Resistance to sunitinib in renal cell carcinoma: From molecular mechanisms to predictive markers and future perspectives.

The introduction of agents that inhibit tumor angiogenesis by targeting vascular endothelial growth factor (VEGF) signaling has made a significant impact on the survival of patients with metastasized renal cell carcinoma (RCC). Sunitinib, a tyrosine kinase inhibitor of the VEGF receptor, has become the mainstay of treatment for these patients. Although treatment with sunitinib substantially improved patient outcome, the initial success is overshadowed by the occurrence of resistance. The mechanisms of resistance are poorly understood. Insight into the molecular mechanisms of resistance will help to better understand the biology of RCC and can ultimately aid the development of more effective therapies for patients with this infaust disease. In this review we comprehensively discuss molecular mechanisms of resistance to sunitinib and the involved biological processes, summarize potential biomarkers that predict response and resistance to treatment with sunitinib, and elaborate on future perspectives in the treatment of metastasized RCC.

Long-term dietary sodium, potassium and fluid intake; exploring potential novel risk factors for renal cell cancer in the Netherlands Cohort Study on diet and cancer.

BACKGROUND: As sodium, potassium and fluid intake are related to hypertension, an established risk factor for renal cell cancer (RCC), they may be independent risk factors for RCC. METHODS: The Netherlands Cohort Study (NLCS) with case-cohort design included 120,852 participants aged 55-69 years. At baseline, diet and lifestyle were assessed with questionnaires. After 17.3 years of follow-up, 485 RCC cases and 4438 subcohort members were available for analyses. RESULTS: Sodium intake increased RCC risk (P-trend=0.03), whereas fluid and potassium intake did not. For high sodium and low fluid intake, the RCC risk additionally increased (P-interaction=0.02). CONCLUSION: Sodium intake is a potential risk factor for RCC, particularly if fluid consumption is low.

[Palliation in patients with metastatic breast cancer often better with antitumour treatment than with only symptomatic treatment]. / Palliatie bij patiënten met gemetastaseerd mammacarcinoom vaak beter door antitumorbehandeling dan door alleen symptoombestrijding.

Two women, aged 57 and 55 years, with metastatic breast cancer were admitted for uncontrolled pain due to bone metastases. Despite the fact that progressive disease was evident, a change in antitumour therapy had not been recommended. The pain control was optimised in both patients. In one patient, palliative chemotherapy was installed, combined with trastuzumab because of HER2/neu overexpression. She was still alive after one and a half year of treatment. The other patient could not adjust mentally to the fact that her palliative therapy was changed to antitumour therapy; she died one month later. It is important to be aware of the various kinds of therapy in metastatic breast cancer because palliative treatment is more than just symptomatic treatment. Systemic antitumour therapy includes hormone therapy, chemotherapy and targeted therapy. Furthermore, in patients with bone metastases, radiotherapy combined with bisphosphonates results in pain relief and can reduce skeletal complications. Because of the ensuing complexity of the treatment of metastatic breast cancer, these patients should be regularly managed by a breast-cancer care team in order to improve the quality of care.

[Temozolomide, an oral chemotherapeutic agent with potential severe toxicity]. / Temozolomide, een oraal chemotherapeuticum met soms ernstige toxiciteit.

Two patients, a 58-year-old man and a 55-year-old woman, both under treatment for glioblastoma multiforme, were admitted with fever and neutropenia a few weeks after starting to take the oncolytic agent temozolomide. The man died of a cerebral haemorrhage against a background of severe thrombocytopenia and febrile neutropenia, and the woman died of neutropenic sepsis. Temozolomide is an oral alkylating agent that is considered to be a well-tolerated chemotherapeutic agent. It is important to be aware of the potentially life-threatening toxicity of every chemotherapeutic agent, including temozolomide. Therefore, temozolomide should be prescribed only by doctors with sufficient clinical experience with treatment by means of oncolytic agents, and with the recognition of the side effects and treatment of the complications of chemotherapy. In view of the multidisciplinary aspects of the treatment of patients with glioblastoma multiforme, treatment by a specialised team is preferable.

Fatigue in Cambodia veterans.

In 1992 and 1993, Dutch military personnel were deployed in the peace operation UNTAC in Cambodia. Since returning, Cambodia veterans have reported health complaints which they perceive to be related to their service. Their symptoms strikingly resemble health problems reported by Gulf War veterans. Four years post-return, a cross-sectional survey on health symptoms in Cambodia veterans was initiated. Questionnaires were sent to all Cambodia veterans and four comparison groups. Forgetfulness, difficulty concentrating and fatigue were the symptoms most commonly endorsed. An operational case definition was constructed using a validated fatigue severity questionnaire. Cases were not uniquely found in Cambodia veterans (17%). In Rwanda and Bosnia veterans, respectively, 28% and 11% also met our case definition. Fatigue severity level was predicted by pre-mission, during-mission and post-mission variables, of which retrospective recollection of side-effects of vaccines and causal attributions also have been shown to be relevant in studies on Gulf-related illness.

Physical activity and exercise performance in symptomatic Cambodia veterans.

BACKGROUND: Dutch (ex-)servicemen who encounter health problems since return from the 1992-3 peace operation UNTAC, commonly complain of reduced activity levels, decreases in physical fitness and aggravation of symptoms after strenuous exercise. AIM: To evaluate these symptoms. DESIGN: A prospective study of 26 symptomatic Cambodia veterans and 26 matched controls (healthy Cambodia veterans). METHODS: Using an actometer and diaries, both groups were followed for a 12-day baseline period prior to an incremental maximal exercise test on a bicycle ergometer, followed by 7 days of post-ergometer data. RESULTS: During baseline, symptomatic Cambodia veterans reported more symptoms, had lower levels of physical activity and took longer periods of rest after high activity periods. Symptomatic veterans did not perceive the exercise test needing more exertion than healthy veterans did, although their physical fitness was decreased. Post-ergometer, daily observed symptoms did not aggravate in symptomatic veterans. Four days post-ergometer, actometer and daily observed activity scores were lowered in both groups. As compared to baseline, one day post-ergometer, levels of physical activity were changed in healthy veterans, but not in controls. DISCUSSION: Complaints about reduced activity levels and decreases in physical fitness in symptomatic Cambodia veterans were confirmed. Post-exertion malaise was not found. The observed post-exertion effects were traced back to weekday patterns.

Normal carnitine levels in patients with chronic fatigue syndrome.

BACKGROUND: Patients with chronic fatigue syndrome (CFS) complain of muscle pain and impaired exercise tolerance. Previous studies show that this is due to systemic carnitine deficiency. We investigated the hypothesis that carnitine deficiency plays an important role in CFS in female CFS patients and compared their results with neighbourhood controls. METHODS: The level of total carnitine, free carnitine, acylcarnitine and carnitine esters were measured in 25 female CFS patients and 25 healthy matched neighbourhood controls in a blinded fashion. RESULTS: The previously reported decreased level of acylcarnitine in CFS patients was not confirmed. There were also no significant differences in levels of total carnitine, free carnitine and 20 carnitine esters between CFS patients and controls. CONCLUSIONS: The present study demonstrates that serum carnitine deficiency does not contribute to or causes the symptoms in many CFS patients.

[Somatic and psychological symptoms in soldiers after military clashes and peace-keeping missions]. / Lichamelijke en psychische klachten bij militairen na oorlogshandelingen en vredesmissies.

Dutch soldiers who have participated in the peace keeping operation United Nations Transitional Authority in Cambodia (UNTAC) have reported various somatic and psychological symptoms since their return. Their symptoms show similarities to the Gulf War Syndrome. The question arises whether Gulf War Syndrome, symptoms in UNTAC soldiers and other symptoms after acts of war and peace operations are unique syndromes or comparable complaints? From an historical overview it is not plausible that new and unique syndromes will occur with each war or peace operation. On the other hand it also seems unlikely that war syndromes can be reduced to one diagnostic category. The post-Cambodia complaints may be described in four hypothetical models: the somatic start model, the psychotrauma start model, the premorbidity model and the complaints-not-related-to-Cambodia model. These models are expected to be applicable, after further validation, to other symptoms after acts of war and peace operations. Also they will provide points of application for prevention and treatment of symptoms after future wars and peace operations.

Natural course of symptoms in Cambodia veterans: a follow-up study.

BACKGROUND: Dutch (ex-)servicemen were deployed in the 1992-3-peace operation UNTAC in Cambodia. Since their return, they have voiced concerns about the health consequences of their service and they have reported symptoms such as fatigue and cognitive problems. The natural course of symptoms in Dutch Cambodia veterans was evaluated in a prospective study. METHODS: At 18-months follow-up, a questionnaire was sent to 354 veterans who met a set case definition for symptoms in Cambodia veterans or who had sub-threshold scores. Initial measurement of fatigue severity, psychological well-being, depression, post-traumatic stress disorder, trait-anxiety, self-efficacy and causal attributions, was used to evaluate predictors for self-reported improvement and low levels of fatigue at follow-up. RESULTS: At follow-up, 19% of the respondents reported complete recovery, 20% felt much better, 57% had the same complaints and 4% had become worse compared with their initial assessment. Self-reported improvement and less severe fatigue at follow-up were predicted by less severe fatigue at initial assessment and more perceived control over symptoms. CONCLUSIONS: Self-reported improvement was reported in a considerable percentage of Cambodia veterans, whereas another substantial percentage of Cambodia veterans continued to suffer with severe levels of fatigue and related symptoms. Predictors of improvement in Cambodia veterans and patients with chronic fatigue syndrome show similarities and also seem to bear importance for Gulf War veterans.

Autonomic function in patients with chronic fatigue syndrome.

Subtle signs of autonomic dysfunction and orthostatic intolerance have been reported in patients with chronic fatigue syndrome (CFS). To assess cardiovascular autonomic function noninvasively in an unselected group of patients with CFS, we examined responsiveness to several cardiovascular reflex tests in 37 CFS patients and 38 healthy control subjects. Blood pressure and heart rate (HR) were recorded continuously by a Finapres device before and during forced breathing, standing up, Valsalva maneuver, and sustained handgrip exercise (HG). In addition, a mental arithmetic test was carried out and questionnaires to assess the severity of CFS symptoms were completed. At rest, there were no significant differences in blood pressure or in HR between the two groups. The in- and expiratory difference in HR tended to be lower in CFS patients (28.4 +/- 10.5 beats) than in healthy controls (32.2 +/- 9.5) (p = 0.11). The maximal increase in HR during standing up was not significantly different between the CFS group (37.6 +/-8.9 beats) and the control group (40.2 +/- 8.9 beats). There were no significant differences between both groups with regard to the Valsalva ratio, but the systolic and diastolic blood pressure responses were significantly larger in CFS patients, despite the fact that many CFS patients were not able to sustain the Valsalva maneuver. The HR response to MA was significantly less in the CFS group (22.6 +/- 9.9) than in the control group (29.5 +/- 16.7) (p < 0.05), suggesting impaired cardiac sympathetic responsiveness to mental stress. The lower HR responses could not be explained by the level of concentration in the CFS group. During HG exercise, the hemodynamic responses were lower in the CFS group than in the control group, but this might be attributed to the lower level of muscle exertion in CFS patients. There were no significant differences between CFS patients with and without symptoms of autonomic dysfunction regarding the hemodynamic responses to the cardiovascular reflex tests. The findings of the study suggest that there are no gross alterations in cardiovascular autonomic function in patients with CFS.

Persistent symptoms in former UNTAC soldiers are not associated with shifted cytokine balance.

BACKGROUND: The pathogenesis of post-combat syndromes, such as Gulf War syndrome, is poorly understood. Recently, it has been postulated that the symptoms of veterans with such syndromes are due to a disturbed cytokine balance shifted towards a T-helper (Th) 2 profile. We investigated this hypothesis in 21 symptomatic former UNTAC soldiers and compared their results with those obtained in 21 healthy former UNTAC soldiers matched for age, sex and military force. DESIGN: The numbers of intracellular interleukin 4 (IL-4) and interferon gamma- (IFN-gamma) producing CD4+ and CD8+ T lymphocytes (CD3+) were determined after in vitro stimulation with phorbol myristate acetate and calcium ionophore in the presence of brefeldin to block secretion of induced cytokines. Circulating concentrations and lipopolysaccharide- (LPS) or phytohaemagglutinin- (PHA) stimulated whole-blood production of the proinflammatory cytokines IL-1beta, IL-1ra, tumour necrosis factor alpha (TNF-alpha) and IL-10 and IFN-gamma were measured. RESULTS: The numbers of CD4+ and CD8+ T lymphocytes positive for IL-4 or IFN-gamma production were not significantly different in patients and control subjects. After stimulation with LPS or PHA, the in vivo circulating concentration and concentration of IL-10 and IFN-gamma were also similar. CONCLUSIONS: The present study demonstrates that there is no shift in cytokine balance towards a Th2 profile in former UNTAC soldiers with symptoms similar to those of the Gulf War syndrome.

Hemodynamic and neurohumoral responses to head-up tilt in patients with chronic fatigue syndrome.

BACKGROUND: Data on the prevalence of orthostatic intolerance (OI) in patients with chronic fatigue syndrome (CFS) are limited and controversial. We tested the hypothesis that a majority of CFS patients exhibit OI during head-up tilt. METHODS: Hemodynamic and neurohumoral responses to 40 minutes of head-up tilt were studied in 36 CFS patients and 36 healthy controls. Changes in stroke volume, cardiac output and peripheral vascular resistance were estimated from finger arterial pressure waveform analysis (Modelflow). Blood samples were drawn before and at the end of head-up tilt for measurement of plasma catecholamines. RESULTS: At baseline, supine heart rate was higher in CFS patients (CFS: 66.4 +/- 8.4 bpm; controls: 57.4 +/- 6.6 bpm; p < 0.001) as was the plasma epinephrine level (CFS: 0.11 +/- 0.07 nmol/l; controls: 0.08 +/- 0.07 nmol/l: p = 0.015). An abnormal blood pressure and/or heart rate response to head-up tilt was seen in 10 (27.8 %) CFS patients (6 presyncope, 2 postural tachycardia, 2 tachycardia and presyncope) and 6 (16.7 %, p = 0.26) controls (5 presyncope, 1 tachycardia, 2 tachycardia and presyncope). Head-up tilt-negative CFS patients showed a larger decrease in stroke volume during tilt (-46.9 +/- 10.6) than head-up tilt-negative controls (-40.3 +/- 13.6 %, p = 0.008). Plasma catecholamine responses to head-up tilt did not differ between these groups. CONCLUSION: Head-up tilt evokes postural tachycardia or (pre)syncope in a minority of CFS patients. The observations in head-up tilt-negative CFS patients of a higher heart rate at baseline together with a marked decrease in stroke volume in response to head-up tilt may point to deconditioning.

Somatic hypotheses of war syndromes.

Since the end of the American Civil War, unexplained symptoms in military personnel arising after a war or peace mission have frequently been described. The pattern of symptoms is highly similar for all of the various war syndromes although the conditions of each war or peace mission are widely different. Many somatic hypotheses have been formulated to explain these syndromes; a considerable proportion of them are already outdated. In the last few years much attention has been given to Gulf War Syndrome and to unexplained symptoms of military personnel who were sent to Cambodia, Rwanda, Burundi, Zaire, or the former Yugoslavia. In this review the symptoms of war syndromes will be considered in more detail and the suggested somatic explanations will be discussed. During the last decade the following somatic causes have been suggested as possible explanations for these symptoms: (persistent) infection, abnormal immune response, administration of multiple vaccinations within a short period of time, use of malaria chemoprophylaxis, neurological abnormalities, exposure to toxicological substances and environmental factors. The various investigations performed to study these hypotheses are discussed. The fact that bias regularly occurs in the course of these investigations is pointed out. For the future, a reliable investigation of a war syndrome should be a prospective multidisciplinary study and should distinguish between causative and sustaining factors.