by Dukes stage or presence of locally advanced or metastatic disease. There was a significant decrease in the prevalence of RT-PCR positivity at 24 hours after surgery compared with before surgery. On subgroup analysis by Dukes stage, only the decrease in Dukes A and B patients reached significance. Seven of the 143 controls were RT-PCR positive. ConclusionsCirculating tumor cells were present before treatment in most patients with colorectal cancer regardless of tumor stage or metastases. Clearance of circulating tumor cells within 24 hours of colorectal cancer excision was greatest in tumors with the best prognosis.

Relaparotomy for suspected intraperitoneal sepsis after abdominal surgery

Relaparotomy may be beneficial in patients developing intraperitoneal sepsis after abdominal procedures. We determined whether joint clinical assessment by intensivist and surgeon (clinician assessment) identified patients with surgically correctable intraperitoneal sepsis. We also assessed the effect of patient age and sex, disease presentation and severity, interval to relaparotomy, and the number of relaparotomies on survival after relaparotomy. Data on clinical, laboratory, and radiologic abnormalities prior to relaparotomy, relaparotomy findings, and in-hospital survival were prospectively collected on a general hospital intensive care unit (ICU) database between January 1997 and January 2002. Altogether, 65 of 1482 (4.4%) patients admitted to the ICU after abdominal surgery underwent relaparotomy at a median of 5 days after the initial procedure. There was an 83% probability of identifying surgically treatable sepsis and 43% in-hospital mortality. Abdominal imaging contributed accurate information in 50% of cases where clinician assessment was uncertain. Patient age and multiorgan failure prior to relaparotomy—but not urgency of initial laparotomy or the acute physiology and chronic health evaluation (APACHE II) score prior to relaparotomy, interval to relaparotomy, or number of relaparotomies—affected the outcome. Clinician assessment after abdominal surgery had a high probability of predicting intraperitoneal sepsis at relaparotomy. The 43% mortality after relaparotomy was unlikely to be greater than with nonoperative treatment of intraabdominal sepsis, but the 78% mortality after relaparotomy in patients older than 75 years of age raised doubts about this approach in the elderly. The identification of intraperitoneal sepsis and performance of relaparotomy earlier after the initial abdominal surgery might reduce the high rate (60%) of multiorgan failure prior to relaparotomy and improve survival after it.RésuméLa laparotomie exploratrice peut être bénéfique chez les patients ayant développé un sepsis après un procédé abdominale chirurgical. Nous avons déterminé si l’évaluation clinique couplée, entre le réanimateur et le chirurgien (EC-RC), pouvait identifier les patients présentant un sepsis intrapéritonéal chirurgicalement corrigible. Nous avons également évalué l’influence de l’âge, du sexe, de la présentation et de la sévérité de la maladie, de l’intervalle avant la re-laparotomie, sur la survie après re-laparotomie. On a prospectivement collecté les données concernant les anomalies cliniques, de laboratoire, et radiologiques avant la re-laparotomie, les données de la re-laparotomie, et la survie pendant l’hospitalisation entrées dans une banque de données d’unité de soins intensifs (SI) entre jan 1997 et jan 2002. Soixante-cinq des 1482 (4.4%) patients admis en SI après la re-laparotomie, cinq jours (médiane) après le procédé initial. La probabilité d’identifier un sepsis chirurgicalement curable et la mortalité hospitalière ont été, respectivement, de 83% et de 43%. L’imagerie abdominale a contribué positivement dans 50% des cas alors que l’EC-RC en était incertain. L’âge du patient et l’existence d’une défaillance multi-viscérale avant la laparotomiemais pas le degré d’urgence de la laparotomie initiale, le score APACHE II avant la re-laparotomie, l’intervalle de temps avant la reprise ou le nombre de re-laparotomies — ont influencé l’évolution.La probabilité de prédire l’existence d’un sepsis intrapéritonéal lors d’une ré-laparotomie après chirurgie abdominale par l’évaluation clinique est élevée. Il se peut que la mortalité post-laparotomie de 43% après ré-laparotomie ne soit pas plus importante après traitement non-opératoire du sepsis intraabdominal, mais la mortalité de 78% après ré-laparotomie chez le patient âgé plus de 75 ans soulève des doutes. L’identification d’un sepsis intrapéritonéal et une ré-laparotomie précoce après la laparotomie initiale pourraient contribuer à réduire le taux élevé de défaillance multi-viscérale (60%) avant la ré-laparotomie et ainsi améliorer la survie après la ré-laparotomie.ResumenLa re-laparatomía puede ser beneficiosa en pacientes que desarrollan sepsis intraperitoneal luego de procedimientos quirúrgicos abdominales. Nos propusimos determinar si la evaluación conjunta entre intensivistas y cirujanos (evaluacién clínica) podía identificar aquellos pacientes con sepsis intraperitoneal susceptible de correccíon quirúrgica y evaluar el efecto de la edad del paciente, el género, la forma de presentación de la enfermedad y su severidad, el intervalo de tiempo hasta la re-laparotomía y el núméro de re-laparotomías sobre la supenivencia después de la re-laparotomia. Se hizo la recolección prospectiva de los hallazgos anormales en el cuadro clinico y en los exámenes de laboratorio y radiológicos previos a la re-laparotomía, de los hallazgos en la re-laparotomía y de la supenivencia intrahospitalaria, todo lo cual fue colocado en una base de datos cubriendo el periodo entre enero de 1997 y enero de 2002. Sesenta y cinco de 1482 (4.4%) pacientes admitidos a la UCI luego de cirugía abdominal fueron sometidos a re-laparotomía en una media de 5 días después del procedimiento original. Se encontró una probabilidad del 83% de identificar sepsis susceptible de tratamiento quirúrgico y una mortalidad intrahospitalaria de 43%. La imagenología abdominal aportó information certera en 50% de los casos en que la evaluación clínica aparecía incierta. La edad del paciente y la falla multiorgánica -pero no la urgencia de la laparotomía inicial o el nivel de APACHE II anterior a la re-laparotomía, o el intervalo hasta la re-laparotomía o el número de re-laparotomíasafectaron el resultado final. La evaluación clínica luego de una operacíon abdominal demostró una alta probabilidad de predecir la presencia de sepsis intraabdominal en la re-laparotomia. La mortalidad de 43% luego de relaparotomia no parece ser mayor que con el tratamiento no operatorio de la sepsis abdominal, pero la mortalidad de 78% luego de re-laparotomia en los pacientes > 75 años crean dudas sobre la bondad de esta conducts en personas de edad avanzada. La identificacíon de la sepsis intraperitoneal y la re-laparotomía precoz luego de la cirugía abdominal inicial podrían reducir la elevada tasa (60%) de falla multiorgánica que se presenta antes de la re-laparotomía y mejorar la supenivencia después de la re-laparotomía.

Role of circulating tumour cells in predicting recurrence after excision of primary colorectal carcinoma.

This study assessed the potential for reverse transcriptase–polymerase chain reaction (RT–PCR)‐based circulating tumour cell identification to predict colorectal cancer recurrence.

Plasma vascular endothelial but not fibroblast growth factor levels correlate with colorectal liver metastasis vascularity and volume

The extent to which plasma levels of angiogenic factors in healthy individuals and tumour volume-related variations in colorectal cancer affect the accuracy of circulating angiogenic factors as predictors of colorectal cancer vascularity is unknown. We used enzyme-linked immunosorbant assay to measure plasma vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) levels in colorectal liver metastasis (CLM) patients, and ‘no cancer’ controls. CLM volume was determined from computerized tomography scans, and tumour vessel count and vessel volume from anti-endothelial antibody-stained biopsies. There was a significant (P = 0.03) increase in plasma VEGF level in 29 CLM patients (median 180.3 pg ml−1, iqr 132.5–284.8 pg ml−1) compared with 19 controls (median 125.8 pg ml−1, iqr 58.2–235.9 pg ml−1). There were significant correlations between plasma VEGF and tumour vessel count (r = 0.66, P = 0.03), tumour vessel volume (r = 0.59, P = 0.03), and CLM volume (r = 0.53, P = 0.03). A VEGF level in the upper quartile of the plasma VEGF distribution had a 70% sensitivity and 75% specificity in predicting an upper quartile liver metastasis tumour vessel count. No relation was identified between CLM and plasma bFGF levels. Plasma VEGF level predicted CLM vascularity, despite an overlap with normal levels and tumour volume-related variations.

62Cu-PTSM and PET used for the assessment of angiotensin II-induced blood flow changes in patients with colorectal liver metastases

Abstract. The aim of this study was to establish a quantitative positron emission tomography (PET) method for investigating angiotensin II (AII)-induced changes in blood flow distribution in the liver. This was in order to evaluate the role of vascular manipulation applied to locoregional chemotherapy treatment in patients with colorectal liver metastases. The tracer selected was copper-62 (II) pyruvaldehyde bis-(N4-methyl)thiosemicarbazone (62Cu-PTSM), which exhibits high first-pass extraction and tissue retention following intra-arterial administration. The short half-life of the tracer and its availability from a 62Zn/62Cu generator enabled short-interval repeat PET scans on patients in a single imaging session. Distribution of tracer within the liver was imaged in a single view using a PET camera with rotating large-area detectors. By optimisation of the acquisition protocol, it was possible to acquire sufficient data to produce good-quality images and to quantify tracer uptake with an accuracy of ≤10%. Reproducibility of the imaging method was assessed in a single patient in whom three consecutive 62Cu-PTSM PET scans were obtained, and in whom no vascular manipulation was performed. Sets of scans (before, during and immediately after a 45-min AII infusion) were obtained in nine patients to assess blood flow changes associated with prolonged vascular manipulation. Significant individual responses, varying in both the magnitude and the duration of flow change, were observed in the majority of cases (7/11 lesions; 7/9 patients). These findings illustrate the potential of 62Cu-PTSM and PET for pharmacological studies. The wide range of individual patient responses to AII infusion suggests that PET blood flow assessment would be of value for selecting patients in whom this procedure may be effective.

Cost‐effectiveness of systemic and regional chemotherapy for the treatment of patients with unresectable colorectal liver metastases

Management of unresectable colorectal liver metastases (CLM) can be by regional (hepatic arterial infusion [HAI]) or systemic chemotherapy, or by symptom control alone. In this study the costs of each type of management were related to clinical outcome in 134 patients with CLM.