Indoleamine 2,3-dioxygenase expression in human cancers: clinical and immunologic perspectives

Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-catabolizing enzyme with immune-regulating activities in many contexts, such as fetal protection, allograft protection, and cancer progression. Clinical trials are currently evaluating IDO inhibition with 1-methyltryptophan in cancer immunotherapy. However, the exact role of tryptophan catabolism by IDO in human cancers remains poorly understood. Here, we review several studies that correlate IDO expression in human cancer samples and tumor-draining lymph nodes, with relevant clinical or immunologic parameters. IDO expression in various histologic cancer types seems to decrease tumor infiltration of immune cells and to increase the proportion of regulatory T lymphocytes in the infiltrate. The impact of IDO on different immune cell infiltration leads to the conclusion that IDO negatively regulates the recruitment of antitumor immune cells. In addition, increased IDO expression correlates with diverse tumor progression parameters and shorter patient survival. In summary, in the vast majority of the reported studies, IDO expression is correlated with a less favorable prognosis. As we may see results from the first clinical trials with 1-methyltryptophan in years to come, this review brings together IDO studies from human studies and aims to help appreciate outcomes from current and future trials. Consequently, IDO inhibition seems a promising approach for cancer immunotherapy.     

A multicentre open-label safety and efficacy study of tetrodotoxin for cancer pain

Background

Cancer pain is highly prevalent, and existing treatments are often insufficient to provide adequate relief.

Objectives

We assessed the long-term safety and efficacy of subcutaneous tetrodotoxin treatment in reducing the intensity of chronic cancer-related pain.

Methods

In this multicentre open-label longitudinal trial, 30 μg tetrodotoxin was administered subcutaneously twice daily for 4 days in a heterogeneous cohort of patients with persistent pain despite opioids and other analgesics. “Responder” was defined as a mean reduction of 30% or more in pain intensity from baseline; and “clinical responder” as some pain reduction, but less than 30%, plus agreement on the part of both the patient and the physician that a meaningful analgesic response to treatment had occurred.

Results

Of 45 patients who entered the longitudinal trial, 41 had sufficient data for analysis. Of all 45 patients, 21 (47%) met the criteria for “responder” [16 patients (36%)] or “clinical responder” [5 patients (11%)]. Onset of pain relief was typically cumulative over days, and after administration ended, the analgesic effect subsided over the course of a few weeks. No evidence of loss of analgesic effect was observed during subsequent treatments (2526 patient–days in total and a maximum of 400 days in 1 patient). One patient withdrew from the study because of adverse events. Toxicity was usually mild (82%) or moderate (13%), and remained so through subsequent treatment cycles, with no evidence of cumulative toxicity or tolerance.

Conclusions

Long-term treatment with tetrodotoxin is associated with acceptable toxicity and, in a substantial minority of patients, resulted in a sustained analgesic effect. Further study of tetrodotoxin for moderate-to-severe cancer pain is warranted.     

Nephrectomy improves the survival of patients with locally advanced renal cell carcinoma

OBJECTIVES

To examine the cancer‐specific survival of patients treated with nephrectomy and compared it to that of patients managed without surgery.

PATIENTS AND METHODS

Of 43 143 patients with renal cell carcinoma (RCC) identified in the 1988–2004 Surveillance, Epidemiology and End Results database, 7068 had locally advanced RCC and with no distant metastasis. These patients had a nephrectomy (6786, 96.0%) or no surgical therapy (282, 4.0%). Multivariable Cox regression models, and matched and unmatched Kaplan‐Meier survival analyses, were used to compare the effect of nephrectomy vs non‐surgical therapy on cancer‐specific survival. Also, competing‐risks regression models adjusted for the effect of other‐cause mortality. Covariates and matching variables consisted of age, gender, tumour size and year of diagnosis.

RESULTS

The 1‐, 2‐, 5‐ and 10‐year cancer‐specific survival of patients who had nephrectomy was 88.9%, 88.1%, 68.6% and 57.5%, vs 44.8%, 30.6%, 14.5% and 10.6% for non‐surgical therapy. In multivariable analyses, relative to nephrectomy, non‐surgical therapy was associated with a 5.8‐fold higher rate of cancer‐specific mortality (P < 0.001). Non‐surgical therapy was also associated with a 5.1‐fold higher rate of cancer‐specific mortality in matched analyses (P < 0.001). Finally, competing‐risks regression confirmed the statistical significance of the variable defining treatment type (nephrectomy vs non‐surgical therapy) in multivariable and matched analyses (P < 0.001).

CONCLUSION

Relative to non‐surgical treatment, nephrectomy improves the cancer‐specific survival of patients with locally advanced RCC; our findings await prospective confirmation.     

Coagulation defects do not predict blood product requirements during liver transplantation

BACKGROUND: In our experience, correction of coagulation defects with plasma transfusion does not decrease the need for intraoperative red blood cell (RBC) transfusions during liver transplantation. On the contrary, it leads to a hypervolemic state that result in increased blood loss. A previous study has shown that plasma transfusion has been associated with a decreased 1-year survival rate. The aim of this prospective study was to evaluate whether anesthesiologists could reduce RBC transfusion requirements during liver transplantation by eliminating plasma transfusion. METHODS: Two hundred consecutive liver transplantations were prospectively studied over a 3-year period. Patients were divided into two groups: low starting international normalized ratio (INR) value <1.5 and high INR > or =1.5. Low central venous pressure was maintained in all patients before the anhepatic phase. Coagulation parameters were not corrected preoperatively or intraoperatively in the absence of uncontrollable bleeding. Phlebotomy and auto transfusion of blood salvaged were used following our protocol. Independent variables were analyzed in both univariate and multivariate fashion to find a link with RBC transfusions or decreased survival rate. RESULTS: The mean number of intraoperative RBC units transfused was 0.3+/-0.8. Plasma, platelet, albumin, and cryoprecipitate were not transfused. In 81.5% of the patients, no blood product was used during their transplantation. The average final hemoglobin (Hb) value was 91.2+/-15.0 g/L. There were no differences in transfusional rate, final Hb, or bleeding between two groups (low or high INR values). The overall 1-year survival rate was 85.6%. Logistic regression showed that avoidance of plasma transfusion, phlebotomy, and starting Hb value were significantly linked to liver transplantation without RBC transfusion. The need for intraoperative RBC transfusion and Pugh's score were linked to the decreased 1-year survival rate. CONCLUSION: The avoidance of plasma transfusion was associated with a decrease in RBC transfusions during liver transplantation. There was no link between coagulation defects and bleeding or RBC or plasma transfusions. Previous reports indicating that it is neither useful nor necessary to correct coagulation defects with plasma transfusion before liver transplantation seem further corroborated by this study. We believe that this work also supports the practice of lowering central venous pressure with phlebotomy to reduce blood loss, during liver dissection, without any deleterious effect.     

Orbital lymphangiomas: clinical, radiologic, and pathologic characteristics

To assess the value of computed tomography (CT) in evaluation of orbital lymphangioma, the CT findings in 11 patients were retrospectively analyzed and correlated with the clinical, hemodynamic, surgical, and pathologic findings. The lesions were classified by location in three categories: superficial (n = 1), deep (n = 6), or combined (n = 6); the latter were evident earlier in life. The CT findings correlated well with the surgical and histologic findings. Orbital lymphangiomas were poorly defined lesions that crossed anatomic boundaries such as the conal fascia and orbital septum. Some degree of enhancement was the rule, ranging from scattered patchy areas to enhancement of the majority of the lesion. Areas of hemorrhage caused cystlike masses with rim enhancement. Preoperative identification of the vascular enhancing component at CT examination enables the surgeon to resect this area to prevent postoperative hemorrhage. High-resolution CT is of great value in the diagnosis and preoperative treatment planning of orbital lymphangioma.     

Characterization of the action of drug-induced stress responses on the immune system: evaluation of biomarkers for drug-induced stress in rats

Toxicological testing of compounds often is conducted at the maximum tolerated dose to identify potential target organs. Toxicities observed at these high doses may result in decreased body weight gain, food consumption and activity. These clinical signs are often associated with a generalized stress response. It has been known that stress may cause increased levels of corticosterone, which causes changes in circulating leukocyte profiles, decreases in thymus and spleen weights and changes in the microscopic structure of lymphoid organs. This makes it difficult to differentiate between stress-related changes and direct toxicity to the immune system in standard non-clinical toxicity testing in rats. In mice, MHC Class II expression was found to be a very sensitive biomarker of stress and maybe useful for the rat. Therefore, the objective of studies presented was to further characterize the effects of corticosterone and stressors on the immune system and identify potential biomarkers of stress in rats. Rats were treated with exogenous corticosterone (20 or 30 mg/kg BID) or ethanol (5 g/kg) for either 1 or 4 days. Restraint stress was also evaluated for a 3-day period. Blood and urine samples were collected during the treatment period for corticosterone measurements. At necropsy, blood samples for leukocyte differentials were collected. Spleen and thymus weights, cellularity, lymphocyte subpopulations and histopathology were also evaluated. Urine corticosterone levels were also investigated as a surrogate to measuring serum corticosterone. The results demonstrate that the pattern of responses to corticosterone or the stressors is different in mice and rats. Although, decreases in MHC Class II were found to be a sensitive indicator of stress in mice, only slight decreases were observed in rats with similar serum corticosterone AUC levels. Decreases in thymus weight were greater than spleen weight with corticosterone or ethanol or restraint stressor. No other single parameter or combination of parameters tested were obvious candidates as sensitive biomarkers of stress in rats. However, the good correlation between urine and serum corticosterone levels suggest that urine corticosterone may be a potential biomarker of stress induced changes to the immune response.     

Prognostic implications of a negative dipyridamole-thallium scan: results in 360 patients.

PATIENTS AND METHODS: A total of 360 patients with either normal perfusion (314) or fixed defects (46) on dipyridamole-thallium scans were followed over an average period of 16 months. Of the 360 patients, 194 subsequently underwent major noncardiac surgery. RESULTS: There were a total of eight cardiac events including two postoperative complications (one fatal and one nonfatal myocardial infarction) and six cardiac events during long-term follow-up (one sudden death and five nonfatal infarctions). During the follow-up period, three patients underwent coronary artery bypass surgery. The low cardiac event rate could not be explained by a low pretest likelihood of coronary artery disease: 77% of the 360 patients had either typical angina pectoris, a previous myocardial infarction, or peripheral vascular disease, which is associated with a high prevalence of coronary artery disease. CONCLUSIONS: In patients with a high pretest likelihood of coronary artery disease, the absence of thallium redistribution on a dipyridamole-thallium scan denotes a very low (1%) cardiac risk for major noncardiac surgery as well as low long-term cardiac mortality (0.3%) and morbidity (1.4%) rates. The coronary death rate is comparable to that of patients with minimal (less than 50%) coronary stenoses.     

Barriers to health-care and psychological distress among mothers living with HIV in Quebec (Canada)

Health-care providers play a major role in providing good quality care and in preventing psychological distress among mothers living with HIV (MLHIV). The objectives of this study are to explore the impact of health-care services and satisfaction with care providers on psychological distress in MLHIV. One hundred MLHIV were recruited from community and clinical settings in the province of Quebec (Canada). Prevalence estimation of clinical psychological distress and univariate and multivariable logistic regression models were performed to predict clinical psychological distress. Forty-five percent of the participants reported clinical psychological distress. In the multivariable regression, the following variables were significantly associated with psychological distress while controlling for sociodemographic variables: resilience, quality of communication with the care providers, resources, and HIV disclosure concerns. The multivariate results support the key role of personal, structural, and medical resources in understanding psychological distress among MLHIV. Interventions that can support the psychological health of MLHIV are discussed.